The Hemodynamic Puzzle ScvO2 Heart Rate Urine Output Mental Status The missing link SVV P(cv-a)CO2 SvO2 GEDV SV NIRS OPSI O2ER Lactate

Oxygen Debt: To Pay or Not to Pay? Full Recovery Possible Delayed Repayment of O2 Debt Oxygen Deficit Oxygen Deficit The principle task of acute care is to avoid or correct oxygen debt by optimization of the oxygen supply and consumption. (Oxygen Consumption) Energy Metabolism (Ml/min/m2) Oxygen Deficit Time Excessive O2 Deficit Produces Lethal Cell Injury with Non-recovery Recovery Possible

Providing the right amount of fluid is vital in a critically ill patient, as both too little and too much can result in poor outcomes Under Resuscitation Over Resuscitation It is just as important to recognize that DO2 and tissue perfusion has normalized, therefore any further measures to increase DO2 may do harm by unnecessary over resuscitation

HR and BP as Resuscitation Endpoint SV Heart Rate The missing link SVV SvO2 ScvO2 O2ER Lactate GEDV NIRS P(cv-a)CO2 OPSI CVP Urine Output Mental Status

Correlation Between Arterial Pressure And Oxygen Delivery 100 300 500 700 900 1100 n= 1232 30 60 90 120 150 180 MAP mmHg DO2 ml*m-2*min-1

Correlation Between Heart Rate And Oxygen Delivery 100 300 500 700 900 1100 n= 1236 30 60 90 120 150 180 HR b/min DO2 ml*m-2*min-1

CVP as a Resuscitation Endpoint SV Heart Rate The missing link SVV SvO2 ScvO2 O2ER Lactate GEDV P(cv-a)CO2 NIRS OPSI CVP Urine Output Mental Status

Passive leg raising (PLR) Volume of blood transferred (usually 200-300 mL) to the heart during PLR is sufficient to increase the left cardiac preload and thus challenge the Frank-Starling curve. Maximal effect occurs at 30-90 seconds and assess for a 10% increase in stroke volume (cardiac output monitor) or using a surrogate such as pulse pressure (using an arterial line) approximately 200 mL of blood from the lower extremities toward the central circulatory compartment

Diagnostic Accuracy of Passive Leg Raising for Prediction of Fluid Responsiveness in Adults: Systematic Review and Meta-analysis of Clinical Studies. Meta-analysis 9 studies PLR changes in CO predicts fluid responsiveness Regardless of ventilation mode and cardiac rhythm Difference in CO of 18% distinguished responder from NR AUC= 0.96 To systematically review the published evidence on the ability of passive leg raising-induced changes in cardiac output (PLR-cCO) and in arterial pulse pressure (PLR-cPP) to predict fluid responsiveness. PLR changes in PP are less reliable The pooled sensitivity and specificity of PLR-cCO were 89.4% (84.1-93.4%) and 91.4% (85.9-95.2%) respectively Cavallaro, F. et al. Intensive Care Med. 2010 Sep;36(9):1475-83

CVP as a Resuscitation Endpoint SV Heart Rate CVP The missing link SVV SvO2 ScvO2 O2ER Lactate GEDV NIRS P(cv-a)CO2 OPSI Urine Output Mental Status

European survey: More the 90% of intensivist or anesthesiologists used the CVP to guide fluid management. Canadian survey: 90% of intensivists used the CVP to monitor fluid resuscitation in patients with septic shock.

Crit Care Med 2013; 41:1774–1781)

Does Central Venous Pressure Predict Fluid Responsiveness Does Central Venous Pressure Predict Fluid Responsiveness?: A Systematic Review of the Literature and the Tale of Seven Mares Paul E. Marik, MD, FCCP; Michael Baram, MD, FCCP; Bobbak Vahid, MD Chest. 2008;134(1):172-178.

Cardiac Filling Pressures are Not  Appropriate to Predict Hemodynamic Response to Volume Challenge The study demonstrates that cardiac filling pressures are poor predictors of fluid responsiveness in septic patients. Therefore, their use as targets for volume resuscitation must be discouraged, at least after the early phase of sepsis has concluded Osman D1, Ridel C, Ray P, Monnet X, Anguel N, Richard C, Teboul JL. Crit Care Med. 2007 Jan;35(1):64-8.

Does the Central Venous Pressure Predict Fluid Responsiveness Does the Central Venous Pressure Predict Fluid Responsiveness? An Updated Meta-Analysis and a Plea for Some Common Sense There are no data to support the widespread practice of using central venous pressure to guide fluid therapy. This approach to fluid resuscitation should be abandoned. Marik PE, Cavallazzi R . Crit Care Med. 2013 Jul;41(7):1774-81..

IVC Diameter and Collapsibility as End Point The missing link Heart Rate CVP SVV SvO2 OPSI P(cv-a)CO2 NIRS ScvO2 SV O2ER Lactate GEDV Urine Output Mental Status

Simultaneous measurements of the central venous pressure (CVP) and IVC diameter at the end of expiration in 108 mechanically ventilated patients Wide variation and the absolute measurements are not applicable with positive pressure ventilation. IVC size is an indicator of volume status and not volume responsiveness - these two are not the same. Completely collapsed IVC means severe hypovolemia in the absence of raised intra-abdominal pressure.

Collapsibility Index = 𝑰𝑽𝑪𝒎𝒂𝒙 −𝑰𝑽𝑪𝒎𝒊𝒏 𝑰𝑽𝑪𝒎𝒂𝒙 >12% = responders (PPV 93% and NPV92%). Marked variation

<12% = non-responders Collapsibility Index = 𝑰𝑽𝑪𝒎𝒂𝒙 −𝑰𝑽𝑪𝒎𝒊𝒏 𝑰𝑽𝑪𝒎𝒂𝒙 <12% = non-responders (PPV 93% and NPV92%). Insignificant variation

Ultrasonographic Measurement of the Respiratory Variation in the Inferior Vena Cava Diameter is Predictive of Fluid Responsiveness in Critically Ill Patients: Systematic Review and Meta-analysis Total of 8 studies/235 Pts ΔIVC measured is of great value in predicting fluid responsiveness, particularly in patients on controlled mechanical ventilation Forest plot indicating the area under the receiver operating characteristic curve (AUROC) and 95% confidence interval (CI) for individual studies and the combined results. Zhongheng Zhang, Xiao Xu, Sheng Ye, Lei Xu. Ultrasound in Medicine and Biology. Volume 40, Issue 5, Pages 845–853, May 2014

Schematic diagrams of different volumes that can be measured (dark shaded areas) with the transpulmonary thermodilution technique. ITTV, intrathoracic thermal volume; PTV, pulmonary thermal volume; GEDV, global end-diastolic volume; ITBV, intrathoracic blood volume; EVLW, extravascular lung water

CO/SV as a Resuscitation Endpoint The missing link Heart Rate CVP SV/CO SVV SvO2 ScvO2 O2ER Lactate NIRS GEDV P(cv-a)CO2 OPSI Urine Output Mental Status

Review of 21 randomized controlled trials with various approaches to treatment revealed statistically significant mortality reductions, with hemodynamic optimization, when patients with acute critical illness were treated early to achieve optimal goals before the development of organ failure, when there were control group mortalities of >20% and when therapy produced differences in oxygen delivery between the control and protocol groups

Effects of Cardiac Output and Stroke Volume Guided Hemorrhage and Fluid Resuscitation 21 animal subjects were bled until CI (n=9) or SVI (n=12) decreased by 50% then resuscitated during 60 minutes with LR till target is achieved CI-group SVI-group Tbsl T0 tend Tend SVI (ml/m2) 33.6 ± 6.2 14.6 ± 10.1 23.4 ± 7.9 26.8 ± 4.7 13.4 ± 2.3 26.6 ± 4.1 CI (l/min/m2) 2.88 ± 0.42 1.79 ± 0.53 2.73 ± 0.35 2.6 ± 0.4 1.8 ± 0.3 2.9 ± 0.5 MAP (mmHg) 127 ± 13.07 75 ± 25 85 ± 22 112 ± 23 74 ± 18 91 ± 19 Heart rate (beats/min) 87 ± 16 140 ± 40 124 ± 37 95 ± 12 131 ± 27 107 ± 16 Central venous oxygen saturation (%) 81 ± 8 58 ± 18 64 ± 15 78 ± 7 61 ± 5 73 ± 9 Venous to arterial carbon dioxide gap (mm Hg) 3.3 ± 3.1 8.9 ± 3.3 7.8 ± 4.8 5.3 ± 2 9.6 ± 2.3 5.1 ± 2.6 GEDV (ml/m2) 317 ± 36 198 ± 57 249 ± 46 309 ± 57 231 ± 61 287 ± 49 Stroke volume variation (%) 10.8 ± 5.5 17.3 ± 5.1 16.4 ± 8.2 13.6 ± 4.3 22.6 ± 5.6 12.2 ± 4.3 Nemeth, M. et al. Acta Anaesthesiol Scand (2014). doi:10.1111/aas.12312

SVV & PPV as End Point CVP ScvO2 SvO2 SVV SV OPSI P(cv-a)CO2 O2ER GEDV Heart Rate CVP SV SVV ScvO2 OPSI P(cv-a)CO2 O2ER SvO2 The missing link GEDV NIRS Urine Output Mental Status

Hemodynamics During Positive Pressure Ventilation: SVV and PPV

Hemodynamics During Positive Pressure Ventilation: SVV and PPV ↑ RV Afterload ↓ RV Preload Positive Pressure Ventilation ↑ LV Preload Increased Blood Pressure in Inspiration

PVI to Help Clinicians Optimize Preload / Cardiac Output Stroke Volume Lower PVI = Less likely to respond to fluid administration 10 % 24 % Increasing preload can have a significant or minimal impact on SV depending on where the patient is at in the Starling curve Higher PVI = More likely to respond to fluid administration Preload Frank-Starling Relationship Maxime Cannesson, MD, PhD

Determine success of fluid by the response in stroke volume/index and SvO2 Fluid Non-Responders Fluid Responders End-Diastolic Volume

Dynamic parameters should be used preferentially to static parameters to predict fluid responsiveness in ICU patients

Limited to patients on controlled ventilation Dynamic Changes in Arterial Waveform Derived Variables and Fluid Responsiveness in Mechanically Ventilated Patients: A Systematic Review of Literature Dynamic changes of arterial waveform-derived variables during MV are highly accurate in predicting volume responsiveness in critically ill patients Limited to patients on controlled ventilation Sens. 0.89 Spec. 0.88 AUC= 0.94 Standardized receiver operating characteristic (SROC) curve with confidence and predictive ellipses for the 14 studies that allowed abstraction of the true/false positive/negative values for the ability of the pulse pressure variation to predict volume responsiveness. SENS, sensitivity; SPEC, specificity; AUC, area under the curve. Marik, PE et al. (2009). Citi Care Med. 37: 2642-2647

Lactic Acid as Endpoint Resuscitation The missing link OPSI Heart Rate CVP SV SVV P(cv-a)CO2 NIRS O2ER ScvO2 SvO2 GEDV Lactate Urine Output Mental Status

A nice theory… Critical DO2 DO2 dependent in septic patients Oxygen consumption VO2 mls/min Critical DO2 DO2 dependent in septic patients Oxygen Debt DO2 independent in normal patients Remember we said that in normal people and beagles..we run along at a certain oxygen consumption which is independent of our oxygen delivery because we have lots of spare oxygen. But at a point we begin to use less oxygen because we are not getting enough at this point here. But the critically ill patient has a higher baseline oxygen consumption, a bigger engine, runs out of petrol sooner and builds up lactate..at this point…so perhaps he needs more petrol delivery from the outset?.. It’s a good theory and perhps ok for the high risk surgical patient..but when Micheele Hays and then gattinoi applied the same supra normal goals to septic patients they found several things Firstly more petrol delivery didn’t mean more survivors, it meant less. Secondly too much petrol 20 mics Dobutamine killed patients Thirdly driving Do2 did not bring down lactate. Lactate Oxygen delivery DO2 mls/min 300mls/min

Prolonged lactate clearance is associated with increased mortality in the surgical intensive care unit J. McNelis et al. The American Journal of Surgery 182 (2001) 481–485

Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Jansen TC,van Bommel J, Schoonderbeek FJ,Sleeswijk Visser SJ, vander Klooster JM, Lima AP, et al. Am J Respir Crit Care Med (2010) 182:752–61.doi:10.1164/rccm.200912-1918OC

Effects of Cardiac Output and Stroke Volume Guided Hemorrhage and Fluid Resuscitation CI-group SVI-group Tbsl T0 tend Tend Oxygen delivery (ml/min/m2) 335 ± 63 158 ± 62 284 ± 52 419 ± 62 272 ± 56 341 ± 62 VO2 (ml/min/m2) 44 ± 25 62 ± 38 76 ± 34 77 ± 26 96 ± 19 82 ± 27 Oxygen extraction (VO2/DO2) 0.13 ± 0.08 0.38 ± 0.19 0.32 ± 0.14 0.20 ± 0.07 0.36 ± 0.05 0.24 ± 0.09 Central venous oxygen saturation (%) 81 ± 8 58 ± 18 64 ± 15 78 ± 7 61 ± 5 73 ± 9 Venous to arterial carbon dioxide gap (mm Hg) 3.3 ± 3.1 8.9 ± 3.3 7.8 ± 4.8 5.3 ± 2 9.6 ± 2.3 5.1 ± 2.6 Lactate (mmol/L) 3.6 ± 1.1 5.0 ± 1.6 4.6 ± 2.0 1.62 ± 0.43 3.86 ± 1.49 3.54 ± 1.9 Hemoglobin (g/L) 9.0 ± 0.7 8.0 ± 2.7 6.9 ± 1.3 12.05 ± 1.37 11.22 ± 1.39 8.45 ± 1.1 Nemeth, M. et al. Acta Anaesthesiol Scand (2014). doi:10.1111/aas.12312

Oxygen Extraction-based Resuscitation P(cv-a)CO2 OPSI NIRS The missing link Oxygen Extraction-based Resuscitation Heart Rate CVP SV SVV SVV SvO2 O2ER GEDV ScvO2 Urine Output Mental Status

Oxygen Extraction-based Resuscitation ScVO2 The main factors, which influence ScvO2, are hemoglobin, arterial oxygen saturation of hemoglobin, CO, and oxygen consumption. Theoretically if three of these factors are kept constant, the value of ScvO2 reflects the changes of the latter. There are multiple physiologic, pathologic, and therapeutic factors, which influence venous oxygen saturation, such as anemia, hypovolemia, contractility, bleeding, sedation, fever, and pain CaO2= [Hb X 1.34 x SaO2] + 0.003 x PaO2 O2ER =𝟏𝟎𝟎 𝐗 VO2 DO2 DO2= CO x [CaO2] VO2= CO x [CaO2-CvO2]

Effects of Cardiac Output and Stroke Volume Guided Hemorrhage and Fluid Resuscitation CI-group SVI-group Tbsl T0 tend Tend Oxygen delivery (ml/min/m2) 335 ± 63 158 ± 62 284 ± 52 419 ± 62 272 ± 56 341 ± 62 VO2 (ml/min/m2) 44 ± 25 62 ± 38 76 ± 34 77 ± 26 96 ± 19 82 ± 27 Oxygen extraction (VO2/DO2) 0.13 ± 0.08 0.38 ± 0.19 0.32 ± 0.14 0.20 ± 0.07 0.36 ± 0.05 0.24 ± 0.09 Central venous oxygen saturation (%) 81 ± 8 58 ± 18 64 ± 15 78 ± 7 61 ± 5 73 ± 9 Venous to arterial carbon dioxide gap (mm Hg) 3.3 ± 3.1 8.9 ± 3.3 7.8 ± 4.8 5.3 ± 2 9.6 ± 2.3 5.1 ± 2.6 Lactate (mmol/L) 3.6 ± 1.1 5.0 ± 1.6 4.6 ± 2.0 1.62 ± 0.43 3.86 ± 1.49 3.54 ± 1.9 Hemoglobin (g/L) 9.0 ± 0.7 8.0 ± 2.7 6.9 ± 1.3 12.05 ± 1.37 11.22 ± 1.39 8.45 ± 1.1 Nemeth, M. et al. Acta Anaesthesiol Scand (2014). doi:10.1111/aas.12312

Mixed Venous Saturation in Critically Ill Patient Oxygen Supply: DO2 Oxygen Demand: VO2 SvO2/ScvO2 Low ↓DO2 ↑VO2 Anemia Bleeding Hypovolemia Hypoxia Heart faliure Pain Agitation Shivering Seizure Fever High ↑DO2 ↓VO2 Hg Oxygen Fluids Inotropics Sedation Analgesia Hypothermia Sepsis

Correlation of Oxygen - Supply to - Demand Ratio with Mixed Venous Oxygen Saturation 25 70 55 40 85 100 1.0 2.8 4.6 6.4 8.2 10.0 r= 0.906 y= -9.58 + 0.19*x n= 1149 DO2/ VO2 SvO2 %

Lee J et al. (1972) Anaesthesiology 36: 472 ScvO2 vs SvO2 100 80 60 40 20 r= 0.73 r= 0.88 Shock Normal % SsvO2 % SvO2 Lee J et al. (1972) Anaesthesiology 36: 472

ScvO2 % Sat SvO2 % Sat r= 0.9761 p< 0.001 n= 131 80 60 40 20 -20 -20 -40 -60 -80 r= 0.9761 p< 0.001 n= 131 ScvO2 % Sat SvO2 % Sat Reinhart K et al, Chest, 1989; 95:1216-1221

SvO2 closely correlates with ScvO2 80 60 40 20 30 90 120 150 180 210 240 Normoxia Bleeding Volume Therapy (HAES) Hypoxia Hyperoxia Mixed venous Central venous % Sat Time (min) Reinhart K et al, Chest, 1989; 95:1216-1221

Multi-Center Study of Central Venous Oxygen Saturation (ScvO2) as a Predictor of Mortality in Patients with Sepsis ScvO2 of < 70%, ScvO2 of > 90%, Pope, J et al. Ann Emerg Med. 55:40-46

Oxygen Parameters as Endpoint OPSI NIRS The missing link Oxygen Parameters as Endpoint Heart Rate CVP SV SVV SVV SvO2 O2ER GEDV ScvO2 P(cv-a)CO2 Urine Output Mental Status

P(cv-a)CO2 ∆PCO2= K X 𝑽𝑪𝑶𝟐 𝑪𝒂𝒓𝒅𝒊𝒂𝒄 𝑶𝒖𝒕𝒑𝒖𝒕 Normal is 2-5 mmHg. Is not a marker of tissue hypoxia but it is a marker of the adequacy of cardiac output Under physiological conditions, DeltaPCO2 ranges from 2 to 5 mmHg. The DeltaPCO2 depends on carbon dioxide and cardiac output by a complex fashion. In this article, we detail the influence of these factors on DeltaPCO2 in normoxic conditions and in hypoxic conditions. We bring evidence that DeltaPCO2 cannot serve as a marker of tissue hypoxia contrary to what was initially thought. However, DeltaPCO2 can be considered as a marker of the adequacy of venous blood flow (i.e. cardiac output) to remove the total CO2 produced by the peripheral tissues. In this regard, the knowledge of DeltaPCO2 should help the clinicians for the decision of giving therapy aimed at increasing cardiac output. B. Lamia et al. Minerva Anestesiol. 2006 Jun; 72(6):597-604

Persistently high venous-to-arterial carbon dioxide differences during early resuscitation are associated with poor outcomes in septic shock The persistence of high Pv-aCO2 during the early resuscitation of septic shock was associated with more severe multi-organ dysfunction and worse outcomes at day-28 Survival probabilities at day 28 by the development of mixed venous-to-arterial carbon dioxide difference during the first 6 hours of resuscitation. Log-rank, Mantel–Cox: 19.21, P <0.001. H-H, mixed venous-to-arterial carbon dioxide difference (Pv-aCO2) high at Time 0 (T0) and 6 hours later (T6); L-H, Pv-aCO2 normal at T0 and high at T6; H-L, Pv-aCO2 high at T0 and normal at T6; and L-L, Pv-aCO2 normal at T0 and T6 H-H, mixed venous-to-arterial carbon dioxide difference (Pv- aCO2) high at Time 0 (T0) and 6 hours later (T6); L-H, Pv- aCO2 normal at T0 and high at T6; H-L, Pv-aCO2 high at T0 and normal at T6; and L-L, Pv-aCO2 normal at T0 and T6 Ospina-Tascón GA et al., Crit Care. 2013; 17(6)

Central Venous-to-Arterial  Gap Is a Useful Parameter in Monitoring Hypovolemia-Caused Altered Oxygen Balance: Animal Study ScvO2 < 73% and CO2 gap >6 mmHg can be complementary tools in detecting hypovolemia-caused imbalance of oxygen extraction. Kocsi S et al, Crit Care Res Pract. 2013; 583-598.

The Hemodynamic Puzzle missing link The Hemodynamic Puzzle Heart Rate CVP SV SVV SVV SvO2 O2ER GEDV ScvO2 P(cv-a)CO2 OPSI NIRS Urine Output Mental Status

Near-infrared spectroscopy (NIRS)

NIRS StO2 (at 20 mm, skeletal muscle) is an index of profusion that tracks DO2 during active resuscitation Shock resuscitation variables during shock resuscitation (first 24 hours) and the following 12 hours StO at 20 mm tracked DO2 Lactate & Base Deficit tracked also but SvO2 from PA cath & StO2 at 6 mm (subcutaneous) did not change significantly Crit Care. 2009; 13(Suppl 5): S10.

NIRS (NIRS) has recently been applied in a novel technology designed to measure skeletal muscle tissue perfusion in critically ill patients. Peripheral circulation will be the first region to manifest tissue hypoperfusion and the last to show signs of reperfusion following resuscitation Initial observational findings recommend cutoff StO2 value of less than 70% to 75% to represent a cause for concern. More research is required to evaluate the clinical utility and its possible use in predicting complications and early identification of patients at risk for complications. Shock resuscitation variables during shock resuscitation (first 24 hours) and the following 12 hours StO at 20 mm tracked DO2 Lactate & Base Deficit tracked also but SvO2 fro PA cath & StO2 at 6 mm (subcutaneous) did not change significantly

Orthogonal Polarization Spectral Imaging (OPS): Sublingual capillaroscopy. Orthogonal polarization spectral (OPS) imaging is an optical imaging technique that uses a handheld microscope and green polarized light to visualize the red blood cells in the microcirculation of organ surfaces

Orthogonal Polarization Spectral Imaging (OPS): Sublingual capillaroscopy. Red blood cells are visualised as black-grey points flowing along the vessels. Up-right and up-left: normal findings; bottom-left: septic shock; bottom-right: after cardiac arrest under therapeutic hypothermia

Hemodynamic monitoring - Pearls Lactate can be slowly changing  over-resuscitation Noncardiac conditions may increase BNP  unreliable in ICU. A positive PLR predicts preload responsiveness (sensitivity of 97% and specificity of 94%.) PAC remains useful when used for the appropriate indication CVP could not predict fluid responsiveness across numerous studies. Dynamic variables more accurate at predicting volume responsiveness Many minimally invasive monitors are potential alternatives to invasive catheterization. Limitations should be understood.

Hemodynamic monitoring - Pearls Measuring IVC diameter and ΔIVC can estimate RA pressure. Less reliable in spontaneous breathing. Several hemodynamic parameters can be evaluated using the different modalities of echocardiography Esophageal Doppler monitor is a minimally invasive, safe, and easy means to continuous monitoring Pcv-aCO2 increase the specificity of ScvO2 to low perfusion when this is falsely elevated due to microcirculation and/or mitochondrial defect. New technologies of NIRS, OPS may develop to have a place in the clinical use A need for investigating the efficacy and outcome improvement using a combination of two modalities

The Hemodynamic Puzzle Heart Rate CVP SV SVV SvO2 O2ER GEDV The missing link ScvO2 P(cv-a)CO2 OPSI NIRS Lactate Urine Output Mental Status