Month: October 2016

[Clinical Art][Circulation] Hemodynamic Monitoring – Tissue Oxygenation and Cardiac Output

October 24, 2016 Cardiology, Clinical Skills, Critical Care, Hemodynamics No comments , , , , , , , , , , , , , , , ,

Key Points

  • No hemodynamic monitoring device will improve patient outcome unless coupled to a treatment, which itself improves outcome.
  • Low venous oxygen saturations need not mean circulatory shock but do imply circulatory stress, as they may occur in the setting of hypoxemia, anemia, exercise, as well as circulatory shock.
  • There is no "normal" cardiac output, only one that is adequate or inadequate to meet the metabolic demands of the body. Thus, targeting a specific cardiac output value without reference to metabolic need, or oxygen-carrying capacity of the blood, is dangerous.
  • Cardiac output is estimated, not measured, by all devices routinely used in bedside monitoring (though we shall call it measured in this text).
  • Cardiac output estimates using arterial pulse pressure contour analysis cannot be interchanged among devices and all suffer to a greater or lesser extent by changes of peripheral vasomotor tone commonly seen in the critically ill.
  • Since metabolic demands can vary rapidly, continuous or frequent measures of cardiac output are preferred to single or widely spaced individual measures.
  • Integrating several physiologic variables in the assessment of the adequacy of the circulation usually gives a clearer picture than just looking at one variable.
  • Integrating cardiac output with other measures, like venous oxygen saturation, can be very helpful in defining the adequacy of blood flow.

Clinical Judgement of Hypoperfusion

Tissue hypoperfusion is a clinical syndrome, thus the presentation depends on which organ(s)/organ system(s) are being hypoperfused.

Table 1 Common Clinical Presentations of Tissue Hypoperfusion
Brain/CNS altered mental status, confusion
Pulmonary system dyspnea on exertion
Gastrointestinal tract slowed bowel function, abdominal discomfort, nausea/vomiting, anorexia
Renal system decrease urine output, increased serum creatinine
Hepatic system increased transaminases
Extremities/constitutional cool extremities, poor capillary refill, general fatigue/malaise
SvO2 in the case of normal CaO2 and VO2, SvO2 would decrease
Serum lactate level elevated serum lactate level

Note that some factors other than tissue hypoperfusion are able to cause the "hypoperfusion"-like presentation(s) which are similar as the one discussed above. For example, in the sepsis, the elevated levels of lactic acid might be caused by reasons other than hypoperfusion. In another case, the low urine output of a patient might be caused by the patient's ESRD per se rather than the low perfusion of kidneys. Also, if the patient had hypoglycemia or severe hyponatremia (which cause the neurons to edema), he or she would definitely lose the consciousness (differential diagnosis? or differential clinical judgement).

Tissue Oxygenation

Although mean artieral pressure (MAP) is a primary determinant of organ perfusion, normotension can coexist with circulatory shock.

Since metabolic demand of tissues varies by external (exercise) and internal (basal metabolism, digestion, fever) stresses, there is no "normal" cardiac ouput that the bedside caregiver can target and be assured of perfusion adequacy. Cardiac output is either adequate or inadequate to meet the metabolic demands of the body. Thus, although measures of cardiac output are important, their absolute values are relevant only in the extremes and when targeting specific clinical conditions, such as preoptimization therapy.

How then does one know that circulatory sufficiency is present or that circulatory shock exists? Clearly, since arterial pressure is the primary determinant of organ blood flow, systemic hypotension (i.e., mean arterial pressure <60 mm Hg) must result in tissue hypotension. Organ perfusion pressure can be approximated as mean arterial pressure (MAP) relative to tissue or outflow pressure. But, if intracranial pressure or intra-abdominal pressure increases, then estimating cerebral or splanchnic perfusion pressure using MAP alone will grossly overestimate organ perfusion pressure. In addition, baroreceptors in the carotid body and aortic arch increase vasomotor tone to keep cerebral perfusion constant if flow decreases, and the associated increased systemic sympathetic tone alters local vasomotor tone to redistribute blood flow away from more efficient O2 extracting tissues to sustain MAP and global O2 consumption (VO2) in the setting of inappropriately decreasing DO2. Thus, although systemic hypotension is a medical emergency and reflects severe circulatory shock, the absence of systemic hypotension does not ensure that all tissues are being adequately perfused.

  • Arterial pulse oximetry: SaO2
  • Venous Oximetry: ScvO2, SvO2
  • Tissue Oximetry
  • StO2 vascular occlusion test

Arterial Pulse Oximetry


Arterial blood O2 saturation (SaO2) can be estimated quite accurately at the bedside using pulse oximetry. Routinely, pulse oximeters are placed on a finger for convenience sake. However, if no pulse is sensed, then the readings are meaningless. Such finger pulselessness can be seen with peripheral vasoconstriction associated with hypothermia, circulatory shock, or vasospasm. Central pulse oximetry using transmission technology can be applied to the ear or bridge of the nose and reflectance oximetry can be applied to the forehead, all of which tend to retain pulsatility if central pulsatile flow is present. Similarly, during cardiopulmonary bypass when arterial flow is constant, pulse oximetry is inaccurate. The primary important functions of SaO2 are summarized below.

  • SaO2 is routinely used to identify hypoxemia. Hypoxemia is usually defined as an SaO2 of <90% (PaO2 of <60 mm Hg).
  • SaO2 is also used to identify the causes of hypoxemia. The most common causes of hypoxemia are ventilation-perfusion (V/Q) mismatch (we will discuss this topic in the clinical art of respiratory medicine) and shunt. With V/Q mismatch alveolar hypoxia ocurs in lung regions with increased flow relative to ventilation, such that the high blood flow rapidly depletes alveolar O2 before the next breath can refresh it. Accordingly, this process readily lends itself to improve oxygenation by increasing FiO2 and minimizing regional alveolar hypoxia. Collapsed or flooded lung units will not alter their alveolar O2 levels by this maneuver and are said to be refractory to increase in FiO2. Accordingly, by measuring the SaO2 response to slight increases in FiO2 one can separate V/Q mismatch (shuntlike states) from shunt (absolute intrapulmonary shunt, anatomical intracardiac shunts, alveolar flooding, atelectasis [collapse]). One merely measures SaO2 while switching from room air FiO2 of 0.21 to 2 to 4 L/min nasal cannula (FiO2 ~0.3). Importantly, atelectatic lung units (collapse alveoli) should be recruitable by lung expansion whereas flooded lung units and anatomical shunts should not. Thus, by performing sustained deep inspirations and having the patient sit up and take deep breaths one should be able to separate easily recruitable atelectasis from shunt caused by anatomy and alveolar flooding. Sitting up and taking deep breaths is a form of exercise that may increaes O2 extraction by the tissues, thus decreasing SvO2. The patient with atelectasis will increase alveolar ventilation increasing SaO2 despite the decrease in SvO2, whereas the patient with unrecruitable shunt will realize a fall in SaO2 as the shunted blood will carry the lower SvO2 to the arterial side. Summary: SaO2 is used to identify V/Q mismatch and shunt, atelectasis and anatomical/flooding shunt, respectively.
  • Detection of volume responsiveness. Recent interest in the clinical applications of heart-lung interactions has centered on the effect of positive-pressure ventilation on venous return and subsequently cardiac output. In those subjects who are volume responsive, arterial pulse pressure, as a measure of left ventricular (LV) stroke volume, phasically decreases in phase with expiration, the magnitude of which is proportional to their volume responsiveness. Since the pulse oximeter's plethysmographic waveform is a manifestation of the arterial pulse pressure, if pulse pressure varies from beat-to-beat so will the plethysmographic deflection, which can be quantified. Several groups have documented that the maximal variations in pulse oximeter's plethysmographic waveform during positive-pressure ventilation covaries with arterial pulse pressure variation and can be used in a similar fashion to identify those subjects who are volume responsive.

PS: Intrapulmonary shunt fraction is increased in the following situations:

  • When the small airways are occluded; e.g., asthma
  • When the alveoli are filled with fluid; e.g., pulmonary edema, pneumonia
  • When the alveoli collapse; e.g., atelectasis
  • When capillary flow is excessive; e.g., in nonembolized regions of the lung in pulmonary embolism

Venous Oximetery


SvO2 is the gold standard for assessing circulatory stress. A low SvO2 defines increased circulatory stress, which may or may not be pathological.

To the extent that SaO2 and hemoglobin concentration result in an adequate arterial O2 content (CaO2), then ScvO2 and SvO2 levels can be taken to reflect the adeuqacy of the circulation to meet the metabolic demands of the tissues. This is the truth. But attention must be paid that one needs to examine the determinants of DO2, global oxygen consumption (VO2), and effective O2 extraction by the tissues before using ScvO2, or SvO2 as markers of circulatory sufficiency.

Since VO2 must equal cardiac output times the difference in CaO2 and mixed venous O2 content (CvO2) (VO2 = CO x [CaO2 – CvO2]),if CaO2 remains relatively constant then CvOwill vary in proportion to cardiac output (CvO2 = CaO2 – VO2 / CO). Since the amount of O2 dissolved in the plasma is very small, the primary factor determining changes in CvO2 will be SvO2. Thus, SvO2 correlates well with the O2 supply-to-demand ratio.

Several relevant conditions may limit this simple application of SvO2 in assessing circulatory sufficiency and cardiac output (Table 32-1). If VO2 were to increase (as occurs with exercise), hemoglobin-carrying capacity to decrease (as occurs with anemia, hemoglobinopathies, and severe hemorrhage), or SaO2 to decrease (as occurs with hypoxic respiratory failure), then for the same cardiac output, SvO2 would also decrease. Similarly, if more blood flows through nonmetabolically extracting tissues as occurs with intravascular shunts, or mitochondrial dysfunction limits O2 uptake by tissues, then SvO2 will increase for a constant cardiac output and VO2 even though circulatory stress exists and may cause organ dysfunction.

Table 32-1 Limitations to the Use of SvO2 to Trend Circulatory Sufficiency
Independent events that decrease SvO2 independent of cardiac output
Event Process
Exercise Increased VO2
Anemia Decreased O2-carrying capacity
Hypoxemia Decreased arterial O2 content
Independent events that increase SvO2 independent of cardiac output
Event Process
Sepsis Microvascular shunting
End-stage hepatic failure Macrovascular shunting
Carbon monoxide poisoning Mitochondrial respiratory chain inhibition


SvO2 and ScvO2 covary in the extremes but may change in opposite directions as conditions change.

ScvO2 threshold values to define circulatory stress are only relevant if low (a high ScvO2 is nondiagnostic).

ScvO2 does not sample true mixed venous blood and most vena cacal blood flow is laminar, thus if the tip is in one of these laminar flow sites it will preferentially report a highly localized venous drainage site O2 saturation. Clearly, the potential exists for spurious estimates of SvO2. Most central venous catheters are inserted from internal jugular or subclavian venous sites with their distal tip residing in the superior vena cava, usually about 5 cm above the right atrium. Thus, even if measuring a mixed venous sample of blood at that site, ScvO2 reflects upper body venous blood while ignoring venous drainage from the lower body. Accordingly, ScvO2 is usually higher than SvO2 by 2% to 3% in a sedated resting patient because cerebral O2 consumption is minimal and always sustained above other organs.

Tissue Oximetry

Tissue O2 saturation (StO2) varies little until severe tissue hypoperfusion occurs.

StO2 coupled to a VOT allows one to diagnose circulatory stress before hypotension develops.

The most currently used technique to measure peripheral tissue O2 saturation (StO2) is near-infrared spectroscopy (NIRS). NIRS is a noninvasive technique based in the differential absorption properties of oxygenated and deoxygenated hemoglobin to assess the muscle oxygenation. Although there is a good correlation between the absolute StO2 value and some other cardiovascular indexes, the capacity of the baseline StO2 values to identify impending cardiovascular insufficiency is limited (sensitivity, 78%; specificity, 39%).

screen-shot-2016-10-24-at-12-52-46-pmHowever, the addition of a dynamic vascular occlusion test (VOT) that induces a controlled local ischemic challenge with subsequent release has been shown to markedly improve and expand the predictive ability of StO2 to identify tissue hypoperfusion. The VOT StO2 response derives from the functional hemodynamic monitoring concept, in which the response of a system to a predetermined stress is the monitored variable. The rate of DeO2 is a function of local metabolic rate and blood flow distribution. If metabolic rate is increased by muscle contraction, the DeO2 slope increases, whereas in the setting of altered blood flow distribution the rate of global O2 delivery is decreased. Sepsis decreases the DeO2. The ReO2 slope is dependent on how low StO2 is at the time of release, being less steep if StO2 is above 40% than if the recovery starts at 30%, suggesting that the magnitude of the ischemic signal determines maximal local vasodilation. This dynamic technique has been used to assess circulatory sufficiency in patients with trauma, sepsis and during weaning from mechanical ventilation.

Cardiac Output

There is no "normal" cardiac output (QT).

QT is either adequate or inadequate

Other measures besides QT define adequacy

Shock reflects an inadequate DO2 to meet the body's metabolic demand and cardiac output is a primary determinant of DO2. Indeed, except for extreme hypoxemia and anemia, most of the increase in DO2 that occurs with resuscitation and normal biological adaptation is due to increasing cardiac output. Since cardiac output should vary to match metabolic demands, there is no "normal" cardiac output. Cardiac output is merely adequate or inadequate to meet the metabolic demands of the body. Measures other than cardiac output need to be made to ascertain if the measured cardiac output values are adequate to meet metabolic demands. The two most common catheter-related methods of estimating cardiac output are indicator dilution and arterial pulse contour analysis.

Indicator Dilution

The principle of indicator dilution cardiac output measures is that if a small amount of a measurable substance (indicator) is ejected upstream of a sampling site and then thoroughly mixed with the passing blood then measured continuously downstream, the area under the time-concentration curve will be inversely proportional to flow based on the Stewart-Hamilton equation. The greater the indicator level, the slower the flow, and the lower the indicator level, the higher the flow. The most commonly used indicator is temperature (hot or cold) because it is readily available and indwelling thermistors can be made to be highly accurate.

Arterial Pulse Contour Analysis

screen-shot-2016-10-24-at-8-44-47-pmThe primary determinants of the arterial pulse pressure are LV stroke volume and central arterial compliance (pulse pressure ≈ SV / C). Compliance is a function of size, age, sex, and physiological inputs, like sympathetic tone, hypoglycemia, temperature, and autonomic responsiveness of the vasculature. Hamilton and Remington explored this interaction over 50 years ago developing the overall approach used by most of the companies who attempt to report cardiac output from the arterial pulse. The main advantage of these arterial pressure-based cardiac output monitoring systems over indicator dilution measurements is their less invasive nature.

However, since all these devices presume a fixed relation between pressure propagation alnog the vascular three and LV stroke volume, if vascular elastance (reciprocal of compliance) changes, then these assumptions may become invalid. Thus, a major weakness of any pulse contour device is the potential for artificial drift in reported values if major changes in arterial compliance occur.

[Clinical Art][Circulation] Interpretation of Hemodynamic Waveforms

October 20, 2016 Cardiology, Critical Care, EKG/ECG, Hemodynamics, Mechanical Ventilation No comments , , , , , , , , , , , , , , , , , , , , , , , , ,

1st_ceb_insigniaBasic Knowledge

Mechanism of Hemodynamic Monitoring

The rapidly occurring events (represent mechanical forces) of cardiac chambers and vessels during cardaic cycle require conversion to an electrical signal to be transmitted and subsequently translated into an interpretable, graphic format. The pressure transducer is the essential component that translates the mechanical forces to electrical signals. The transducer may be located at the tip of the catheter (micromanometer) within the chamber or, more commonly, the pressure transducer is outside of the body, and a pressure waveform is transmitted from the catheter tip to the transducer through a column of fluid. These transducers consist of a diaphragm or membrane attached to a strain-gauge-Wheatstone bridge arrangement. When a fluid wave strikes the diaphragm, an electrical current is generated with a magnitude dependent on the strength of the force that deflects the membrane. The output current is amplified and displayed as pressure versus time.

Clinical Art

Pre-operations Before Recording

Old generations of transducers required calibration against a mercury manometer; fortunately, the factory-calibrated, disposable, fluid-filled transducers in clinical use today no longer need this. Table-mounted transducers do require balancing or "zeroing," which refers to the establishment of a reference point for subsequent pressure measurements. The reference or "zero" position should be determined before any measurements are made. By convention, it is defined at the patient's midchest in the anteroposterior dimension at the level of the sternal angle of Louis (fourth intercostal space). This site is an estimation of the location of the right atrium and is also known as the phlebostatic axis. A table-mounted transducer is placed at this level and the stopcock is opened to air (atmospheric pressure) and set to zero by the hemodynamic system. The system is now ready for presure measurements. It is important to emphasize that the pre-operation of the hemodynamic monitor is very important, because if the "zero" level is not properly set and the transducer not appropriately balanced, the hemodynamic data recorded would be misleading, even fatal.

Interpretation of pressure waveforms requires a consistent and systematic approach in Table 2-1. Careful scrutiny of the waveform ensures a high-fidelity recording without over- or under-damping. Each pressure event should be timed with EKG.

Table 2-1 A Systematic Approach to Hemodynamic Interpretation
1.Establish the zero level and balance transducer
2.Confirm the scale of the recording
3.Collect hemodynamics in a systematic method using established protocols
4.Critically assess the pressure waveforms for proper fidelity
5.Carefully time pressure events with the EKG
6.Review the tracings for common artifacts

At present, in the clinical setting, 3 pressure waveforms can be obtained at bedside with invasive hemodynaic monitoring devices (central venous cathether/CVC and pulmonary artery catheter/PAC), including right atrial pressure/Prapulmonary artery pressure/Ppa, and pulmonary artery wedge pressure/Ppw. The pressurewave form is recorded along with a synchronized EKG.

Normal Pressure Waveform

Atrial Pressure

The goal of measuring the atrial pressure is to measure the pressure in the ventricles  at the end of diastole, to idenfify a "filling pressure". The goal for any atrial pressure measurement is to obtain the measurement at the every end of diastole, when the atrial pressure is closest to the ventricular pressure. The normal Pra is 2-8 mm Hg and is characterized by a and v waves and x and y descents. The causes of a, v waves and x, y descents are listed below.

PS: The Rationale Reason for the Formation of Pra waveform

a wave represents the pressure rise within the right atrium due to atrial contraction follows the P wave on the EKG by about 80 msec
descet represents the pressure decay following the a wave and reflect both atrial relaxation and the sudden downward motion of the atrioventricular junction that occurs because of early ventricular systole  
c wave is sometimes observed after the a wave and is due to the sudden motion of the tricuspid annulus toward the right atrium at the onset of ventricular systole the c wave follows the a wave by the same time as the PR interval on the EKG
v wave when the tricuspid valve is closed, the pressure rise responsible for the v wave is due to passive venous filling of the atrium, represent atrial diastole. the peak of the right atrial v wave corresponds with the end of T wave on the surface EKG; the ORS alawys appears before the v wave is produced
y wave is due to rapid emptying of the right atrium when the tricuspid valve opens  

Atrial waveform interpretation in detail

v wave

The atrial pressures initially increase during systole as the contracting ventricles return blood to the atria, refilling the upper chambers. This rise in the atrial pressure is identified as the "v" wave. The upstroke of the v wave is the rise in atrial pressure as a result of atrial filling. Because it is produced as a result of ventricular contraction, its location is relative to the QRS on the EKG. Ejection eventually leads to the return of blood to the atria (left ventricular contraction refills the right atrium and produces the right atrial v wave; right ventricular contraction refills the left atrium and produces the left atrial v wave). Thus, the QRS causes the v wave, however, the QRS always appears before the v wave is produced.


The normal pulmonary artery systolic pressure/Ppas is 15-30 mm Hg, the normal diastolic pressure/Ppad is 4-12 mm Hg, and the mean 9-18 mm Hg. The components pulmonary artery pressure include a rapid rise in pressure, systolic peak, a pressure decay associated with a well-defined dicrotic notch from pulmonic valve closure, and a diastolci trough.

PA and arterial pressure waveforms have similar morphology. Systole begins with the opening of the pulmonic valves. Prior to opening of the pulmonary valve, the pulmonary artery pressure is very low (the pulmonary vascular system does not need a high pressure system to perfuse). As the ventricles contact, they eject blood into the pulmonary artery. This causes an immediate rise in the arterial pressure. As blood enters the great vessels, the pressure rise quickly and steadily, producing a steep vertical rise. Late in systole, the rate of ejection slows as the pressure gradient between the right ventricle and pulmonary artery narrows. Although blood is still moving from the ventricle to the great vessels, the rate of movement is slowed to the point where the pressure begins to decline. This cause the early downslope in the arterial tracing that represents this period of reduced ejection. Like the right atrial v wave, the pulmonary artery systolic wave typically coincides with the T wave of the EKG.

Later, the ventricle begins to relax, causing the ventricular pressure to drop below the pressure in great vessels. This causes the pulmonic valves to close, producing a small rise in the PA pressure, known as the dicrotic notch. Following closure of the semi-lunar valves, the pulmonary artery continues to fall as blood leaves the great vessels to perfuse the tissues and lungs.


The normal mean pulmonary artery wedge pressure/Ppw is obtained when the inflated catheter obstructs forward flow within a branch of the pulmonary artery, creating a static column of blood between the tip of the catheter and the j point in the pulmonary venous bed where it intersects with flowing blood. The Ppw tracing contains the same sequence of waves and descents as the Pra tracing. However, when referenced to the ECG, the waves and descents of the Ppw will be seen later than those of the Pra, because the pressure waves from the left atrium must travel back through the pulmonary vasculature and a longer length of catheter. Therefore, in the Ppw tracing, the a wave usually appears after the QRS complex, and the v wave is seen after the T wave.
screen-shot-2016-10-19-at-2-19-49-pmInterpretation of CVP and PAWP measurements

Correlation to the EKG

The easiest wave to evaluate an atrial tracing is to first locate the v wave. Generally, it will appear immeidately after the peak of T wave on a CVP waveform, however, it will be 80-120 ms after the T wave on a PAWP tracing. You can generally identify the v wave by ruling out other waves. It must be after the peak of the T wave. Once the v wave is identified, the a and c can be determined.

Observe the EKG rhythm. If the patient has a sinus rhythm, an a wave should be present. The a should be in the PR interval for a CVP. It is later in the PAWP, appearing within or even afte QRS. If the patient does not have a P wave, the a wave will be absent. If the P wave is not synchronized to the QRS, very large a wave may be present. These large a waves may appear as one very large wave during a cardiac cycle. The large a waves are called cannon a waves. They are actually exaggerated atrial pressures that occur when the atria contract against a closed AV valve, adding to the pressure that is already being generated due to the c or v wave.

If present, the c wave is generally within the QRS for a CVP. It will be after the QRS for a PAWP.

Where to Measure CVP and PAWP

At the very end of ventricular diastole, the atrial pressure equilibrates with the ventricular pressure, at the very end of ventricular filling. Measurement of the atrial pressure at the end of diastole provides the best opportunity to capture ventricular filling pressure. The location on the atrial pressure wave that best reflects end-diastolic pressure is the point just prior to the c wave. However, c wave is often absent or difficult to find, espeically true in the PAWP waveform, which is subject to considerable movement artifact from right ventricular systole and breathing. If we cannot use the mehtod based on c wave to measure the filling pressure, instead we can use other two ways to capture the filling pressure, where the second method for identification of the end-diastolic pressure is to take the mean of the highest and lowest a wave pressure; and the thrid method is used if the a wave is hard to interpret or absent, that is, the end-diastolic pressure can be estimated by identifying the Z point. Draw a line from the end of the QRS to the atrial tracing. The point where the line intersects with the waveform is the Z line. Note that for a PAWP waveform the Z line should be estimated as 0.08-0.12 seconds to the left of the end of the QRS (Z point is delayed 0.08-0.12 seconds from the QRS on the PAWP).

Respiratory Influences on Hemodynamic Data: Transmural Pressure

The Pra and Ppw are used as surrogates for RV and LV filling pressure (so the preload), but remember that when evaluating the patient's preload the end-diastolic volume of the ventricles should also be included in the interpretation. Here in this section we focus our discussion on the respiratory influecnes on the recorded hemodynamic data. OK, it is the transmural (intravascular minus pleural) pressure that represents the distending pressure for cardiac filling. During normal breathing, Ppl is slightly negative at end-expiration and intrathoracic vascular pressures measured at this point in respiratory cycle provide the best estimate of transmural pressure. Either a strip recording or the cursor method should be used to define the end-expiratory pressure.

One error is the assumption that during mechanical ventilation the lowest point in the pressure tracing reflects end expiration. While this is true during controlled ventilation, inspiratory efforts that trigger mechanical breaths produce a nadir in the pressure tracing. Identification of end expiration in the Ppw tracing is aided by the knowledge that expiration is usually longer than inspiration, two exceptions being marked tachypnea and inverse-ratio ventilation. Identification of end expiration from the pressure tracing should not be difficult when interpreted in relationship to the patient's ventilatory pattern. When confusion occurs, a simultaneous airway pressure tracing may be used.

The Pra and Ppw will overestimate transmural pressure if intrathoracic pressure is positive at end expiration. This can occur from an increase in end-expiratory lung volume due to applied positive end-expiratory pressure (PEEP) or auto-PEEP, or from increased intra-abdominal pressure due to active expiration or intra-abdominal hypertension.

Common Errors and Artifacts

screen-shot-2016-10-20-at-7-58-42-pmMost errors in the collection and interpretation of hemodynamic data are listed in Table 2-2.

Probably the most commonly observed artifacts relate to an improper degree of damping. The over-damped tracing indicates the presence of excessive friction absorbing the force of the pressure wave somewhere in the line from the catheter tip to the transducer. The tracing lacks proper fidelity and appears smooth and rounded because of loss of frequency response. This will result in loss of data and will falsely lower peak pressures. Typically, the dicrotic notch on the aortic or pulmonary artery waveforms is absent, and the right atrial or PAPW waveforms will lack distinct a and v waves.

Under-damping causes overshoot or ring artifact. This artifact typically appears as one or more narrow "spikes" overshooting the true pressure during the systolic pressure rise with similar, negatively directed waves overshooting the true pressure contour during the downstroke. This artifact may lead to overestimation of the peak pressure and underestimation of the pressure nadir. Tiny air bubbles that oscillate rapidly back and forth, transmitting energy back to the transducer, cause this artifact. Flushing the catheter or transducer often corrects this artifact; alternatively, introduction of a filter to the hemodynamic system may be necessary to eliminate this artifact.

Related to overshoot or ring artifact is catheter whip or fling artifact. This artifact is created by acceleration of the fluid within the catheter from rapid catheter motion and is commonly seen with balloon-tipped catheters in hyperdynamic hearts or balloon-tipped catheters placed in the pulmonary artery with extraneous loops. Similar to ring artifact, catheter whip causes overestimation of the systolic pressure and underestimation of the diastolic pressure. This artifact is difficult to remedy; eliminating the extra loops or deflation of the balloon can improve the appearance and limit this artifact.

Catheter malposition creates several interesting artifacts.

[Endocrinology] The Agonist-Receptor Interaction and Pharmacodynamics of Thyroid Hormone

October 14, 2016 Endocrinology, Pharmacodynamics, Pharmacology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , ,

rs_634x1024-160907091929-634-justin-chambers-greys-anatomy-abcThyroid Hormone Receptors and Cellular Events

Thyroid hormone receptors are expressed in virtually all tissues and affect multiple cellular events. The cellular actions of thyroid hormones are mediated by multiple thyroid hormone receptor isoforms derived from 2 distinct genes (alpha and beta) encoding thyroid hormone receptors. The functional significance of the different isoforms has not yet been elucidated. Thyroid hormone recetpors are nuclear receptors intimately associated wtih chromatin. Thyroid hormone receptors are DNA-binding transcription factors that function as molecular switches in response to hormone binding. The hormone receptor can activate or repress gene transcription, depending on the promoter context and ligand-binding status. Unoccupied thyroid hormone receptors are bound to DNA thyroid hormone response elements and are associated with a complex of proteins containing corepressor proteins. Hormone binding to the receptor promotes corepressor dissociation and binding of a coactivator, leading to modulation of gene transcription. Thyroid hormone receptors bind the hormone with high affinity and specificity. They have low capacity but high affinity for T3. The majority (85%) of nuclear-bound thyroid hormone is T3, and approximately 15% is T4.

Thyroid hormones enter cells by a carrier-mediated energy-, temperature-, and Na+-dependent process. Several transporters have been identified to be involved in their entry into the cell, including those belonging to the sodium taurocholate cotransporting polypeptide (NTCP), the sodium-independent organic anion transporting polypeptide (OATP), L- and T-type amino acid transporters, and members of the monocarboxylate transporter family. Two transporters have been demonstrated to have particular specificity for thyroid hormone transport, the OATP1C1, which shows preference for T4 and the MCT8 which shows preference for T3. Mutations or deletions in the MCT8 gene have been linked to psychomotor retardation and thyroid hormone resistance, indicating their contribution to optimal thyroid hormone function.

Cellular Events of Thyroid Hormone

  • Transcription of cell membrane Na+/K+-ATPase, leading to an increase in oxygen consumption
  • Transcription of uncoupling protein, enhancing fatty acid oxidation and heat generation without production of adenosine triphosphate
  • Protein synthesis and degradation, contributing to growth and differentiation
  • Epinephrine-induced glycogenolysis, and insulin-induced glycogen synthesis and glucose utilization
  • Cholesterol synthesis and low-density lipoprotein receptor regulation

Physiologic Effects of Thyroid Hormone

Thyroid hormones are essential for normal growth and development; they control the rate of metabolism and hence the function of practically every organ in the body (remember that the thyroid hormone receptors are expressed in virtually all tissues). Their specific biologic effects vary from one tissue to another.

The effects of thyroid hormone are mediated primarily by the transcriptional regulation of target genes, and are thus known as genomic effects. Recently, it has become evident that thyroid hormones also exert nongenomic effects, which do not require modification of gene transcription. Some of these effects include stimulation of activity of Ca2+ adenosine triphosphatease (ATPase) at the plasma membrane and sarcoplasmic reticulum, rapid stimulation of the Na+/H+ antiporter, and increases in oxygen consumption. The nature of the receptors that mediate these effects and the signaling pathways involved are not yet completely elucidated. However, T3 exerts rapid effects on ion fluxes and electrophysiologic events, predominantly in the cardiovascular system.


Thyroid hormone is essential for bone growth and development through activation of osteoclast and osteoblast activities. Deficiency during childhood affects growth. In adults, excess thyroid hormone levels are associated with increased risk of osteoporosis.

Cardiovascular System

Thyroid hormone has cardiac inotropic and chronotropic effects, increases cardiac ouput and blood volume, and decreases systemic vascular resistance. These responses are mediated through thyroid hormone changes in gene transcription of several proteins including Ca2+-ATPase, phospholamban, myosin, beta-adrenergic receptors, adenylyl cyclase, guanine-nucleotide-binding proteins, Na+/Ca2+ exchanger, Na+/K+-ATPase, and voltage-gated potassium channels.


Thyroid hormone induces white adipose tissue differentiation, lipogenic enzymes, and intracellular lipid accumulation; stimulates adipocyte cell proliferation; stimulates uncoupling proteins; and uncouples oxidative phosphorylation. Hyperthyroidism enhances and hypothyroidism decreases lipolysis through different mechanisms. The induction of catecholamine-mediated lipolysis by thyroid hormones results from an increased beta-adrenoceptor number and a decrease in phosphodiesterase activity resulting in an increase in cAMP level and hormone-sensitive lipase activity.


Thyroid hormone regulates triglyceride and cholesterol metabolism, as well as lipoprotein homeostasis. Thyroid hormone also modulates cell proliferation and mitochondrial respiration.


Thyroid hormone regulates the synthesis of pituitary hormones, stimulates growth hormone production, and inhibits TSH.


Thyroid hormone controls expression of genes involved in myelination, cell differentiation, migration, and signaling. Thyroid hormone is necessary for axonal growth and development.

[Endocrinology] The Regulation and Clinical Art of Thyroid Hormones

October 13, 2016 Clinical Skills, Endocrinology, Pharmacokinetics, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

Thyroid Hormone Synthesis Process

The Source Components of Thyroid Hormone

Thyroglobulin (Tg), plays an important role in the synthesis and storage of thyroid hormone. Tg is a glycoprotein containing multiple tyrosine residues. It is synthesized in the thyroid follicular epithelial cells and secreted through the apical membrane into the follicular lumen, where it is stored in the colloid. A small amount of noniodinated Tg is also secreted through the basolateral membrane into the circulation. Although circulating levels of Tg can be detected under normal conditions, levels are elevated in diseases such as thyroiditis and Graves disease.

screen-shot-2016-10-13-at-3-48-24-pmTg can be considered a scaffold upon which thyroid hormone synthesis takes place. Once Tg is secreted into the follicular lumen, it undergoes major posttranslational modification during the production of thyroid hormones. At the apical surface of the thyroid follicular epithelial cells, multiple tyrosine residues of Tg are iodinated, followed by coupling of some of the iodotyrosine residues to form T3 and T4.

The iodide required for thyroid hormone synthesis is readily absorbed from dietary sources, primarily from iodized salt, but also from seafood and plants grown in soil that is rich in iodine. Following its absorption, iodide is confined to the extracellular fluid, from which it is removed primarily by the thyroid (20%) and the kidney (80%). The total excretion of iodide by the kidneys is approximately equal to daily intake. The balance between dietary intake and renal excretion preserves the total extracellular pool of iodide.

The Uptake and Iodination of Iodine

Iodine uptake

Iodide is concentrated in thyroid epithelial cells by an active, saturable, energy-dependent process mediated by a Na+/I symporter located in the basolateral plasma membrane of the follicular cell. Additional tissues that express the Na+/I symporter include the salivary glands, the gastric mucosa, the placenta, and the mammary glands. However, transport of iodine in these tissues is not under TSH regulation.

Iodine efflux (after the transformation from anion cation?, see below)

The iodination of Tg residues is a process that occurs at the apical membrane. Thus, once inside the cell, iodine must leave the follicular cell through apical efflux by an iodide-permeating mechanism consisting of a chloride-iodide transporting protein (iodide channel) located in the apical membrane of the thyroid follicular cell. The uptake, concentration, and efflux of iodide through the iodide channel are all a function of TSH-stimulated transepithelial transport of iodide.

Organification and coupling

In the follicular lumen, tyrosine residues of Tg are iodinated by iodine (I+; formed by oxidation of I by TPO). This reaction requires hydrogen peroxide, which is generated by a flavoprotein Ca++-dependent reduced nicotinamide adenine dinucleotide phosphate oxidase at the apical cell surface and serves as an electron acceptor in the reaction process. Iodine bonds to carbon 3 or to carbon 5 of the tyrosine residues on Tg in a process referred to as the organification of iodine. This iodination of specific tyrosines located on Tg yields monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT) residues that are enzymatically coupled to form triiodothyronine (T3) or tetraiodothyronine (T4). The coupling of iodinated tyrosine residues, either of 2 DIT residues or of 1 MIT and 1 DIT residues, is catalyzed by the enzyme thyroid peroxidase. Because not all of the iodinated tyrosine residues undergo coupling, Tg stored in the follicular lumen contains MIT and DIT residues as well as formed T3 and T4.

Release of Thyroid Hormone

The synthesis of thyroid hormone takes place in the colloid space. As mentioned previously, the apical surface of the follicular epithelial cell faces the colloid and not the interstitial space, and thus has no access to the bloodstream. Therefore, thyroid hormone release involves endocytosis of vesicles containing Tg from the apical surface of the follicular cell. The vesicles fuse with follicular epithelial phagolysosomes, leading to proteolytic digestion and cleavage of Tg. In addition to the thyroid hormones T4 and T3, the products of this reaction include iodinated tyrosine residues (MIT and DIT). MIT and DIT are deiodinated intracellularly, and iodide is transported by apical efflux into the follicular colloid space, where it is reused in thyroid hormone synthesis. T4 and T3 are released from the basolateral membrane into the circulation. The thyroid gland releases greater amounts of T4 than T3, so plasma concentrations of T4 are 40-fold higher than those of T3 (90 vs 2 nM). Most of the circulating T3 is formed peripherally by deiodination of T4, a process that involves the removal of iodine from carbon 5 on the outer ring of T4. Thus, T4 acts as a prohormone for T3. Although this deiodination occurs predominantly in the liver, some occurs in the thyroid follicular epithelial cell itself. This intrathyroidal deiodination of T4 is the result of TSH stimulation of the type I deiodinase.

Two additional facts regarding thyroid hormone activity and storage should be noted. First, at physiologic levels, T4, is relatively inactive because it possesses 100-fold lower affinity than T3 for binding to the thyroid receptor and does not enter the cell nucleus at high enough concentrations to occupy the ligand-binding site of the thyroid hormone receptor. Second, in contrast to most endocrine glands, which do not have storage capacity for their product, the thyroid gland is able to store 2-3 months' supply of thyroid hormones in the Tg pool.

Transport and Tissue Delivery of Thyroid Hormones

Once thyroid hormones are released into the circulation, most of them circulate bound to protein. Approximately 70% of T4 and T3 is bound to thyroid-binding globulin. Other protein involved in thyroid binding include transthyretin, which binds 10% of T4, and albumin, which binds 15% of T4 and 25% of T3. A small fraction of each hormone (0.03% of T4 and 0.3% of T3) circulates in its free form. This fraction of the circulating hormone pool is bioavailable and can enter the cell to bind to the thyroid receptor. Of the 2 thyroid hormones, T4 binds more tightly to binding proteins than T3 and thus has a lower metabolic clearance rate and a longer half-life (7 days) than T3 (1 day). The kidneys readily excrete free T4 and T3. Binding of thyroid hormones to plasma proteins ensures a circulating reserve and delays their clearance.

The release of hormone from its protein-bound form is in a dynamic equilibrium. Although the role of binding proteins in delivery of hormone to specific tissues remains to be fully understood, it is known that drugs such as salicylate may affect thyroid hormone binding to plasma proteins. The binding-hormone capacity of the individual can also be altered by disease or hormonal changes. The changes in total amount of plasma proteins available to bind thyroid hormone will impact the total amout of circulating thyroid hormone because of a constant homeostatic adjustment to changes in free hormone levels. A decrease in free thyroid hormone because of an increase in plasma-binding proteins will stimulate the release of TSH from the anterior pituitary, which will in turn stimulate the synthesis and release of thyroid hormone from the thyroid gland. In contrast, a decrease in binding-protein levels, with a resulting rise in free thyroid hormone levels, will suppress TSH release and decrease thyroid hormone synthesis and release. These dynamic changes occur throughout the life of the individual, whether in health or disease. Disruption in these feedback mechanisms will result in manifestations of excess or deficient thyroid hormone function.

Thyroid Hormone Metabolism

As already mentioned, the thyroid releases mostly T4 and very small amounts of T3, yet T3 has greater thyroid activity than T4. The main source of circulating T3 is peripheral deiodination of T4 by deiodinases (I, II and III). Approximately 80% of T4 produced by the thyroid undergoes deiodination in the periphery. Approximately 40% of T4 is deiodinated at carbon 5 in the outer ring to yield the more active T3, principally in liver and kidney. In approximately 33% of T4, iodine is removed from carbon 5 in the inner ring to yield reverse T3 (rT3). Reverse T3 has little or no biologic activity, has a higher metabolic clearance rate than T3, and has a lower serum concentration than T3. Following conversion of T4 to T3 or rT3, these are converted to T2,  a biologically inactive hormone. Therefore, thyroid hormone peripheral metabolism is a sequential deiodination process, leading first to a more active form of thyroid hormone (T3) and finally to complete inactivation of the hormone. Thus, loss of a single iodine from the outer ring of T4 produces the active hormone T3, which may either exit the cell, enter the nucleus directly, or possibly even both. Thyroid hormones can be excreted following hepatic sulfo- and glucuronide conjugation and biliary excretion.

Type I deiodinase catalyzes outer- and inner-ring deiodination of T4 and rT3. It is found predominantly in the liver, kidney, and thyroid. It is considered the primary deiodinase responsible for T4 to T3 conversion in hyperthyroid patients in the periphery. This enzyme also converts T3 to T2. The activity of type I deiodinase expressed in the thyroid gland is increased by TSH-stimulated cAMP production and has a significant influence on the amount of T3 released by the thyroid. Propylthiouracil and iodinated x-ray contrast agents such as iopanoic acid inhibit the activity of this enzyme and consequently the thyroidal production of T3.

Type II deiodinase is expressed in the brain, pituitary gland, brown adipose tissue, thyroid, placenta, and skeletal and cardiac muscle. Type II deiodinase has only outer-ring activity and converts T4 to T3. This enzyme is thought to be the major source of T3 in the euthyroid state. This enzyme plays an important role in tissues that produce a relatively high proportion of the receptor-bound T3 themseleves, rather than deriving T3 from plasma. In these tissues, type II deiodinases are an important source of intracellular T3 and provide more than 50% of the nuclear receptor-bound T3. The critical role of type II deiodinases is underscored by the fact that T3 formed in the anterior pituitary is necessary for negative feedback inhibition (long loop) of TSH secretion.screen-shot-2016-10-13-at-9-21-09-pm

Type III Deiodinase is expressed in the brain, placenta, and skin. Type III deiodinase has inner-ring activity and converts T4 to rT3, and T3 to T2, thus inactivating T4 and T3. This process is an important feature in placental protection of the fetus. The placental conversion of T4 to rT3, and of T3 to T2 reduces the flow of T3 from mother to fetus. Small amounts of maternal T4 are transferred to the fetus and converted to T3, which increases the T3 concentration in the fetal brain, preventing hypothyroidism. In the adult brain, the expression of type III deiodinases is enhanced by thyroid hormone excess, serving as a protective mechanism against high thyroid hormone concentrations.

The Hypothalamic-pituitary-thyroid Axis

Hypothalamic Regulation of Thyroid-Stimulating Hormone Release (releasing factor)

Thyroid hormone synthesis and release are under negative feedback regualtion by the hypothalamic-pituitary-thyroid axis. TRH is a tripeptide synthesized in the hypothalamus and released from nerve terminals in the median eminence from where it is transported through the portal capillary plexus to the anterior pituitary. TRH binds to cell membrane Gq/11 receptors on thyrotrophs of the anterior pituitary gland, where it activates phospholipase C, resulting in the hydrolysis of phosphatidylinositol bisphosphate and the generation of inositol triphosphate and diacylylycerol. This process leads to an increase in the intracellular Ca2+ concentration, resulting in stimulation of exocytosis and release of TSH into the systemic circulation.

Thyroid-Stimulating Hormone Regulation of Thyroid Hormone Release (tropic effect)

TSH is transported in the bloodstream to the thyroid gland, where it binds to the TSH receptor located on the basolateral membrane of thyroid follicular epithelial cells. The TSH receptor is a cell membrane G protein-coupled receptor. Binding of TSH to its receptor initiates signaling through cyclic 3', 5'-adenosine monophosphate (cAMP), phospholipase C, and the protein kinase A signal transduction systems. Activation of adenylate cyclase, formation of cAMP, and activation of protein kinase A regulate iodide uptake and transcription of Tg, thyroid peroxidase (TPO), and the activity of the sodium-iodide (Na+/I) symporter. Signaling through phospholipase C and intracellular Ca2+ regulate iodide efflux, H2O2 production, and Tg iodination. The TSH receptor is an important antigenic site involved in thyroid autoimmune disease. Autoantibodies to the receptor may act as agonists mimicking the actions of TSH, or antagonists in the case of autoimmune hypothyroidism.

TSH receptor activation results in stimulation of all of the steps involved in thyroid hormone synthesis, including 1) iodine uptake and organification, 2) production and release of iodothyronines from the gland, and 3) promotion of thyroid growth. Specifically, the biologic effects of TSH include stimulation of gene transcription of the following: 1) Na+/I symporter, the protein involved in transporting and concentrating iodide in the thyroid epithelial cell; 2) Tg, the glycoprotein that serves as a scaffold for tyrosine iodination and thyroid hormone synthesis, as well as storage of thyroid hormone; 3) TPO, the enzyme involved in catalyzing the oxidation of iodide and its incorporation into thyrosine residues of Tg; and 4) thyroid hormones T4 and T3 (triiodothyronine).

TSH control the energy-dependent uptake and concentration of iodide by the thyroid gland and its transcellular transport through the follicular epithelial cell. However, iodine metabolism within the thyroid can also be reglated independently of TSH. This mechanism is important when plasma iodide levels are elevated (15-20-fold above normal) because this elevation inhibits the organic binding of iodine within the thyroid. This autoregulatory phenomenon consisting of inhibition of the organification of iodine by elevated circulating levels of iodide is known as the Wolff-Chaikoff effect. This effect lasts for a few days and is followed by the so-called escape phenomenon, at which point the organification of intra-thyroidal iodine resumes and the normal synthesis of T4 and T3 returns. The escape phenomenon results from a decrease in the inorganic iodine concentration inside the thyroid gland from downregulation of the Na+/I symporter. This relative decrease in intrathyroidal inorganic iodine allows the TPO-H2O2 system to resume normal activity. The mechanisms responsible for the acute Wolff-Chaikoff effect have not been elucidated but may be caused by the formation of organic iodocompounds within the thyroid.

Thyroid Hormone Regulation of Thyroid-Stimulating Hormone Release (long loop)

The production and release of thyroid hormones are under negative feedback regulation by the hypothalamic-pituitary-thyroid axis. The release of TSH is inhibited mainly by T3, produced by conversion of T4 to T3 in the hypothalamus, and in the anterior pituitary by type II deiodinase. The contribution of this intracellularly derived T3 in producing the negative feedback inhibition of TSH release is greater than that of T3 derived from the circualtion. Other neuroendocrine mediators that inhibit TSH release include dopamine, somatostatin, and glucocorticoids at high levels, which produce partial suppression of TSH release.