Right atrial pressure as back-pressure for venous return

A presentation by Per Möller at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.

All available content from SSAI2017: https://scanfoam.org/ssai2017/

Delivered in collaboration between scanFOAM, SSAI & SFAI.

1. Right atrial pressure as back-pressure for venous return Per Werner Möller – M.D. Department of Anaesthesiology and Intensive Care Medicine , Institute of Clinical Sciences at the Sahlgrenska Academy , University of Gothenburg , Sahlgrenska University Hospital, Gothenburg , Sweden Department of Intensive Care Medicine , Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland - integrating volume shift , driving pressure and flow

2. American Journal of Physiology – Heart and Circulatory Physiology

3. Fig 1. Cardiac response curves to RAP with the heart under different conditions Fig 2. Venous return curves illustrating the effect of RAP on venous return when the MCFP is maintained at different levels Guyton, A. (1955). Determination of cardiac output by equating venous return curves with cardiac response curves. Physiological Reviews, 35(1), 123-129. CO = VR = (MSFP-RAP)/R VR CO = VR = VRdP/R VR

4. Which variable did he control – RAP or pump function ? Can Guyton’s model , defined for steady state , be applied to dynamic changes ? The problem: Can RAP simultaneously be a determinant of venous return and related to preload , governing stroke volume ? …so did venous return respond to changes in RAP or changes in pump function ? Is it «set» by the volume re-distribution of heart work? Does a high RAP oppose the inflow to the right heart? What is the role of RAP?

5. ECMO SVC flow probe IVC flow probe ECMO flow probe Pulmonary artery ligated AV shunt clamp venous clamp arterial clamp Position for RAP measurement Venous drainage cannula Arterial reperfusion cannula Aortic flow probe Pigs under anaesthesia ; n =10, propofol and fentanyl Veno-arterial ECMO; Cardiohelp , HLS Set Advanced 5.0 Centrally cannulated Ligated pulomary artery Closed chest Volume controlled ventilation ; PEEP 5 cm H 2 O, tidal volume 7 mL /kg Q VR = Q SVC + Q IVC transit time ultra sound probes

6. Euvolemia Volume Expansion Hypovolemia Pump speed maneuvers Airway pressure maneuvers Stop flow maneuvers Pump speed maneuvers Airway pressure maneuvers Stop flow maneuvers Pump speed maneuvers Airway pressure maneuvers Stop flow maneuvers Infusion of HES 9.75 mL/kg Bleeding up to 19.5 mL/kg, or MAP=35 mmHg

7. variable pump speed experimentally controlled variable constant airway pressure Pump speed maneuvers Stop flow maneuvers constant pump speed variable airway pressure Airway pressure maneuvers Beat-to-beat extraction of Q VR -RAP data-pairs from one respiratory cycle

8. 5 s 40 80 mmHg RAP ABP P AW Stop flow maneuver Baseline rpm Expiratory hold Maximum rpm Expiratory hold 75% rpm Expiratory hold 50% rpm Expiratory hold Stop flow maneuver Expiratory hold 20 10000 5000 7500 2500 5 s 10 mmHg Q ECMO P AW Pump speed maneuver mL/min

9. Inspiratory hold maneuver Zero PEEP maneuver 5 s 20 Δ Q VC max pre early 1 s 10 mmHg 10.000 5.000 mL/min 7.500 2.500 20 10 5 15 10.000 5.000 mL/min 7.500 2.500 late P AW ( mmHg ) RAP ( mmHg ) ECG (mV) Q IVC ( mL /min) Q SVC (mL/min ) Q Aorta (mL/min ) pre Δ Q VC max early late mmHg

10. Euvolemia Volume Expansion Hypovolemia MSFP 10.3 (0.5) mmHg MSFP 12.3 (1.2) mmHg MSFP 8.7 (1.0) mmHg p < 0.0005* p < 0.0005 p = 0.012 p = 0.002 *one-way repeated measures ANOVA; n=9; within-subjects effect volume state. Post-hoc parwise comparison with Bonferroni correction for multiple comparisons. C vasc : 183 (75) mL/mmHg or 4.3 (1.8) mL/kg/mmHg; (n=9) r 2 0.915 (0.472-0.999)

11. Pump speed- and Stop flow maneuvers combined Volume Expansion (VE) Hypovolemia (Hypo) Euvolemia (Euvol) 3 Euvol r 2 0.947 VE r 2 0.949 Hypo r 2 0.999 4 Euvol r 2 0.964 VE r 2 0.978 Hypo r 2 0.993 5 Euvol r 2 0.999 VE r 2 0.992 Hypo r 2 0.925 8 Euvol r 2 0.982 VE r 2 0.988 Hypo r 2 0.997 9 Euvol r 2 0.965 VE r 2 0.989 Hypo r 2 0.987 7 Euvol r 2 0.894 VE r 2 0.960 Hypo* r 2 0.859 *MSFP missing, 4-pt regr. 6 Euvol r 2 0.998 VE r 2 0.995 Hypo r 2 0.951 10 Euvol r 2 0.978 VE r 2 0.890 Hypo r 2 0.989 1 Euvol r 2 0.979 VE r 2 0.986 Hypo r 2 0.946 11 Euvol r 2 0.994 VE r 2 0.991 Hypo r 2 0.859 Regressions for all animals: Euvolemia r 2 0.978 (0.894-0.999) Volume Expansion r 2 0.987 (0.890-0.995) Hypovolemia r 2 0.969 (0.859-0.999)

12. Inspiratory hold maneuver Zero PEEP maneuver Volume Expansion Hypovolemia Euvolemia pre Δ Q VC max early late pre Δ Q VC max early late Q VR RAP

13. Venous return plots – all maneuvers combined Volume Expansion (VE) Hypovolemia ( Hypo ) Euvolemia (Euvol) 3 Euvol r 2 0.764 VE r 2 0.762 Hypo r 2 0.907 4 Euvol r 2 0.594 VE r 2 0.772 Hypo r 2 0.887 5 Euvol r 2 0.991 VE r 2 0.919 Hypo r 2 0.865 8 Euvol r 2 0.904 VE r 2 0.889 Hypo r 2 0.892 9 Euvol r 2 0.960 VE r 2 0.946 Hypo r 2 0.846 7 Euvol r 2 0.806 VE r 2 0.835 Hypo* r 2 0.638 *MSFP missing 6 Euvol r 2 0.949 VE r 2 0.912 Hypo r 2 0.962 10 Euvol r 2 0.937 VE r 2 0.862 Hypo r 2 0.955 11 Euvol r 2 0.825 VE r 2 0.748 Hypo r 2 0.780 1 Euvol r 2 0.943 VE r 2 0.873 Hypo r 2 0.970 Regressions for all animals: Euvolemia r 2 0.921 (0.594-0.991) Volume Expansion r 2 0.867 (0.748-0.946) Hypovolemia r 2 0.889 (0.638-0.970

14. RAP exerts its role as back-pressure for venous return at any time point Conclusions RAP represents the operating point of an equilibrated cardiovascular system only after volume shifts caused by transient imbalance between VR and CO have settled Although the pressure effects of these volume shifts are small , it follows that VRdP is itself dynamically changing in the transit between steady states The change in VRdP is dominated by change in RAP The effect of volume shift is to restore both RAP and VRdP to the levels present before the imbalance – unrelated to reflex mechanisms Guyton’s model, originally defined for steady states, can be applied to qualitatively predict the dynamic transit between steady states

15. Euvolemia Euvolemia; Pump speed maneuver and MSFP Euvolemia; Tidal ventilation and immediate Airway pressure maneuvers * Volume Expansion; Pump speed maneuver and MSFP Volume Expansion; Tidal ventilation and Airway pressure maneuvers * Hypovolemia ; Pump speed maneuver and MSFP Hypovolemia ; Tidal ventilation and Airway pressure maneuvers * *Immediate effects ("pre" and " Δ Q VC max ") included Volume Expansion and Hypovolemia; Animal 10 excluded due to possible caval collapse. Volume Expansion Venous return plots and Generalized Estimating Equations Hypovolemia Figure 7

16.   Euvolemia Volume Expansion Hypovolemia p rpm: min -1 (n=10) 3095 (175) 3224 (247) ‡ 2550 (153) # <0.0005 Q ECMO ; mL×min -1 (n=10) 3497 (76) 3782 (160) ‡ 2605 (84)# <0.0005 Q VR : mL×min -1 (n=10) 3126 (412) 3329 (654) ‡ 2307 (297) # <0.0005 S v O 2 : % (n=9) 52 (4) 55 (6) ‡ 38 (6) # <0.0005 RAP † : mmHg (n=10) 4.5 (1.8-6.0) 5.7 (3.6-8.0) ‡ 2.4 (-1.6-4.6) <0.0005 † Lactate: mmol×L -1 (n=8) 2.6 (0.8) 3.5 (1.2) 3.9 (2.1) 0.042 MAP † : mmHg (n=10) 60 (51-74) 60 (53-73) ‡ 45 (36-57) # <0.0005 † Heart rate: beats×min -1 (n=10) 93 (15) 96 (19) 107 (36) n.s. MSFP: mmHg (n=9) 10.3 (0.5)* 12.3 (1.2) ‡ 8.7 (1.0) # <0.0005 VRdP † : mmHg (n=9) 5.2 (4.9-9.1) 6.6 (4.8-9.5) 5.9 (4.7-10.7) n.s. † RVR † : mmHg×L -1 ×min -1 (n=9) 1.9 (1.3-2.9) 1.9 (1.3-2.8) ! 2.5 (2.0-5.6) 0.013 † Data is averaged over three heart beats in expiratory hold at PEEP 5 cmH 2 O and Baseline pump speed, S v O 2 and lactate was sampled at Baseline pump speed in beginning of each volume state. Data is mean (SD) or median (range) if not normally distributed (†). p -values: one-way repeated measures ANOVA for effect of volume state or Friedman test (†) was performed as appropriate. Post hoc analysis with Bonferroni correction is indicated as: * Euvolemia vs. Volume Expansion ( p = 0.002 ) ‡ Volume Expansion vs. Hypovolemia ( p ≤ 0.001; ! for RVR p = 0.029) # Hypovolemia vs. Euvolemia ( p ≤ 0.012) rpm= revolutions per min; RAP= right atrial pressure; Q ECMO = ECMO flow; Q VR = venous return flow (sum of caval vein flows); MAP= mean arterial pressure; MSFP= mean systemic filling pressure; VRdP= venous return driving pressure (VRdP=MSFP-RAP); RVR=resistance to venous return (RVR=VRdP/Q VR ).

17.   pre ΔQ VC max early late p Euvolemia P AW †: mmHg 4.4 (4.1-5.5) 12.4 (8.9-15.1) * 13.6 (11.5-17.2) * 12.0 (10.6-15.5) <0.0005† RAP: mmHg 5.2 (1.2) 6.1 (1.2) *‡ 5.9 (1.2) *‡ 5.6 (1.4) 0.001 Q VR : mL/min 2263 (323) 1635 (272) *‡# 2135 (249) ‡ 2297 (234) <0.0005 Q Aorta : mL/min 1758 (191) 1815 (182) * 1772 (195) 1819 (203) 0.014 Volume Expansion P AW †: mmHg 4.3 (3.9-5.0) 13 (8.9-19.0) * 14.3 (13.0-18.7) * 13.1 (12.1-16.9) <0.0005† RAP†: mmHg 6.7 (2.0-7.9) 8.0 (3.6-9.4) *‡ 7.6 (2.7-9.2) * 6.9 (1.1-9.0) <0.0005† Q VR : mL/min 2501 (305) ‡ 1946 (393) *‡# 2440 (379) ‡ 2596 (328) * 0.001 Q Aorta : mL/min 2109 (382) 2096 (366) 2114 (418) 2170 (410) n.s. Hypovolemia P AW : mmHg 4.3 (0.4) ‡ 13.8 (1.7) *# 15.4 (1.5) *‡ 13.8 (1.3) * <0.0005 RAP†: mmHg 4.1 (1.0-5.9) 5.4 (2.0-6.9) * 5.0 (1.6-6.8) 5.2 (1.0-6.6) 0.002† Q VR : mL/min 1508 (345) 913 (306) *‡# 1385 (306) ‡ 1517 (276) <0.0005 Q Aorta : mL/min 1261 (215) 1300 (199) 1269 (202) 1285 (190) n.s. Inspiratory hold maneuver Data is averaged according to figure 4 left panels; n=9. p -values: one-way repeated measures ANOVA († or Friedman test if appropriate) for effect of changing airway pressure. Post hoc analysis with Bonferroni correction is indicated as; *significant difference to pre ; # significant difference to early ; ‡ significant difference to late .

18. Data is averaged according to figure 4 right panels; n=9. p -values: one-way repeated measures ANOVA († or Friedman test if appropriate) for effect of changing airway pressure. Post hoc analysis with Bonferroni correction is indicated as; *significant difference to pre ; # significant difference to early ; ‡ significant difference to late.   pre ΔQ VC max early late p Euvolemia P AW †: mmHg 12.4 (11.0-15.7) ‡ 0.7 (0.1-4.3) 0.2 (-0.1-0.3) * 0.1 (-0.1-0.5) * <0.0005† RAP: mmHg 5.9 (1.7) 4.6 (1.9) * 4.8 (1.7) * 5.2 (1.7) <0.0005 Q VR †: mL/min 2292 (1777-2410) 2876 (2513-4703) *‡ 2476 (1895-3115) 2404 (1877-2997) <0.0005† Q Aorta : mL/min 1743 (234) 1772 (265) 1814 (186) 1841 (225) n.s. Volume Expansion P AW †: mmHg 12.9 (10.6-16.2) ‡ 0.3 (-0.5-7.1) 0.2 (-0.3-0.4) * 0.1 (-0.1-0.2) * <0.0005† RAP†: mmHg 6.8 (1.1-8.9) 6.4 (0.1-7.2) *‡ 5.9 (0.6-7.5) 6.7 (1.3-8.0) 0.002† Q VR : mL/min 2563 (338) 3198 (571) *‡ # 2668 (391) 2528 (358) 0.001 Q Aorta : mL/min 2110 (363) 2135 (441) 2138 (414) 2147 (421) n.s. Hypovolemia P AW †: mmHg 13.2 (10.8-16.5) ‡ 0.5 (-0.3-2.8) 0.2 (-0.1-0.3) * 0.0 (-0.1-0.2) * <0.0005† RAP: mmHg 4.8 (1.7) 3.5 (1.7) * 3.7 (1.8) * 4.1 (2.1) <0.0005 Q VR †: mL/min 1447 (970-1945) 2115 (1491-3500) *‡ 1537 (1339-2544) 1459 (981-2253) <0.0005† Q Aorta : mL/min 1255 (203) 1227 (220) 1278 (210) 1293 (215) n.s. Zero PEEP maneuver

19.   Method Covariate Dependent variable Interaction covariate*method Equation parameters   rpm n (%) P AW n (%) RAP; mmHg Q VR ; mL/min p Slope m (95% CI) mL/mmHg Intercept b (95% CI) mL p Euvolemia 50 (35) 94 (65) 4.7 (-0.8-10.9) 2749 (0-5097) 0.084 -450.8 (-525.4--376.1) 4618 (4016-5220) < 0.0005 ‡ Volume Expansion * 45 (35) 84 (65) 6.5 (2.83-14.5) 2890 (0-5135) 0.897 -494.4 ( -589.9 - -398.9 ) 5870 ( 4969 - 6770 ) Hypovolemia * 44 (32) 92 (68) 3.3 (0.8-10.6) 1978 (0-3500) 0.724 -381.3 (-423.8--338.7) 3235 (2864-3606) Generalized Estimation Equations Generalized Estimating Equations. *Due to negative RAPs and possible caval collapse, Animal 10 is not included in analysis for Volume Expansion and Hypovolemia . Values for RAP and Q VR are given as median (range). rpm: data pairs from Pump speed and Stop flow maneuvers ; P AW : data pairs from Tidal ventilation and the immediate effect of Airway pressure maneuvers (pre and impact). ‡ p -value for equations valid for both slopes and intercepts.