Article published online: 2023-09-05

THIEME
Review Article

Monitoring Macro- and Microcirculation in the

Critically Ill: A Narrative Review
Syed Nabeel Muzaffar1 Akshyaya Pradhan2 Suhail Sarwar Siddiqui1 Shubhajeet Roy3
Timil Suresh3

1 Department of Critical Care Medicine, King George’s Medical Address for correspondence Syed Nabeel Muzaffar, MD, DM,
University (KGMU), Lucknow, Uttar Pradesh, India Department of Critical Care Medicine, King George’s Medical
2 Department of Cardiology, King George’s Medical University University (KGMU), Lucknow, Uttar Pradesh, India
(KGMU), Lucknow, Uttar Pradesh, India (e-mail: [email protected]).
3 Faculty of Medical Sciences, King George’s Medical University
(KGMU), Lucknow, Uttar Pradesh, India

Avicenna J Med

Abstract Circulatory shock is a common and important diagnosis in the critical care environ-
ment. Hemodynamic monitoring is quintessential in the management of shock. The
Keywords currently used hemodynamic monitoring devices not only measure cardiac output but
► circulatory shock also provide data related to the prediction of fluid responsiveness, extravascular lung
► hemodynamic water, and also pulmonary vascular permeability. Additionally, these devices are
monitoring minimally invasive and associated with fewer complications. The area of hemodynamic
► fluid responsiveness monitoring is progressively evolving with a trend toward the use of minimally invasive
► personalized devices in this area. The critical care physician should be well-versed with current
hemodynamic hemodynamic monitoring limitations and stay updated with the upcoming advances in
monitoring this field so that optimal therapy can be delivered to patients in circulatory shock.

Introduction (peripheral pulse, heart rate, noninvasive blood pressure

(BP), urine output, and fluid balance), central venous pres-
Hemodynamic monitoring is an essential tool to understand sure (CVP),4,5 and pulmonary artery occlusion pressure
the etiology and pathophysiology underlying various shock (PAOP)6–8 monitoring. But there are numerous fallacies of
states, and thereby, administer life support therapies (fluid these methods. Extremes of CVP (too low or too high) will
resuscitation, vasopressors, or inotropes) in an appropriate miss correct fluid responsiveness or lack of it in many cases. A
and timely manner.1–3 Hemodynamic monitoring devices is large meta-analysis conducted in 2013, which included 22
broadly divided into those pertaining to macrocirculation studies from intensive care unit (ICU) and 22 from operating
and microcirculation. room, did not support the use of CVP for guiding fluid
administration.9 The use of pulmonary artery catheter
(PAC) has also decreased since its introduction in the
Assessment of Macrocirculation
1970s after randomized trials failed to show an improvement
Fluid resuscitation is usually the first step in the manage- in outcome of patients with PAC.10–12 Moreover, volumetric
ment of circulatory shock. Fluid responsiveness has been indices for end-diastolic volumes (like right ventricular end-
defined as > 15% increase in stroke volume (SV) within diastolic volume, global end-diastolic volume [GEDV], and
15 minutes of 250 to 500 mL or 6 mL/kg crystalloid over 20 left ventricular end-diastolic area index) may be influenced
to 30 minutes.1,2 Traditionally, decisions for fluid respon- by diastolic compliance.13 Some of the reasons why these
siveness have relied upon assessment of clinical parameters pressometric (CVP/delta CVP/PAOP) and volumetric indices

DOI https://doi.org/ © 2023. The Author(s).

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Monitoring Macro- and Microcirculation in the Critically Ill Muzaffar et al.

Fig. 1 Frank-Starling curve. Patient at point 1 (steep part of curve) is more fluid responsive than patient at point B (flat part of curve).

of hemodynamic monitoring, also known as static indices of the effects of volume expansion on cardiac index. Later on,
preload,14 poorly predict fluid responsiveness are1–4,15: Cavallaro et al22 classified these indices into three groups as
described in ►Table 1. All these indices are known as
• Frank-Starling principle: As per the Frank-Starling principle,
dynamic indices of preload.21–24 A brief description of
the heart adjusts its SV on the basis of its sarcomere length
some of these indices has been mentioned below.
(end-diastolic volume or preload). This relationship be-
tween SV and preload is curvilinear. As preload increases,
Physiology Behind Group A and B Indices23
SV increases until a point beyond which SV shows no
To understand the physiologic rationale behind group A and B
further change to increasing preload. So, a favorable hemo-
indices, it is important to recapitulate the concept of heart-
dynamic response to fluids can be expected only if the heart
lung interaction within a closed thoracic cavity. During inspi-
is operating in the steep part of the curve (►Fig. 1).
ratory phase of controlled positive pressure ventilation, there
• Fluid challenge16–18 may be a good way to find out if a
is increased intrathoracic pressure (ITP) causing decrease in
patient is fluid responsive or not (position on steep or flat
preload to right ventricle (RV) and as a result of decreased
part of the Frank-Starling curve), although only half of the
venous return. Thus, the blood volume being ejected in that
critically ill population may be fluid responsive. The initial
cardiac cycle from RV decreases, which leads to decreased PA
fluid challenge technique was described by Weil and Hen-
blood flow, left ventricle (LV) filling, and hence, fall in LV SV,
ning in 1979 which comprised of 2 to 5 rule for CVP and 3 to
which manifests in expiration due to a delay caused by
7 rule for PAOP.19 Later on, a modified fluid challenge
pulmonary circuit transit time. Simultaneously, in the same
technique was proposed by Vincent and Weil in 2006
inspiratory cycle LV SV increases due to decreased LV afterload
including four components: type of fluid, rate of infusion,
and squeezing of the alveolar vessels into the left atrium.
desired therapeutic response, and assessment of safety
Therefore, phasic variations are noticed in positive pressure
limits.20 Fluid challenge might be used in clinical scenarios
ventilation, which gets exaggerated in hypovolemia. Larger
unless for obvious safety concerns such as florid heart
changes are noticed when patient is lying on steep portion of
failure, refractory hypoxemia, massive fluid overload, etc.
the Frank-Starling curve.

Dynamic Indices of Preload to Predict Fluid

Responsiveness Systolic Pressure Variation (►Fig. 2)
21
In the 2000s, Marik et al introduced the concept of dynamic Systolic pressure variation (SPV) is calculated directly from
indices of fluid responsiveness, associating respiratory var- arterial pressure waveform as SPV ¼ maximum systolic pres-
iations in arterial BP with volume status of patient and hence, sure (SPmax) – minimum systolic pressure (SPmin) or as a

Avicenna Journal of Medicine © 2023. The Author(s).

 Monitoring Macro- and Microcirculation in the Critically Ill Muzaffar et al.

Table 1 Dynamic indices of preload

Dynamic indices of preload

Group A Group B Group C
MV-induced variation in SV MV-induced variation in nonstroke Preload redistributing maneuvers
or SV-derived parameters volume-derived parameters different from standard MV
• Systolic pressure variation (SPV) • Respiratory variability of inferior • PLR-induced change in cardiac output
• Stroke volume variation (SVV) and superior vena cava (PLR-cCO)
• Pulse pressure variation (PPV) • Left ventricular pre-ejection • Respiratory systolic variation test (RSVT)
• Ventilation induced- plethysmography period variation (delta PEP) • End expiratory occlusion test (EEOT)
variation (VPV) • Valsalva maneuver
• Peak aortic flow velocity (delta Vpeak)
• Aortic blood flow variation (delta ABF)

Abbreviations: ABF, aortic blood flow; EEOT, end-expiratory occlusion test; MV, mechanical ventilation; PEP, pre-ejection period; PLR, passive leg
raising; PLR-cCO, PLR-induced change in cardiac output; PPV, pulse pressure variation; RSVT, respiratory systolic variation test; SPV, systolic pressure
variation; SV, stroke volume; SVV, stroke volume variation, Vpeak, peak aortic flow velocity; VPV, ventilation-induced plethysmographic variation.

Fig. 2 Systolic pressure variation (SPV). dDown, delta down; dUP, delta UP.

percentage, SPV% ¼ [(SPmax – SPmin)/ ½ (SPmax þ SPmin)] that dUp ¼ SPmax – SP ref and dDown ¼ SPref – SPmin.
 100. SPV can be further divided into two components, delta dDown a more reliable indicator of fluid responsiveness
up (dUp) and delta down (dDown), using a reference systolic because it reflects the expiratory decrease in LV SV related
pressure (SPref) measured during end-expiratory pause so to inspiratory decrease in RV ejection fraction. A cutoff of

Avicenna Journal of Medicine © 2023. The Author(s).

Monitoring Macro- and Microcirculation in the Critically Ill Muzaffar et al.

Fig. 3 Stroke volume variation (SVV). SVmax, maximum stroke volume; SVmin, minimum stroke volume.

8.5 mm Hg has a sensitivity of 82%, specificity of 86%, and Two large multicenter studies (around 800 patients, 62
area under the receiver operating curve (AUC) of 0.92 for ICUs) have recently evaluated the utility of PPV and observed
predicting fluid responsiveness. dDown threshold of 5 mm that PPV is suitable in 1 to 2% ICU patients only.27,28 In these
Hg has AUC of around 0.97.23,25 studies, among those on controlled ventilation one of the
important inhibiting factors to institution of PPV was use of
lung protective ventilation (tidal volume < 8 mL/kg ideal
Stroke Volume Variation (►Fig. 3)
body weight [IBW]). Recently, Myatra et al have devised a
Stroke volume variation (SVV) calculates the difference test called “Tidal Volume Challenge” to assess fluid respon-
between SV during the inspiratory and expiratory phases of siveness in settings of low tidal volume mechanical ventila-
respiration. It was earlier calculated using aortic probes but tion (MV), in which the tidal volume is transiently increased
now-a-days, SVV can be directly estimated by pulse contour to 6 to 8 mL/kg IBW for 1 minute to assess SVV/PPV with a
analysis based cardiac output (CO) monitoring devices (like cutoff of 2.5 and 3.5% taken as thresholds for fluid respon-
PiCCO, LiDCO, and FloTrac). SVV% ¼ [(SVmax – SVmin)/ ½ siveness for SVV and PPV, respectively.29
(SVmax þ SVmin)]  100. SVV threshold of 9.5 to 11.5% has
AUC of 0.87 to 0.88 for predicting fluid responsiveness.23,26
Respiratory Variation in Inferior Vena
Cava/Superior Vena Cava
Pulse Pressure Variation (►Fig. 4)
Inferior vena cava (IVC) and superior vena cava (SVC) are
Pulse pressure is the difference between arterial systolic and distensible blood vessels. Their diameter and flow vary
diastolic pressures. It is influenced by SV and aortic compli- with respiration and the changes in size are exaggerated
ance. As comparison of pulse pressures is done over a single by hypovolemia.30–32 IVC enters the right atrium (RA)
respiratory cycle, change in arterial compliance is considered immediately after crossing the diaphragm so its intramural
to be minimal. Pulse pressure variation (PPV) can be calculated pressure is similar to RA pressure while its extramural
either directly from the arterial waveform or it can be directly pressure represents intra-abdominal pressure (IAP). In
recorded by PiCCO. PPV% ¼ [(PPmax – PPmin)/ ½ (PPmax þ positive pressure ventilation, pleural pressure gets trans-
PPmin)]  100. PPV threshold of 13% has AUC of 0.98 with 94% mitted fully to RA and partially to the abdomen. Therefore,
sensitivity and 96% specificity for predicting fluid responsive- IVC gets distended during inspiratory phase of positive
ness.23 In a systematic review of 29 studies by Marik et al in pressure ventilation. IVC distensibility can be measured
2009 on the role of dynamic changes in arterial waveform by transthoracic echocardiography or transabdominal
variables in predicting fluid responsiveness, PPV was found to ultrasonography. IVC distensibility index is calculated as
have better AUC, sensitivity, specificity, and likelihood ratio dIVC ¼ [(Dmax – Dmin)/(Dmin)]  100. dIVC > 18% has
as compared to SPV, SVV, and some static parameters of been shown to have AUC of 0.91 for predicting fluid
preload.21 responsiveness.30,31

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 Monitoring Macro- and Microcirculation in the Critically Ill Muzaffar et al.

Fig. 4 Pulse pressure variation (PPV). PPmax, maximum pulse pressure; PPmin, minimum pulse pressure.

Unlike IVC, SVC has mainly an intrathoracic course. Posi- vanishes completely once the legs are returned back to
tive pressure ventilation decreases its transmural pressure, horizontal position. Thus, PLR acts as a “self and reversible”
and hence, SVC gets collapsed. SVC collapsibility index can be volume challenge. PLR-induced change in aortic blood flow
calculated using transesophageal echocardiography or of 8 to 10% has been found to have AUC of 0.91 to 0.96 for
esophageal Doppler and as cSVC ¼ [(Dmax – Dmin)/(Dmax)] predicting fluid responsiveness. Studies have shown that
 100. cSVC > 36% has been found to have AUC of 0.99 for PLR-induced change in CO (PLR-cCO) is at least as accurate
predicting fluid responsiveness.30 as PPV and is better than SVV and SPV for predicting fluid
However, there are some limitations of group A and B responsiveness.35 Another advantage of PLR is that it is
indices which restrict their applicability in critically ill reliable in conditions where other indices of fluid respon-
patients, as mentioned below23: siveness fail, like spontaneous respiration, arrhythmias, low
tidal volume ventilation, and low lung compliance.32,36,37
1. Positive pressure, controlled ventilation, sinus rhythm,
There are certain essential points that need to be kept in
and large tidal volume  8 mL/kg are needed to ensure
mind while doing PLR:
sufficient change in ITP for correct assessment of these
indices. 1. PLR should start from semirecumbent position (and not
2. Further studies are needed to validate these indices in the from supine position).
setting of vasoactive drugs and in open chest or abdomen 2. PLR effects must be assessed by direct measurement of CO
conditions. (and not by simple measurement of BP).
3. In scenarios like cardiac tamponade, RV failure, raised IAP, 3. Technique used to measure CO must be able to detect the
and arrhythmias. short and transient changes induced by PLR as effects of
4. Morbid obesity and postlaparotomy conditions, assess- PLR may disappear after 1 minute.
ment of IVC/SVC changes is difficult. 4. CO should be measured not only before and during PLR
but also when patient is moved back to semirecumbent
Group C Indices position to check return of CO to baseline.
5. Avoid pain, cough, discomfort, and awakening-induced
Passive Leg Raising33–35
adrenergic stimulation (adjust bed and do not raise
Lifting legs in circulatory collapse has been used by first aid
patient’s legs, explain procedure to conscious patients,
rescuers for many years. In passive leg raising (PLR), there is a
and aspirate tracheal secretions).
gravitational transfer of around 300 mL blood from the lower
part of the body toward the central circulatory compartment An algorithmic approach to assessment of fluid respon-
which acts as a fluid challenge. Moreover, any change in CO siveness has been shown in ►Fig. 5.

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Monitoring Macro- and Microcirculation in the Critically Ill Muzaffar et al.

Fig. 5 Algorithm for guiding fluid resuscitation in patients with shock on the basis of fluid responsiveness. SPV, systolic pressure variation; SVV,
stroke volume variation; PPV, pulse pressure variation; PLR-cCO, passive leg raising-induced change in cardiac output; FoCUS, focus cardiac
ultrasound; Lung USG, lung ultrasonography.

Cardiac Output Monitoring38 insertion, difficulty in data interpretation, and lack of evidence
Adolf Fick described about CO estimation in 1870 for the first in favor of PAC. PAC still has limited use in the management and
time. Until the introduction of PAC, Fick’s principle was the diagnosis of pulmonary hypertension, undifferentiated shock,
reference standard for CO determination. Since the last decade, cardiogenic shock, heart failure, and obscure hemodynamics
many noninvasive CO monitors have been introduced which (e.g., congenital heart disease).
do not require the introduction of PAC, as shown in the
classification of CO monitoring devices in ►Table 2.
Minimally Invasive Cardiac Output
Monitoring39
Invasive Cardiac Output Monitoring
Esophageal Doppler40,41
7
Pulmonary Artery Catheter Esophageal Doppler monitors CO by measuring blood flow in
PAC is still the reference gold standard method which calcu- the descending thoracic aorta. In sedated and MV patients,
lates CO using intermittent (or semicontinuous) bolus ther- esophageal Doppler probe is introduced either by oral or by
modilution (TD) method. Five to 10 mL cold saline ( 25°C) is nasal route and fixed at 35 to 40 cm from teeth. The tip of the
injected into the RA which mixes with venous blood and cools probe is then rotated to face the descending aorta. The
down. Change in temperature is recorded in PA by a thermistor characteristic velocity signal from the descending aorta
near the tip of the PAC. Thus, a TD curve is generated which appears as a swoosh sound. D-shaped piezoelectric crystal
calculates CO by Stewart-Hamilton equation. An average of is present at the tip of the probe which acts as Doppler
three values is finally taken as CO. PAC also provides data transducer and transmits sound waves either as 4 MHz
regarding right atrial pressure, PA pressures, PAOP, and mixed continuous wave or as 5 MHz pulsed wave. Signals reflected
venous oxygen saturation (SvO2). It has certain limitations, back by red blood cells (RBCs) are then recorded to calculate
including invasiveness, possibility of complications while Doppler shift.

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Table 2 Classification of cardiac output monitoring devices

Classification of cardiac output (CO) monitoring devices

Invasive CO monitoring
• PAC: intermittent bolus thermodilution (gold standard)
Minimally invasive CO monitoring
• Esophageal Doppler
• Pulse contour analysis
• Calibrated: Transpulmonary thermodilution: PiCCO (Pulsion Medical Systems, Munich, Germany),
LiDCO (LiDCO Group Plc, London, U.K.)
• Noncalibrated: FloTrac (Vigileo, Edwards Life Sciences, Irvine, California, United States)
Noninvasive CO monitoring
• Thoracic bioimpedance
• Partial CO2 rebreathing system (NICO, Respironics, Murrysville, Pennsylvania, United States)
• Pulse wave analysis (noninvasive): ClearSight system, CNAP system
• Pulse wave transit time (PWTT): Nihon Kohden

Abbreviations: CO, cardiac output; LiDCO, lithium dilution cardiac output; NICO, noninvasive cardiac output monitor; PAC, pulmonary artery
catheter; PiCCO, pulse contour cardiac output.

Estimation of aortic blood flow is done by measurement of After calibration by TPTD, pulse contour analysis is done
velocity time integral (VTI). SV is then calculated by the which is based on the Windkessel model. This model states
formula, SV ¼ VTI  cross-sectional area (cross-sectional that the volume of blood entering a vessel of infinite length is
area is determined from the aortic diameter which in turn equal to the volume of blood leaving that vessel over the
is calculated by a nomogram based on age, weight, and height period of cardiac contraction. During systole, vessels expand
[Cardio Q] or by M mode echo [HemoSonic 100]). while during diastole, they contract. The aorta acts as a
There are certain assumptions in esophageal Doppler capacitor and systemic arterioles act as resistors.
monitoring system which limits its applicability: Based on the relationship among BP, SV, arterial compliance,
and systemic vascular resistance, SV is calculated as the area
1. Proportion of blood flow in ascending and descending
under systolic portion of arterial waveform as an integral of change
aorta is assumed to be fixed and “flat” (same RBC speed).
in pressure (P) from end-diastole (t0) to end-systole (t1) over time
2. Aortic diameter is considered to be fixed during systole.
and is inversely proportional to impedance (Z) of the aorta.
3. Angle between ultrasound beam and blood flow is
Arterial compliance is calculated from the shape of
assumed to be fixed (45–60 degrees).
diastolic portion of arterial pressure waveform.
4. A fixed proportion of 30% blood flow is thought to be
TPTD devices have good agreement with PAC but require
diverted to the heart, brain, and limbs before reaching the
frequent calibration and suffer from the limitations inherent
descending thoracic aorta.
in any monitoring system based on arterial pressure wave-
form analysis.
Transpulmonary Thermodilution and Pulse
These devices give continuous and real-time CO monitoring
Contour Analysis42
and other fluid responsiveness data and are calibrated devices.
Two different proprietary devices use transpulmonary TD They use two methods of CO measurement, namely, TPTD and
(TPTD) techniques, namely: PiCCO (Pulsion Medical systems, arterial pulse contour analysis. While arterial pressure contour
Germany) and VolumeView (Edwards Lifesciences, USA). analysis gives continuous and real-time CO, TPTD is used to
These devices come in the category of minimally invasive externally calibrate and thus it is more reliable in critical care
devices as they are less invasive than PAC, which traverses settings as compared to uncalibrated CO monitors.
through the pulmonary vasculature and calculates intermit-
tent CO using thermistor lodged in the PA. LiDCO43,44
TPTD is done for external calibration of system. Both central LiDCO is another pulse contour analysis method based on
venous (internal jugular vein /subclavian vein) cannulation lithium indicator dilution in which LiCl 0.002 to 0.004 mmol/kg
and femoral/axillary artery cannulation are required. A known is injected via central or peripheral vein. There is a lithium
volume of ice cold saline injection is injected into the central sensor attached to the peripheral arterial line. Three milliliters
vein and changes in blood temperature are recorded in femoral of blood is withdrawn through the arterial line and a lithium
or axillary artery. TD curve is generated and CO is estimated time (dye dissipation) curve is generated from which CO is
from the curve using Stewart-Hamilton equation similar to analyzed by Stewart-Hamilton equation. This method is as
PAC (average of three values is recorded). Other important reliable as other TD methods but is unable to predict CO
variables recorded are GEDV (preload), cardiac function index accurately in patients on neuromuscular blockers and those
(contractility), extravascular lung water (EVLW), SVV, PPV and taking therapeutic lithium, and also, there are chances of anemia
pulmonary vascular permeability index. due to frequent blood sampling and overall lithium is costly.27

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Monitoring Macro- and Microcirculation in the Critically Ill Muzaffar et al.

FloTrac System45,46 where VCO2 ¼ CO2 clearance, and CaCO2 ¼ arterial CO2
FloTrac system is also a pulse contour analysis method which content (estimated from end-tidal CO2).
includes FloTrac sensor and Vigileo monitor and requires only a However, this system measures only pulmonary capillary
peripheral arterial catheter (usually radial artery catheter) for blood flow and is inaccurate in high shunt conditions. It is not
CO estimation. It does not require any external calibration. A applicable in low minute ventilation conditions and for
proprietary algorithm analyzes the arterial pressure waveform spontaneously breathing patients.
and samples it at 100 Hz and updates it every 20 seconds.
Characteristics of the arterial waveform are then coupled with Thoracic Bioimpedance49
patient’s demographics to calculate CO. This algorithm oper- A high-frequency, low-magnitude electric current of known
ates on the principle that pulse pressure is proportional to SV frequency and amplitude is applied across thorax and changes
and inversely proportional to vascular compliance. Continuous in voltage are measured. The ratio between voltage and current
self-calibration goes on by an automatic vascular tone adjust- amplitude is then calculated to determine impedance (Zo). SV
ment property of software algorithm which eliminates the is proportional to product of maximal rate of change of Zo and
need for any external calibration. ventricular ejection time (VET) (VET is calculated from electro-
But FloTrac does not track changes in SV accurately and has cardiography). Electrical resistance of thorax is assumed to be
poor agreement with PAC. This device is a noncalibrated device directly related to intrathoracic blood volume.
and may not be very suitable for prolonged use in critical care It is inaccurate in ICU settings (excess body motion, noise,
environment than for short-term use in operating rooms.28 and excess EVLW). Moreover, Zo depends on electrode
placement, body size, temperature, and humidity.
Pulse wave analysis by finger-cuff (volume clamp tech-
Noninvasive Cardiac Output Monitoring
nique; ClearSight and CNAP systems) and pulse wave velocity
Partial CO2 Rebreathing System47,48 (based on pulse wave transit time) are other noninvasive
Partial CO2 rebreathing system is used which consists of CO2 techniques to monitor CO but they have not been validated
infrared sensor, airflow/pressure pneumotachometer, pulse for clinical usage.48,49
oximeter, and a disposable partial rebreathing loop. According ►Table 3 shows the merits and demerits of various
to the Fick principle, CO is calculated by the following formula: hemodynamic monitoring devices and ►Fig. 6 shows which
hemodynamic monitoring device may be preferable in vari-
CO ¼ Change in VCO2/Change in CaCO2 ous ICU settings.

Table 3 Merits and demerits of various hemodynamic monitoring devices

Tool Accuracy Other variables Mean % error Demerits

besides CO (vs. TD)
• PAC: Gold standard; calibrated; directly measures right heart and PA; but invasive
• Minimally invasive devices
Reliability Additional % Error Demerits
features
TPTD (calibrated) Good ITBV, GEDV, CFI, Accurate Damping, aortic diameter variability,
e.g., PiCCO PVPI, EVLW aortic valve and vessel pathology, cannot
differentiate between RV and LV dysfunction
LiDCO (calibrated) Good  41 Li, NMBs Frequent sampling
PRAM (noncalibrated) Fair  41 For stable patients only
Esophageal Doppler Fair Yes; preload Aortic size assumptions
Contractility, Probe position, only descending aortic flow;
afterload; SVV sedated and MV patients only
• Noninvasive devices
ClearSight Less  44 Noncalibrated
PWTT Less  62 Noncalibrated
CO2 rebreathing Less  40 Noncalibrated, healthy lungs only, for sedated
patients on controlled MV only
Bioimpedance Less  40–45 Noncalibrated, for stable patients only

Abbreviations: CFI, cardiac function index; CO, cardiac output; CO2 rebreathing, carbon dioxide rebreathing; EVLW, extravascular lung water; GEDV,
global end-diastolic volume; ITBV, intrathoracic blood volume; LiDCO, lithium dilution cardiac output; LV, left ventricle; MV, mechanical ventilation;
NMBs, Na-metal batteries; PA, pulmonary artery; PAC, pulmonary artery catheter; PiCCO, pulse contour cardiac output; PRAM, pressure recording
analytical method; PVPI, pulmonary vascular permeability index; PWTT, pulse wave transit time; RV, right ventricle; SVV, stroke volume variation;
TPTD, transpulmonary thermodilution.

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 Monitoring Macro- and Microcirculation in the Critically Ill Muzaffar et al.

Fig. 6 Hemodynamic monitoring devices in intensive care unit (ICU) settings. ECG, electrocardiography; NIBP, noninvasive blood pressure;
SpO2, oxygen saturation; CVP, central venous pressure; IABP, invasive arterial blood pressure; SVV, stroke volume variation; EEOT, end-
expiratory occlusion test; PLR, passive leg raising; TPTD, transpulmonary thermodilution; EVLW, extravascular lung water; PVPI, pulmonary
vascular permeability index; CO, cardiac output; RV, right ventricle; PAH, pulmonary artery hypertension; LV, left ventricle; ARDS, acute
respiratory distress syndrome; PAC, pulmonary artery catheter.

Echocardiography Tissue Oxygenation

Echocardiography is an important, noninvasive, repeatable, Normal CO is frequently mistaken to represent normal flow
bedside tool to examine and monitor cardiac structure and of oxygen to vital organs. However, both are not the same. To
function50–52 and provides comprehensive information assess the balance between oxygen delivery and metabolic
about the following parameters: demand of tissues, indicators of tissue oxygenation like
venous oximetry, blood lactates, and capillary refill time
1. Preload estimation (end-diastolic volumes)
(CRT) are commonly used.
2. Fluid responsiveness indices: IVC/SVC assessment, left
ventricular outflow tract VTI variation, and ascending
aortic blood velocity/flow variation by pulsed wave Lactates
Doppler
Lactates are produced as an end product of glycolysis and
3. Systolic and diastolic function of LV and RV
are normally cleared out from the body by liver and
4. Others: Regional wall motion abnormality, valves, throm-
kidneys. Hyperlactatemia is defined as serum lactate > 2
bus, and pericardial effusion
mmol/L and lactic acidosis is hyperlactatemia associated
Two-dimensional echocardiography along with critical with metabolic acidosis (pH < 7.35).55 High lactate levels
care ultrasonography is increasingly gaining importance in generally indicate an underlying anaerobic metabolic state
emergency and ICU settings for timely diagnosis and man- (secondary to poor oxygen delivery to tissues) leading to
agement of shock as shown by Kanji et al in 201453 and overproduction of lactates and are helpful in risk stratifi-
Atkinson et al in 201854. cation and prognostication of patients.56–58 Decrease in
►Table 4 shows the application of abovementioned he- lactates (lactate clearance) with initial management strat-
modynamic monitoring devices in different pathophysiolog- egies has been found to improve patient outcomes59,60 and
ical conditions. persistent hyperlactatemia should alarm the clinician to

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Table 4 Application of hemodynamic monitoring devices in different pathophysiological conditions.

SPV, SVV, Vt challenge IVC PLR-cCO TPTD-EVLW 2D ECHO

PPV SVC
Tidal volume (Vt) > 8 mL/kg IBW and Yes  Yes Yes Yes Yes
controlled ventilation
Arrhythmias   Yes Yes Yes Yes
ARDS  SVV/PPV þ Yes Yes Yes Yes
Vt challenge
Spontaneous ventilation    Yes  Yes (with PLR)
Open chest, e.g., intercostal    Yes Yes Yes
chest drain (ICTD)
RV failure    Yes Yes Yes
Raised IAP    Yes  Yes

Abbreviations: ARDS, acute respiratory distress syndrome; IAP, intra-abdominal pressure; ICTD, intercostal chest drain; IVC, inferior vena cava; PLR,
passive leg raising; PLR-cCO, passive leg raising-induced change in cardiac output; PPV, pulse pressure variation; RV, right ventricle; SPV, systolic
pressure variation; SVC, superior vena cava; SVV, stroke volume variation; TPTD-EVLW, transpulmonary thermodilution-extravascular lung water; 2D
ECHO, two-dimensional echocardiography.

immediately address the adequacy of the underlying source Peripheral Skin Perfusion
of control measures.55
There may be various causes of hyperlactatemia besides The compensatory sympathetic activation in shock diverts
tissue hypoperfusion. Therefore, it is essential to approach blood flow away from skin to vital structures like brain and
and manage hyperlactatemia in the appropriate clinical heart. Moreover, there is no autoregulation in blood vessels of
scenario.61 skin. So, skin perfusion assessment in the form of skin mottling
(around the knee)72,73 and CRT may play an important role in
the assessment of tissue perfusion and oxygenation.
Venous Oximetry
The recently conducted ANDROMEDA-SHOCK trial74 com-
Central venous oxygen saturation (ScVO2) measured from pared peripheral perfusion-targeted strategy (by CRT at
central venous catheter with its tip at the junction of SVC and ventral part of the right index finger) to lactate-targeted
RA or mixed venous oxygen saturation (SvO2) (measured by resuscitation in early septic shock and found no significant
distal tip of PA catheter) assesses the balance between difference between the two strategies in terms of 28-day
oxygen delivery and consumption.62–64 Changes in ScVO2 mortality. However, the study was underpowered and un-
closely parallel that of SvO2 in critically ill patients.65 ScVO2 blinded and a Bayesian analysis of the ANDROMEDA study
< 70% indicates poor oxygen delivery to tissues. In 2001, the found mortality benefit with CRT-targeted resuscitation.75
early goal-directed trial (EGDT) by Rivers et al showed a CRT may thus be considered as an alternative to lactate-
mortality benefit if ScVO2 > 70% was targeted as resuscita- targeted resuscitation pending further trials.
tion endpoint.66 However, the recent studies (ARISE, Pro-
CESS, and ProMISe)67–69 assessing the protocolized (goal-
Assessment of Microcirculation
directed) resuscitation strategies targeting ScvO2 > 70%
failed to show a mortality benefit pointing more toward Circulatory shock often involves disturbances of microcircu-
the benefit of an individualized or personalized resuscitation lation, which comprises of vessels < 100 μm in diameter
strategy (focusing on early antibiotics and judicious fluid including arterioles, capillaries, and venules. Derangements
resuscitation) rather than focusing on a predefined and fixed of microcirculation include heterogeneity of blood flow
target. (stagnant, intermittent on/off, obstructed or increased blood
Besides lactates and venous oximetry, CO2 gap can pro- flow), reduced perfused vascular density, and impaired
vide further information by assessing the adequacy of re- oxygen diffusion.76 “Hemodynamic coherence” between
gional blood flow.70,71 In areas of decreased perfusion, CO2 microcirculation and macrocirculation is essential to ensure
diffuses through the tissues and accumulates in venous blood adequate tissue perfusion and oxygenation.77
leading to increased venous CO2 content as compared to Hemodynamic indices described above assess the macro-
arterial CO2 content. circulation (global hemodynamic indices) and failed to assess
An example of CO2 gap is the PCO2 gap which measures microcirculation. Some of the important tools for assessing
difference in partial pressure of CO2 between central venous microcirculatory markers of perfusion include laser Doppler
blood (PvCO2) and arterial blood (PaCO2). PCO2 gap (PvCO2– to measure RBC velocity in small tissues, near-infrared
PaCO2) > 6 mm Hg reflects poor regional blood flow. spectroscopy, orthogonal polarization spectral, and side-

Avicenna Journal of Medicine © 2023. The Author(s).

 Monitoring Macro- and Microcirculation in the Critically Ill Muzaffar et al.

stream dark field imaging and assessment of sublingual 13 Bing RJ, Heimbecker R, Falholt W. An estimation of the residual
microcirculation (hand-held video-microscopy). However, volume of blood in the right ventricle of normal and diseased
these tools are still under research.78–80 human hearts in vivo. Am Heart J 1951;42(04):483–502
14 Nahouraii RA, Rowell SE. Static measures of preload assessment.
Crit Care Clin 2010;26(02):295–305
Conclusion 15 Michard F, Teboul JL. Predicting fluid responsiveness in ICU
patients: a critical analysis of the evidence. Chest 2002;121
Hemodynamic monitoring is an integral part of critical care. (06):2000–2008
Its major role is to optimize administration of fluids and 16 Marik PE, Lemson J. Fluid responsiveness: an evolution of our
understanding. Br J Anaesth 2014;112(04):617–620
vasoactive drugs at the right time in the right dose titrated as
17 Marik PE, Monnet X, Teboul JL. Hemodynamic parameters to
per personal needs of the patient. Since the last couple of
guide fluid therapy. Ann Intensive Care 2011;1(01):1
years, our awareness about fluid responsiveness is improv- 18 Cecconi M, Hofer C, Teboul JL, et al; FENICE Investigators ESICM
ing. Many advanced CO monitors have turned up for opti- Trial Group. Fluid challenges in intensive care: the FENICE study: a
mally evaluating a patient’s hemodynamics and the field is global inception cohort study. Intensive Care Med 2015;41(09):
continuously evolving. As such, there is no monitoring device 1529–1537
19 Weil MH, Henning RJ. New concepts in the diagnosis and fluid
which is ideal for all patients and a good physician should
treatment of circulatory shock. Thirteenth annual Becton, Dick-
embrace a combination of bedside clinical examination and inson and Company Oscar Schwidetsky Memorial Lecture. Anesth
corroborate it with data obtained from all these hemody- Analg 1979;58(02):124–132
namic monitoring methods for judicious management of 20 Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med
critically ill patients. 2006;34(05):1333–1337
21 Marik PE, Cavallazzi R, Vasu T, Hirani A. Dynamic changes in
arterial waveform derived variables and fluid responsiveness in
Conflict of Interest mechanically ventilated patients: a systematic review of the
None declared. literature. Crit Care Med 2009;37(09):2642–2647
22 Cavallaro F, Sandroni C, Antonelli M. Functional hemodynamic
monitoring and dynamic indices of fluid responsiveness. Minerva
References Anestesiol 2008;74(04):123–135
1 Pinsky MR. Hemodynamic evaluation and monitoring in the ICU. 23 Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT.
Chest 2007;132(06):2020–2029 Will this hemodynamically unstable patient respond to a bolus of
2 Vincent JL, Rhodes A, Perel A, et al. Clinical review: update on intravenous fluids? JAMA 2016;316(12):1298–1309
hemodynamic monitoring–a consensus of 16. Crit Care 2011;15 24 Monnet X, Marik PE, Teboul JL. Prediction of fluid responsiveness:
(04):229 an update. Ann Intensive Care 2016;6(01):1–11
3 Pinsky MR. Functional hemodynamic monitoring. Crit Care Clin 25 Perel A. Assessing fluid responsiveness by the systolic pressure
2015;31(01):89–111 variation in mechanically ventilated patients. Systolic
4 Marik PE, Baram M, Vahid B. Does central venous pressure predict pressure variation as a guide to fluid therapy in patients
fluid responsiveness? A systematic review of the literature and with sepsis-induced hypotension. Anesthesiology 1998;89
the tale of seven mares. Chest 2008;134(01):172–178 (06):1309–1310
5 Eskesen TG, Wetterslev M, Perner A. Systematic review including 26 Zhang Z, Lu B, Sheng X, Jin N. Accuracy of stroke volume variation
re-analyses of 1148 individual data sets of central venous pres- in predicting fluid responsiveness: a systematic review and meta-
sure as a predictor of fluid responsiveness. Intensive Care Med analysis. J Anesth 2011;25(06):904–916
2016;42(03):324–332 27 Teboul JL, Monnet X, Chemla D, Michard F. Arterial pulse pressure
6 Marik PE, Cavallazzi R. Does the CVP predict fluid responsiveness? variation with mechanical ventilation. Am J Respir Crit Care Med
An updated meta-analysis and a plea for some common sense. Crit 2019;199(01):22–31
Care Med 2013;41:1774–1781 28 Mahjoub Y, Lejeune V, Muller L, et al. Evaluation of pulse pressure
7 Hadian M, Pinsky MR. Evidence-based review of the use of the variation validity criteria in critically ill patients: a prospective
pulmonary artery catheter: impact data and complications. Crit observational multicentre point-prevalence study. Br J Anaesth
Care 2006;10(Suppl 3, Suppl 3):S8 2014;112(04):681–685
8 Marik PE. Obituary: pulmonary artery catheter 1970 to 2013. Ann 29 Myatra SN, Monnet X, Teboul JL. Use of ‘tidal volume challenge’ to
Intensive Care 2013;3(01):38 improve the reliability of pulse pressure variation. Crit Care 2017;
9 De Backer D, Vincent JL. The pulmonary artery catheter: is it still 21(01):60
alive? Curr Opin Crit Care 2018;24(03):204–208 30 Charron C, Caille V, Jardin F, Vieillard-Baron A. Echocardiographic
10 Sandham JD, Hull RD, Brant RF, et al; Canadian Critical Care measurement of fluid responsiveness. Curr Opin Crit Care 2006;
Clinical Trials Group. A randomized, controlled trial of the use 12(03):249–254
of pulmonary-artery catheters in high-risk surgical patients. N 31 Zhang Z, Xu X, Ye S, Xu L. Ultrasonographic measurement of the
Engl J Med 2003;348(01):5–14 respiratory variation in the inferior vena cava diameter is predic-
11 Richard C, Warszawski J, Anguel N, et al; French Pulmonary Artery tive of fluid responsiveness in critically ill patients: systematic
Catheter Study Group. Early use of the pulmonary artery catheter review and meta-analysis. Ultrasound Med Biol 2014;40(05):
and outcomes in patients with shock and acute respiratory 845–853
distress syndrome: a randomized controlled trial. JAMA 2003; 32 Airapetian N, Maizel J, Alyamani O, et al. Does inferior vena cava
290(20):2713–2720 respiratory variability predict fluid responsiveness in spontane-
12 Harvey S, Harrison DA, Singer M, et al; PAC-Man study collabora- ously breathing patients? Crit Care 2015;19:400
tion. Assessment of the clinical effectiveness of pulmonary artery 33 Monnet X, Rienzo M, Osman D, et al. Passive leg raising predicts
catheters in management of patients in intensive care (PAC-Man): fluid responsiveness in the critically ill. Crit Care Med 2006;34
a randomised controlled trial. Lancet 2005;366(9484):472–477 (05):1402–1407

Avicenna Journal of Medicine © 2023. The Author(s).

Monitoring Macro- and Microcirculation in the Critically Ill Muzaffar et al.

34 Monnet X, Teboul JL. Passive leg raising. Intensive Care Med 2008; 55 Pino RM, Singh J. Appropriate clinical use of lactate measure-
34(04):659–663 ments. Anesthesiology 2021;134(04):637–644
35 Cavallaro F, Sandroni C, Marano C, et al. Diagnostic accuracy of 56 Kruse O, Grunnet N, Barfod C. Blood lactate as a predictor for in-
passive leg raising for prediction of fluid responsiveness in adults: hospital mortality in patients admitted acutely to hospital: a
systematic review and meta-analysis of clinical studies. Intensive systematic review. Scand J Trauma Resusc Emerg Med 2011;19:74
Care Med 2010;36(09):1475–1483 57 Bakker J, Nijsten MW, Jansen TC. Clinical use of lactate monitoring
36 De Backer D, Pinsky MR. Can one predict fluid responsiveness in in critically ill patients. Ann Intensive Care 2013;3(01):12
spontaneously breathing patients? Intensive Care Med 2007;33 58 Fuller BM, Dellinger RP. Lactate as a hemodynamic marker in the
(07):1111–1113 critically ill. Curr Opin Crit Care 2012;18(03):267–272
37 Alvarado Sánchez JI, Caicedo Ruiz JD, Diaztagle Fernández JJ, 59 Jansen TC, van Bommel J, Schoonderbeek FJ, et al; LACTATE study
Amaya Zuñiga WF, Ospina-Tascón GA, Cruz Martínez LE. Predic- group. Early lactate-guided therapy in intensive care unit
tors of fluid responsiveness in critically ill patients mechanically patients: a multicenter, open-label, randomized controlled trial.
ventilated at low tidal volumes: systematic review and meta- Am J Respir Crit Care Med 2010;182(06):752–761
analysis. Ann Intensive Care 2021;11(01):28 60 Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline
38 Mohammed I, Phillips C. Techniques for determining cardiac JAEmergency Medicine Shock Research Network (EMShockNet)
output in the intensive care unit. Crit Care Clin 2010;26(02): Investigators. Lactate clearance vs central venous oxygen satura-
355–364 tion as goals of early sepsis therapy: a randomized clinical trial.
39 Teboul JL, Saugel B, Cecconi M, et al. Less invasive hemodynamic JAMA 2010;303(08):739–746
monitoring in critically ill patients. Intensive Care Med 2016;42 61 Bakker J, Postelnicu R, Mukherjee V. Lactate: where are we now?
(09):1350–1359 Crit Care Clin 2020;36(01):115–124
40 Laupland KB, Bands CJ. Utility of esophageal Doppler as a mini- 62 Reinhart K, Bloos F. The value of venous oximetry. Curr Opin Crit
mally invasive hemodynamic monitor: a review. Can J Anaesth Care 2005;11(03):259–263
2002;49(04):393–401 63 Marx G, Reinhart K. Venous oximetry. Curr Opin Crit Care 2006;12
41 Singer M. Oesophageal Doppler. Curr Opin Crit Care 2009;15(03): (03):263–268
244–248 64 Kandel G, Aberman A. Mixed venous oxygen saturation. Its role in
42 Monnet X, Teboul JL. Transpulmonary thermodilution: advan- the assessment of the critically ill patient. Arch Intern Med 1983;
tages and limits. Crit Care 2017;21(01):147 143(07):1400–1402
43 Pearse RM, Ikram K, Barry J. Equipment review: an appraisal of 65 Reinhart K, Kuhn HJ, Hartog C, Bredle DL. Continuous central
the LiDCO plus method of measuring cardiac output. Crit Care venous and pulmonary artery oxygen saturation monitoring in
2004;8(03):190–195 the critically ill. Intensive Care Med 2004;30(08):1572–1578
44 Linton RA, Jonas MM, Tibby SM, et al. Cardiac output measured by 66 Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy
lithium dilution and transpulmonary thermodilution in patients Collaborative Group. Early goal-directed therapy in the treatment
in a paediatric intensive care unit. Intensive Care Med 2000;26 of severe sepsis and septic shock. N Engl J Med 2001;345(19):
(10):1507–1511 1368–1377
45 Manecke GR. Edwards FloTrac sensor and Vigileo monitor: easy, 67 Peake SL, Delaney A, Bailey M, et al; ARISE Investigators ANZICS
accurate, reliable cardiac output assessment using the arterial Clinical Trials Group. Goal-directed resuscitation for patients
pulse wave. Expert Rev Med Devices 2005;2(05):523–527 with early septic shock. N Engl J Med 2014;371(16):1496–1506
46 Cannesson M, Musard H, Desebbe O, et al. The ability of stroke 68 ProCESS Investigators Yealy DM, Kellum JA, Huang DT, et al. A
volume variations obtained with Vigileo/FloTrac system to moni- randomized trial of protocol-based care for early septic shock. N
tor fluid responsiveness in mechanically ventilated patients. Engl J Med 2014;370:1683–1693PubMed
Anesth Analg 2009;108(02):513–517 69 Mouncey PR, Osborn TM, Power GS, et al; ProMISe Trial Inves-
47 Berton C, Cholley B. Equipment review: new techniques for tigators. Trial of early, goal-directed resuscitation for septic shock.
cardiac output measurement–oesophageal Doppler, Fick princi- N Engl J Med 2015;372(14):1301–1311
ple using carbon dioxide, and pulse contour analysis. Crit Care 70 Mallat J, Lemyze M, Tronchon L, Vallet B, Thevenin D. Use of
2002;6(03):216–221 venous-to-arterial carbon dioxide tension difference to guide
48 Cholley BP, Payen D. Noninvasive techniques for measurements of resuscitation therapy in septic shock. World J Crit Care Med
cardiac output. Curr Opin Crit Care 2005;11(05):424–429 2016;5(01):47–56
49 Marik PE. Noninvasive cardiac output monitors: a state-of the-art 71 Ospina-Tascón GA, Hernández G, Cecconi M. Understanding the
review. J Cardiothorac Vasc Anesth 2013;27(01):121–134 venous-arterial CO2 to arterial-venous O2 content difference
50 Brown JM. Use of echocardiography for hemodynamic monitor- ratio. Intensive Care Med 2016;42(11):1801–1804
ing. Crit Care Med 2002;30(06):1361–1364 72 Ait-Oufella H, Lemoinne S, Boelle PY, et al. Mottling score predicts
51 Griffee MJ, Merkel MJ, Wei KS. The role of echocardiography in survival in septic shock. Intensive Care Med 2011;37(05):
hemodynamic assessment of septic shock. Crit Care Clin 2010;26 801–807
(02):365–382 73 Dumas G, Lavillegrand JR, Joffre J, et al. Mottling score is a strong
52 Soliman-Aboumarie H, Breithardt OA, Gargani L, Trambaiolo P, predictor of 14-day mortality in septic patients whatever vaso-
Neskovic AN. How-to: focus cardiac ultrasound in acute settings. pressor doses and other tissue perfusion parameters. Crit Care
Eur Heart J Cardiovasc Imaging 2022;23(02):150–153 2019;23(01):211
53 Kanji HD, McCallum J, Sirounis D, MacRedmond R, Moss R, Boyd 74 Hernández G, Ospina-Tascón GA, Damiani LP, et al; The ANDROM-
JH. Limited echocardiography-guided therapy in subacute shock EDA SHOCK Investigators and the Latin America Intensive Care
is associated with change in management and improved out- Network (LIVEN) Effect of a resuscitation strategy targeting
comes. J Crit Care 2014;29(05):700–705 peripheral perfusion status vs serum lactate levels on 28-day
54 Atkinson PR, Milne J, Diegelmann L, et al. Does point-of-care mortality among patients with septic shock: the ANDROMEDA-
ultrasonography improve clinical outcomes in emergency depart- SHOCK randomized clinical trial. JAMA 2019;321(07):654–664
ment patients with undifferentiated hypotension? An interna- 75 Zampieri FG, Damiani LP, Bakker J, et al. Effects of a resuscitation
tional randomized controlled trial from the SHoC-ED strategy targeting peripheral perfusion status versus serum
investigators. Ann Emerg Med 2018;72(04):478–489 lactate levels among patients with septic shock. A Bayesian

Avicenna Journal of Medicine © 2023. The Author(s).

 Monitoring Macro- and Microcirculation in the Critically Ill Muzaffar et al.

reanalysis of the ANDROMEDA-SHOCK trial. Am J Respir Crit Care 78 Merz T, Denoix N, Huber-Lang M, Singer M, Radermacher P,
Med 2020;201(04):423–429 McCook O. Microcirculation vs. mitochondria-what to target?
76 Guven G, Hilty MP, Ince C. Microcirculation: physiology, patho- Front Med (Lausanne) 2020;7:416
physiology, and clinical application. Blood Purif 2020;49(1- 79 Dubin A, Henriquez E, Hernández G. Monitoring peripheral perfu-
2):143–150 sion and microcirculation. Curr Opin Crit Care 2018;24(03):173–180
77 Ince C. Hemodynamic coherence and the rationale for moni- 80 De Backer D, Hollenberg S, Boerma C, et al. How to evaluate the
toring the microcirculation. Crit Care 2015;19(Suppl 3):S8 microcirculation: report of a round table conference. Crit Care
PubMed 2007;11(05):R101

Avicenna Journal of Medicine © 2023. The Author(s).