Sumit Ray

Chairperson

Critical Care Medicine

Artemis Hospital

Delhi NCR

India

Definition � When septic cardiomyopathy (SCM) was initially described (1984, by

Parker et al), it was defined as an acutely depressed LVEF with ventricular dilation that occurred during sepsis →These EF abnormalities are reversible, with full recovery of cardiac function over 7-10 days in survivors.

� Cardiac dysfunction in sepsis can manifest in multiple different ways, including LV and/or RV impairment during systole or diastole, inadequate CO & O2 delivery, or primary myocardial cellular injury

� LVEF has been increasingly acknowledged to be an inaccurate marker

of intrinsic cardiac function, as it depends profoundly on loading conditions

Parker MM, et al: Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984; 100:483–490

Definition

Echo variables beyond LVEF to evaluate cardiac dysfunction in sepsis

1.The myocardial performance index (MPI) (“the Tei index” ) is based on the proportion of the working cycle of the heart that is spent in isovolumic activity during which the heart does not actively circulate blood. A lower MPI value is associated with better function. 2.Afterload-adjusted cardiac performance (ACP) is a ratio of measured to predicted cardiac output, adjusted for systemic vascular resistance. These measures are obtained from an indicator-dilution or pulse contour analytic cardiac output monitoring device 3.Longitudinal strain→a measure of the deformation of the myocardium. It is a replacement for LVEF to determine LV function. Myocardial strain can be measured using speckle-tracking echocardiography. Evaluation of the actual displacement of points in the ventricular wall in relation to each other during systole. By measuring contractility in the actual muscle, strain is less dependent on loading conditions

In septic patients with preserved LVEF (>50 %), 50% had a depressed LV global function, defined as a LV global strain > −15 %, compared to 8.7 % in the non-septic group (p = 0.0014).

Incidence

INCIDENCE 1. 18% to 50% by LVEF= < 50% method

2. If Diastolic dysfunction was added = 35-60% 3. LV longitudinal strain method= 35-60%

ATTRIBUTABLE MORTALITY

??? 0-25% ???

Pathophysiology of sepsis induced HF

DAMPS→HMGB-1 /Histones Regulated in part by secretoneurin

Optimisation of CO

Preload Contractility Afterload Chronotropy/HR

Frank-Starling mechanism

8

Understanding cardiac output

Cardiac Output- is the amount of blood flow in the CVS in unit time

CO = Heart Rate x Stroke Volume

Stroke Volume

Oxygen delivery

CO X CaO2

Hb (g/dl) X 1.34 X SaO2 DO2 = CO X

5000 ml/min x 15 x 1.34 x 98

5000 ml/min x 20 ml/dl

DO2 = 1000 ml/min

Oxygen consumption

VO2 = CO X ( CaO2 – CvO2 )→VO2 = 250 ML / MIN

Oxygen extraction ratio

O2ER = ( CaO2 – CvO2 ) / CaO2 O2ER = 0.25 TO 0.30

Defining shock:

�“Shock is best defined as a life-threatening, generalized form of acute circulatory failure associated with inadequate oxygen utilization by the cells.”

�“It is a state in which the circulation is unable to deliver sufficient oxygen to meet the demands of the tissues, resulting in cellular dysfunction.”

Frank-Starling Curve

�↑ preload increases myosin-actin overlap, resulting in ↑ stroke volume (SV)

�↑ contractility →↑ SV for a given preload

�↑ afterload →↓SV for a given preload Preload

Str

ok

e V

olu

me

Factors affecting venous return→ Preload

(A)1.Fluid below outlet →

unstressed venous volume→ does not contribute to flow out of the tank.

2.Additional fluid in the tank

→ stressed volume → drives venous return.

3.↓RAP or ↑MSP → ↑ Preload i.e. Venous return(VR).

(B) 1.The proportion of stressed

volume can be ↑ by fluids (attenuated somewhat by reflex venodilatation)

or 2.↓ the size of the tank

(vasopressors to convert unstressed to stressed volume).

Unstressed volume

Stressed volume

VR (Preload)= MSP −RAP/ SVR VR is Venous Return RAP is Rt Atrial Pressure SVR is Systemic Vascular Resistance MSP is Mean Systemic Pressure = Pressure in venous capacitance vessels

MSP

Fluids

Vasopressors

↑ Stressed volume

↑ Stressed volume

B

Factors affecting venous return →Preload

Normal Heart ↑ed Contractility does not ↑ CO ↑ed VR →↑es CO

“In health CO is primarily controlled by the peripheral circulation”

Failing Heart ↑ed VR →Does not ↑ CO →↑ RAP ↑ed contractility & ↓ed afterload → ↑es CO

Effects of Venous return, contractility & afterload on normal & failing heart

Interaction of venous return curves with ventricular function curves

Physiology of sepsis induced heart failure

↑ ↓ in SV can be compensated by an ↑ in LVEDV by FR & ↓ afterload due to vasodilation

1. EF is ↓ed less in non-survivors than survivors of sepsis → due to ↓ed LV afterload → due to ↓ SVR (more in non-survivors than survivors) → a greater ↓ in LV afterload facilitates systolic ejection & preserves EF more in non-survivors 2.↑ed diastolic dysfunction → due to ↓ed diastolic compliance → ↓es diastolic filling → ↓es SV but does not ↓EF as much as ↓ed systolic contractility does.

Vasodilation ↑↑

16 studies – 1507 pts

19

Assessment of PRELOAD is not

assessment of PRELOAD DEPENDENCE

Stroke volume

Ventricular preload

normal heart

failing heart

preload-dependence

preload-independence

Thus it’s necessary to look for preload dependance i.e fluid responsiveness!

21

Preload indicators � Static Measures of Fluid responsiveness

� PAOP

� CVP/RAP

� Dynamic Measures of Fluid responsiveness

� Systolic Pressure Variation (SPV)

� Pulse Pressure Variation (PPV)

� Stroke volume variation (SVV)

� Respiratory variation in vena cava diameter

� Passive Leg Raise(PLR)/ Fluid Challenge technique

Based on Heart-Lung Interactions in Mechanically ventilated

USG/ECHO

Does Central Venous Pressure predict fluid responsiveness? A systemic review of literature and the tale of seven mares. Paul E. Marik, M. Baram, B. Vahid. Chest 2008;134:172-178

Expansive literature search to identify all trials evaluating the relationship between

1.CVP & blood volume 2. Association between CVP or Δ CVP and fluid responsiveness

24 studies identified – 5 comparing CVP with measured blood volume; -19 studies comparing relationship between CVP/ΔCVP & change in cardiac performance after fluid challenge

Poor correlation between •CVP and blood volume •CVP or ∆CVP and hemodynamic response to fluid challenge → overall probability of patients responding to a fluid challenge was 56%! ( AUROC=0.56)

1.The protocol starts by identifying a ‘trigger’ that could be corrected by giving volume.

2. After the volume is given the response of CI is checked.

3.If CI did not ↑by ≥0.3 l/min → CVP is checked to see if the volume bolus was adequate.

4.The key box is in the lower left →If CVP ↑es by ≥2mmHg & CI ↑es by ≤0.3 l/min/m2 (i.e ≤ 10% ↑) further volume boluses are not given and the abnormality is treated pharmacologically

End–expiratory

Airway

Pressure

Arterial

Pressure

Up

Down

SPV

Systolic Pressure Variation (SPV)

Normal SPV < 10mmHg ∆down < 5 mmHg ∆up < 5mmHg

Fluid responsiveness SPV > 10mmHg ∆down > 5 mmHg

PPmax

PPmin

PP % = PPmax – PPmin PPmean

Pulse Pressure Variation

(PiCCO/Volumeview/LiDCO)

SVmax

SVV = SVmax – SVmin SVmean

Stroke Volume Variation

SVmin

(PiCCO/Volumeview/Flotrac)

(+ve >13%) (+ve > 12%)

SYSTOLIC PRESSURE VARIATION- SPV

Systolic pressure variation as a guide to fluid therapy in patients with sepsis induced hypotension Taverneir B, Dupont J. Anesthesiology 1998, 89:1313-1321

Caveats: ∆up- increased in hypervolemia and LVF In the presence of large ∆up the SPV & PPV will be less effective in predicting fluid responsiveness

∆ down-not increased in RVF despite hypovolemia.

*Cardiovascular monitoring Chapter 32, page 1327, Miller’s Anesthesia 7th edi

∆ down- threshold value of 5 mmHg was associated with Increase in stroke volume ≥ 15% on giving fluid bolus Positive predictive value- 95%, Negative predictive value- 93%

SPV ≥ 10mm Hg ,AUROC of 0.91 for predicting fluid responsiveness Michard et al.Am J Respir Crit Care Med (2000)162:134-138

IVC distensibility index (dIVC) ≥ 18% predictive of ↑ in CI ≥15%

Sensitivity-90%, Specificity-90%

divc=(Dmax-Dmin)/ Dmin AUROC (± SEM)

dIVC = 0.91±0.07

SVC collapsibility index ≥ 36% identified preload responders.

dSVC= (Dmax-Dmin)/ Dmax

The AUROC for SVC collapsibility (0.993 ±0.013) AUROC curve for ∆PP (0.9400 ±.038)

Requires TEE Not affected by raised IAP

Affected by raised IAP & High doses of vasoconstrictors

�Only in MV pts without any spontaneous effort.

�Tidal volume ≥8ml/kg of ideal body weight;

�Total respiratory system compliance ≥ 30 ml cm H2O

�A heart rate/respiratory rate ratio > 3.6

�No significant valvular abnormalities

�Regular cardiac rhythm– no arrythmias

Limitations of dynamic measures to predict fluid responsiveness

The study was designed to evaluate the proportion of patients satisfying criteria for valid application of ∆PP Of the 170 patients with an arterial line in place, only five (3%) satisfied the validity criteria.

Increases right cardiac preload

Increase in right cardiac output

Increased left ventricular filling

Increase in cardiac output/SV/PP ICM 2008;34:659-63

? Measure CVP

•Rapid response CO/SV measurement •Aortic flow velocity •Pulse Pressure

Approx 300 ml challenge

Responder= >10% ↑

The Fluid challenge

Passive Leg Raising

1.The global predictive value of PLR was strong with a pooled sensitivity of 86%,specificity of 92%, and a summary AUROC of 0.95.

2.The diagnostic performance of PLR was unaffected by ventilation mode, type of fluid used, PLR starting position, or technique measuring the change in flow induced by PLR.

3.However,changes in pulse pressure (PP) on PLR were inferior in predicting fluid responsiveness compared with changes in flow variables (i.e: SV/CO/VTI etc)

4 ml/kg over 5 mins was significantly associated with a positive response (OR, 7.73; CI, 1.78–31.04).

Venous return equals CO; an effective FC should be able to ↑the Pmsf in order to challenge the cardiac response. Otherwise, the volume given may have no hemodynamic effect, and it would be possible that a number of non- responders might be actually non-challenged.(Target ↑of Pmsf ≥ 14%)

∆CVP >2.3mm in 4 ml/kg group

33

PLR-CO = AUC 0.89 PLR-PP = AUC 0.76

Best Cut-off values= 8% ↑(PP) & 7% ↑(CO)

PLR with ∆CVP ≥ 2mm, PLR-CO →AUC= 0.98, PLR-PP → AUC=0.91

A low CVP (< 8mmHg) was associated with fluid responsiveness (FR) (positive LR (PLR)=2.6; Specificity, 76%)

CVP > 8 mm Hg → FR less likely (negative LR(NLR)=0.50; Sensitivity 62%).

Respiratory variation in IVC diameter (distensibility index >15%) predicted FR in pts on MV (PLR=5.3 ; Specificity, 85%).

Patients with less vena cava distensibility were not as likely to be FR (NLR=0.27; Sensitivity, 77%).

Augmentation of cardiac output or related parameters following PLR predicted FR (Positive LR= 11 ; Specificity, 92%).

The lack of ↑ in cardiac output with PLR identified patients unlikely to be FR (Negative LR=0.13 ; Sensitivity, 88%).

Meta-analysis & systematic review of 50 studies --2260 pts

ECHO performed during a 50-ml infusion of crystalloid solution over 10 seconds and a further 450 ml over 15 minutes. CO, SV, VTI & LVEF were recorded.

50 pts → 27 responders

AUROC (Cut-off) ∆SV50=0.96 (↑>10%) ∆CO50=0.95 (↑>6%) ∆VTI50 =0.91 (↑>9%)

ΔSV50 was strongly and significantly correlated with ΔSV500, as was ΔCO50 with ΔCO500 (r = 0.90; P <0.01)

Algorithm for Fluid Responsiveness with ECHO/USG

8ml/kg

Algorithm for Fluid Responsiveness with ECHO

>10%

24 Studies

Echocardiographic assessment of cardiac output

Overall, the majority of studies showed small bias, wide LOA, and high PE (% error) between CO measured by ECHO & thermodilution.

The PEs (specified and calculated a posteriori) ranged from approximately 16 to 69 % for LVOT & approx 16 to 43 % for aortic valve

SV/CO/VTI ∆PP+CVP

SV/CO/VTI ∆PP+CVP

The Frank-Starling & Marik-Phillips curves

-The limits of fluid resuscitation

95% of hydraulic conductance is through small pores in basal state

Endothelial glycocalyx damage leading to increased “leakiness” in sepsis / inflammation

Limits of fluid resuscitation- “Between the devil &

the deep blue sea!”

Tissue O2 Delivery

Transpulmonary Thermodilution technique of CO monitoring

RA RV LA LV

Limits of Resuscitation :Extravascular Lung Water (EVLW)

ITTV (Intra-Thoracic Thermal Volume)

GEDV (Global End Diastolic Volume)

PTV Pulmonary Thermal Volume

GEDV = ITTV - PTV

ITBV = GEDV X 1.25

EVLW = ITTV - ITBV EVLWI= 4-7 ml/kg

GEDVI= 600-750 ml/m2, ITBVI= 800-1000ml/m2

PiCCO/Volumeview

Pulmonary vascular permeability index (PVPI)is calculated as the ratio of EVLW:ITBV.

Utility Limits of fluid Resuscitation

Quantification of Pulmonary

edema

Defining ARDS

Enghard P et al. Simplified lung USG protocol shows excellent prediction of EVLW in ventilated intensive care patients. Crit Care 2015;19:36

The 2012 recommendations of an international committee on point-of-care LUS recognized LUS as ideally suited for “monitoring pulmonary congestion changes in heart failure patients as they disappear or clear upon adequate medical treatment.”

International Liaison Committee on Lung Ultrasound (ILC-LUS) for International Consensus Conference on Lung USG(ICC-LUS). International evidence-based recommendations for point-of-care lung USG Volpicelli G et al, Intensive Care Med 2012;38:577–591.

SV/CO/VTI ∆ETCO2 ∆ PP+CVP

Lactate Clearance & Pv-aCO2

EVLW

The overall pooled RR for mortality was 0.38 (95% CI, 0.29–0.50) in pts with higher lactate clearance

AJRCCM 2010;182(6):752–61.

ATLAS Trial: Critical Care 2011

Arterial and mixed-venous blood gases & hemodynamic variables at catheter insertion (T0) & 6 h after (T6). Simultaneous Sidestream dark-field device to acquire sublingual microcirculatory images for blinded semiquantitative analysis.

P<0.001

% o

f p

erfu

sed

ves

sels

T6

2015 Veno-arterial CO2 difference P(v-a)CO2

Pv-aCO2 <6.0 6-9.9 > 10 FCD

=Fu

nct

ion

al c

apil

lary

Den

sity

Pv-aCO2 <6.0 6-9.9 > 10

Conclusions: During both early & later phases of resuscitation of septic shock, Pv-aCO2 could reflect the adequacy of micro-vascular blood flow

G. Vasoactive agents

Levosimendan= Ca++ sensitizer of the myocytes → ↑es Cardiac contractility without ↑ing myocardial O2 consumption + Opening of ATP-sensitive K+ channels in vascular smooth muscle results in vasodilatation

54

Methods: A prospective, non-randomised, interventional study of graded dobutamine challenge (0, 5, 10, and 15 μg/kg/min) in patients of SS/SSh who had PA catheterisation (8 survivors/15 non-survivors)

∆SV was the strongest predictor of outcome (p = 0.0003). A cut-off value of 8.5 mL/ m2 ↑in SVI indicated survival

The mean increase in LVEF was significantly greater in survivors than in non-survivors (p =0.0160)

Blinded infusion of levosimendan (0.05 to 0.2 μg/kg/min) for 24 hours or placebo in addition to standard care → 516 pts

CONCLUSIONS: The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia.

10 studies- 1036 patients

Levosimendan could not reduce mortality significantly in severe sepsis and septic shock (OR 0.89,CI 0.69 to 1.16, P=0.39).

Levosimendan use could reduce serum lactate more effectively & enhance cardiac contractibility with increased cardiac index & LVEF

Its use also increased fluid infusion but could not reduce norepinephrine dose

No significant benefit in mortality could be observed of levosimendan versus dobutamine use, or in patients with proven cardiac dysfunction.

To summarize

�Sepsis induced heart failure is fairly common - depending on how it is defined

�Tissue perfusion is maintained by a balance of venous return (dependant on MSP) & cardiac contractility

�Early use of vasopressors in septic shock- due to “leaky” endothelium & to ↑ stressed volume → ↑MSP → ↑VR

�Drugs ↑ing contractility, like Levosimendan & Dobutamine do not seem to consistently improve outcome

�LVDD maybe the main culprit in sepsis induced heart failure

�Fluid resuscitationbased on PLR/mini-fluid challenge with real time SV/CO/VTI monitoring possibly the best?

�EVLW by TPTD or USG to determine limits of resuscitation

�Clinical judgment based on patient response is THE most important evaluation!!!

Thank you!

PLR→↑ETCO2 ≥ 5% / CO ≥ 12% / PP ≥ 11%

AUROC

0.97 0.94 0.73

PLR→↑ETCO2 ≥ 5% / CO ≥ 10% / PP ≥ 7%

AUROC 0.98

0.93

0.65

Total pts= 40 Responders =21 Total pts= 37 Responders = 21

64

The end-expiratory occlusion significantly increased pulse pressure (PP) by 15% ± 15% and cardiac index (CI) by 12% ± 11% in responders whereas PP and CI did not change significantly in nonresponders.

Fluid responsiveness was predicted by EEO by: ↑ PP ≥ 5% AUROC=0.957 ↑ CI by ≥ 5% AUROC = 0.972 ↑ SP by ≥ 4% AUROC= 0.714 PLR induced ↑ CI ≥10% AUROC=0.937 PLR induced ↑ PP ≥11% AUROC=0.675

� CO2 concentration in venous blood reflects the global tissue blood flow relative to metabolic demand.

� CO2 is ≈20 times more soluble than O2 → diffuses out of ischemic tissues, to a much greater extent into the venous effluent → more sensitive marker of hypoperfusion.

� Where an O2 diffusion barrier exists (resulting from non-functional and obliterated capillaries), ‘‘masking’’ poor O2 extraction ,CO2 still diffuses out, ‘‘unmasking’’ the low perfusion state → venous-to arterial CO2 difference (Pv-a CO2)

� △△△△PCO2 inversely related to CO (Cardiac Output) →Thus, if CO is low, Pv-aCO2 is expected to be high (>6mmHg)

The Veno-arterial CO2 difference P(v-a)CO2

2013 Premier Hospital Discharge database = 23,513 patients with SS/septic shock

Day 1 fluid categories → 1 L wide, starting with 1–1.99 L up to ≥9 L

USA

Results: 1.Low volume resuscitation (1–4.99 L) was associated with a small but significant ↓ in mortality, of −0.7% per liter (p = 0.02). 2.In patients receiving high volume resuscitation (5 to ≥9 L), the mortality ↑ by 2.3% (95% CI 2.0,-2.5%; p = 0.0003) for each additional liter above 5 L. 3.Total hospital cost ↑ by $999 for each liter of fluid above 5 L

Prospective study/5 French Hospitals/540 pts

NR R

Conclusions: -ΔVmaxAo had the best sensitivity & ΔSVC the best specificity in predicting FR. - ΔSVC had a greater diagnostic accuracy than ΔIVC & ΔPP, but its measurement requires TEE

Sepsis-induced dysregulated inflammatory response has been directly linked to cardiomyocyte dysfunction.

Pathophysiology

↑ed cardiomyocyte oxidative stress

At the cellular level, these changes are accompanied by ↑ed proteolysis, mitochondrial damage, dysregulated NO, β-adrenoceptor down-regulation & Ca++ mishandling → triggering myocardial dysfunction.

LV strain � Strain is defined as the difference between the final length of the

cardiac segment relative to its resting length.

� Measured by a technique based on the generation of USG B-mode echoes called “speckles” that represent discrete myocardial areas and are tracked throughout the cardiac cycle.

� Changes in the distance between individual speckles, assess changes in the length of segments in longitudinal (long axis from base to apex), radial (inward short axis), & circumferential (rotational short axis) planes

� As the myocardial length shortens in ventricular systole, longitudinal & circumferential strain values are -ve with normal function, whereas radial strain is +ve

� Longitudinal strain has been shown to be more sensitive than EF at diagnosing LV dysfunction & myocardial ischemia early, corelating extremely well with gold-standard MRI measurements.

Initial assessment ECHO

Complex pts- PAC/TPTD

CVC/Art Line in unresponsive shock

ScvO2 & Pv-aCO2

Serial Lactates

CO/SV monitoring only in pts not responding to initial therapy

PAC only in refractory shock & RV dysfunction

TPTD/PAC in severe shock ± ARDS

Less invasive devices only after validation

No routine use of CO monitoring in responsive shock

ECHO can be used for sequential evaluation in shock

SVC RA RV

PA

LA

LV

SaO2 Hb

Preload CVP / RAP

Preload PAOP

DO2 / VO2 balance ScvO2 Pv-aCO2 SvO2

DO2 MAP Preload SPV,PPV,SVV

Lactate Cardiac

output

Cold solution Thermistor

PA Catheter Cold solution Lithium

Thermistor Lithium sensor

Femoral art. catheter

Thermodilution PiCCO Lithium dilution LiDCO

Arterial Waveform analysis PiCCO, LiDCO Flotrac

Doppler Oesophageal Doppler Suprasternal Doppler

Thoracic Bioimpedance

Cardiac Output Monitoring

Newer minimally invasive of CO Monitors

PP ≈ SV

sd(AP) ≈ PP

sd(AP) ≈ SV FloTrac/Vigileo PP

SBP

DBP

≈ SV

PiCCO monitoring uses vascular accesses that are usually required in the critically ill. It is a combination of transpulmonary thermodilution and pulse contour analysis

PiCCO/Volumeview- Principles of Measurement

Central venous catheter

Arterial thermodilution catheter (femoral, axillary)

Injectate temperature sensor housing

→CO module

→Pressure module

Lungs

Pulmonary Circulation

Central venous bolus injection

Body Circulation

Arterial thermodilution catheter

Right Heart Left Heart

Tb x dt

(Tb - Ti) x Vi x K

Tb Injection

t

∫ ∆∆∆∆ = COTD a

Tb = Blood temperature

Ti = Injectate temperature

Vi = Injectate volume

∫ ∆ Tb . dt = Area under the thermodilution curve

K = Correction constant,

The CO is calculated by analysis of the thermodilution curve using the modified Stewart-Hamilton algorithm

Calculation of Cardiac Output

The pulse contour analysis is calibrated through the transpulmonary thermodilution and is a beat to beat real time analysis of the arterial pressure curve

Calibration of the Pulse Contour Analysis

Howell MD, Shapiro NI, Donnino M, et al. Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med 2007;33(11):1892–9.

Prognostic value of lactate

PATIENTS ON POSITIVE PRESSURE VENTILATION

Could be affected by raised IAP

Assessment of Preload by USG Respiratory variation in inferior vene-caval diameter

IVC distensibility index ( DDIVC) ≥ 12% predictive of increase in C.I. by at least 15%

Positive predictive value- 93 %, negative predictive value- 92% Feissel M, Michard F. Inten Car Med 2004;30:1834-7

DDivc=(Dmax-Dmin)/ (Dmax+Dmin)/2

Shock:

� “Shock is best defined as a life-threatening, generalized form of acute circulatory failure associated with inadequate oxygen utilization by the cells.”

� “It is a state in which the circulation is unable to deliver sufficient oxygen to meet the demands of the tissues, resulting in cellular dysfunction.”

Oxygen delivery

CO X CaO2

Hb (g/dl) X 1.34 X SaO2 DO2 = CO X

5000 ml/min x 15 x 1.34 x 98

5000 ml/min x 20 ml/dl

DO2 = 1000 ml/min

Oxygen consumption

VO2 = CO X ( CaO2 – CvO2 )→VO2 = 250 ML / MIN

Oxygen extraction ratio

O2ER = ( CaO2 – CvO2 ) / CaO2 O2ER = 0.25 TO 0.30

IVC distensibility index (dIVC) ≥ 18% predictive of ↑ in CI ≥15%

Sensitivity-90%, Specificity-90%

divc=(Dmax-Dmin)/ Dmin

AUROC (± SEM)

dIVC = 0.91±0.07 CVP =0.57±0.13 p=0.008.

AUROC (± SEM)

dIVC = 0.91±0.07

The study of respiratory variations in IVC diameter is limited in various ways:

1. Difficult & inaccurate in obese or post- laparotomy → 2. Inaccurate in predicting fluid responsiveness in patients with higher IAP 3. Infusion of vasoconstrictors or pts with moderate-severe PAH can have altered respiratory variation in IVC.

23 pts

Meta-analysis & systematic review of 50 studies --2260 pts

Conclusions: -ΔVmaxAo had the best sensitivity & ΔSVC the best specificity in predicting FR. - ΔSVC had a greater diagnostic accuracy than ΔIVC & ΔPP, but its measurement requires TEE

� CO2 concentration in venous blood reflects the global tissue blood flow relative to metabolic demand.

� CO2 is ≈20 times more soluble than O2 → diffuses out of ischemic tissues, to a much greater extent into the venous effluent → more sensitive marker of hypoperfusion.

� Where an O2 diffusion barrier exists (resulting from non-functional and obliterated capillaries), ‘‘masking’’ poor O2 extraction ,CO2 still diffuses out, ‘‘unmasking’’ the low perfusion state → venous-to arterial CO2 difference (Pv-a CO2)

� △△△△PCO2 inversely related to CO (Cardiac Output) →Thus, if CO is low, Pv-aCO2 is expected to be high (>6mmHg)

The Veno-arterial CO2 difference P(v-a)CO2

Hypotension and shock

“We recommend that the presence of arterial hypotension [defined as systolic blood pressure of <90 mmHg, or mean arterial pressure (MAP) of <65 mmHg, or a decrease of >40 mmHg from baseline], while commonly present, should not be required to define shock.” Recommendation. Level 1; QoE moderate (B).

1. IVC could not be measured by experts in 22% 2. IVCEE predicted FR and fluid unresponsiveness in ≈23% of patients (123/540) with a specificity of ≈ 80% → 13mm (62 pts) & 25 mm (61 pts), respectively 3. FR remained undetermined in 77% of the cases 4. Relationship between FR and IVCEE was even worse in the presence of elevated IAP (≥ 12 mmHg) ≈ 30% of pts

540 pts in 5 French ICUs --Experts in CCE

Supplementary Appendix

AUROCs of RAP(CVP) & IVCEE to predict Fluid Responsiveness

A specific ventricular function curve

applies to a specific ventricular contractile

state, diastolic compliance, and afterload.

Using cardiac output as pump output, if

ventricular contractility increases (at a

constant afterload), then the ventricular

function curve shifts up and to the left so

that, at the same end-diastolic pressure

(preload), a greater stroke volume and

cardiac output is achieved

Improved ventricular diastolic compliance

and

decreased afterload (aortic pressure) also

results in increased stroke volume (at a

constant contractile state) so these

changes also shift the ventricular function

curve up.

2018

Lactic acidosis

Due to hypoperfusion, Acidosis persists Pyruvate : Lactate ratio increases (>10:1)

Due to stress leading to excess lactate production Pyruvate : Lactate normal (10:1)

SIRS, ARDS, Leukocytosis

Conclusions: “…higher cumulative fluid balance at day 3 but not in the first 24 hours after ICU admission was independently associated with an increase in the hazard of death.”

738 ICU’s in 84 countries 1808 pts of Sepsis

Assessment of PRELOAD is not assessment of PRELOAD DEPENDENCE

Thus it’s necessary to look for preload dependance i.e fluid responsiveness!

Results:

Overall only six (2%)patients satisfied all validity criteria.

Of the 170 patients with an arterial line in place, only five (3%) satisfied the validity criteria.

∆PP had been used to assess fluid responsiveness in 15 of these cases (19%).

The study was designed to evaluate the proportion of patients satisfying criteria for valid application of ∆PP

Results: 64 pairs of CO-PAC and CO-TTE measurements were compared. The 2 measurements were significantly correlated (r = 0.95; p < 0.0001). The median bias was 0.2 L/min, the limits of agreement (LOAs) were –1.3 and 1.8 L/min, and the percentage error (PE)was 25%. 26 pairs of ΔCO measurements were compared. There was a significant correlation between ΔCO-PAC and ΔCO-TTE (r = 0.92; p < 0.0001)

Significant benefit in terms of 28-day mortality was observed among the TTE patients compared to the control (no TTE) group (odds ratio = 0.78, 95% CI 0.68–0.90, p < 0.001). The amount of fluid administered (2.5 vs. 2.1 L on day 1, p < 0.001), use of dobutamine (2% vs. 1%, p = 0.007), and the maximum dose of norepinephrine (1.4 vs. 1 mg/min, p = 0.001) were significantly higher for the TTE patients. Importantly, the TTE patients were weaned off vasopressors more quickly than those in the no TTE group (vasopressor-free days on day 28 of 21 vs. 19, p = 0.004). Conclusion: In a general population of critically ill patients with sepsis, use of TTE is associated with an improvement in 28-day mortality

EVLW = intrathoracic thermal volume(ITTV)– intrathoracic blood volume(ITBV) EVLW is expressed in mL and as mL/kg when indexed to PBW (EVLWi),

PVPI is calculated as the ratio of EVLW:ITBV.

132 pts undergoing high risk cardiac/vascular surgery

High Risk → Pulmonary Edema = CPE or ARDS

ARDS

AUROC= 0.79 to predict pulmonary edema AUROC= 0.77 to predict ARDS

Pathophysiology � Sepsis-induced dysregulated inflammatory response has been directly

linked to cardiomyocyte dysfunction.

�Cytokines like IL–1b, IL-6, TNF-α and the p38 mitogen activated protein kinases pathway, the complement system, NO dysregulation, HMGB-1 & LPS have been implicated as potential causative agents.

�Temporal association between increased cardiomyocyte oxidative stress and the development of septic cardiomyopathy → use of reactive oxygen species scavengers in murine models leads to partial reversal of septic cardiomyopathy.

� At the cellular level, these changes were accompanied by increased proteolysis, mitochondrial damage, dysregulated NO, β-adrenoceptor down-regulation, and calcium mishandling and have thus all been implicated in triggering myocardial dysfunction during sepsis

Patterns of myocardial dysfunction in sepsis

Oxygen Delivery and Consumption

Supply independence

DO2 CRITICAL NORMAL

VO2

Hyper

Lactatemia

“The result is cellular dysoxia, i.e. the loss of the physiological independence between oxygen delivery and oxygen consumption, associated with increased lactate levels.”

No difference in mortality: Vasopressin gr=30.9% vs Norepi gr= 27.5% No difference in renal failure rates: Vasopressin gr= 43% vs Norepi gr= 41% ↓ Use of RRT in Vasopressin group: Vasopressin gr = 25% vs Norepi gr=35% Odds Ratio = 0.40 (95% CI, 0.20-0.73) Vasopressin spared the total dose of norepi required to maintain the blood pressure

DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, RCT, 18 ICU’s in UK adult pts with septic shock (Feb 2013 to May 2015) 409 pts …. 4 Groups 1. Vasopressin 2. Vasopressin + Steroids 3.Norepi 4. Norepi + Steroids

Arterial and mixed-venous blood gases & hemodynamic variables were obtained at catheter insertion (T0) & 6 h after (T6). Simultaneous Sidestream dark-field device to acquire sublingual microcirculatory images for blinded semiquantitative analysis.

P<0.001 P<0.001

% o

f p

erfu

sed

ves

sels

T 0 T6

Pv-aCO2 <6.0 6-9.9 > 10 Pv-aCO2 <6.0 6-9.9 > 10

2015

Veno-arterial CO2 difference P(v-a)CO2

T0 T6

P<0.001 P<0.001

Pv-aCO2 <6.0 6-9.9 > 10 Pv-aCO2 <6.0 6-9.9 > 10 Fu

nct

ion

al c

apil

lary

den

sity

Conclusions: During both early & later phases of resuscitation of septic shock, Pv-aCO2 could reflect the adequacy of micro-vascular blood flow

Good agreement between P(v-a)CO2 and PPV/FCD was maintained FC

D =

Fun

ctio

nal

cap

illa

ry D

ensi

ty

121

SOAP II Trial 1679 pts

122

VASST Trial

Heart rate & the rates of norepinephrine infusion was significantly lower in the vasopressin group than in the norepinephrine group over the first four days (P < 0.001 for both)

No difference in mortality: ↓ed use of RRT in Vasopressin group: Vasopressin spared the total dose of norepi required to maintain the BP

Low flow state Hyperkinetic state

Combination of forms

4 patterns

SOAP II Trial De Backer et al NEJM 2010

Hemorrhagic Non Hemorrhagic

Myopathic Arrythmias

Septic Anaphylactic Neurogenic

Evaluation of patterns of shock using ECHO

124

∆PP of ≥≥≥≥ 13% predicts fluid

responsiveness → AUROC 0.98

SPV ≥ 10mm Hg has an AUROC of 0.91

ROC=0.98

ROC=0.91

ROC=0.51

ROC=0.40

Small VT ventilation leads to a↓ability of ∆PP to predict fluid responsiveness → AUROC(PPV) = 0.77 ≈ AUROC(CVP)= 0.76

Muller et al.ICM(2010)36:496-504

AUROC SVV: 0.68 (0.63–0.76) AUROC PPV: 0.69 (0.61–0.77) Macdonald et al, BJA:doi:10,1093/bja/aeu398

125

PREDICTION OF PRELOAD DEPENDENCE Effect of Positive Pressure Mechanical Ventilation on Hemodynamics