## Factors That Alter Clearance

Body Surface Area (BSA)

Most literature values for clearance are expressed as volume/kg/time or as volume/70 kg/time. There is some evidence, however, that drug clearance is best adjusted on the basis of BSA rather than weight.

The patient’s BSA can be obtained from a nomogram, estimated from below:

BSA in m2 = [(Patient’s Weight in Kg / 70 kg)^0.7]*(1.73 m2)

or

BSA in m2 = (W^0.425)(H^0.725)*0.007184

The following formulas can be used to adjust the clearance values reported in the literature for specific patients. There are other equations one can use depending on units used in the literature for clearance.

• Patient’s Cl = (Literature Cl per m2)(Patient’s BSA)
• Patient’s Cl = (Literature Cl per 70 kg) (Patient’s BSA / 1.73 m2)
• Patient’s Cl = (Literature Cl per 70 kg)(Patient’s Weight in Kg / 70 kg)
• Patient’s Cl = (Literature Cl per kg)(Patient’s Weight in kg)

When patients do not differ significantly from 70 kg, the difference between using weight versus BSA becomes less significant.

The underlying assumption in using weight or BSA to adjust clearance is that the patient’s liver and kidney size (and hopefully function) vary in proportion to these physical measurements. This may not always be the case; therefore, clearance values derived from the patient populations having a similar age and size should be used whenever possible. If the patient’s weight is reasonably close to 70 kg (BSA = 1.73 m2), the patient’s calculated clearance will be similar whether weight or BSA are used to calculate clearance. If, however, the patient’s weight differs significantly from 70 kg, then the use of weight or surface area is likely to generate substantially different estimates of the patient’s clearance. When a patient’s size is substantially greater or less than the standard 70 kg, or 1.73 m2, a careful assessment t should be made to determine if the patient’s body stature is normal, obese, or emaciated. In obese and emaciated patients, neither weight nor surface area is likely to be helpful in predicting clearance, since the patient’s body size will not reflect the size or function of the liver and kidney.

Plasma Protein Binding

For highly protein-bound drugs, diminished plasma protein binding is associated with a decrease in reported steady-state plasma drug concentrations (total of unbound plus free drug) for any given dose that is administered. It would be misleading, however, to assume that because the calculated clearance is increased, the amount eliminated per unit of time has increased. Actually the amount eliminated per unit of time equals is the production of both Cl and C. In summary, when the same daily dose of a drug is given in the presence of diminished protein binding, an amount equal to that dose will be eliminated from the body each day at steady state despite a diminished steady-state plasma concentration and an increase in the calculated clearance. This is one way to explain the un-changed RE (rate of elimination). In another way to explain, when Css ave changes, the free or unbound fraction of drug in the plasma generally increases (even though Css ave decreases) with diminished plasma protein binding. As a result, the amount of free drug eliminated per unit of time remains unchanged.

And also what is important is that the pharmacologic effect achieved will be similar to that produced by the higher serum concentration observed under normal protein binding conditions. This example re-emphasizes the principle that clearance alone is not a good indicator of the amount of drug eliminated per unit of time (RE).

Extraction Ratio

The direct proportionality between calculated clearance and fraction unbound (fu) does not apply to drugs that are so efficiently metabolized or excreted that some (perhaps all) of the drug bound to plasma protein is removed as it passes through the eliminating organ. In this situation the plasma protein acts as a “transport system” for the drug, carrying it to the eliminating organs, and clearance becomes dependent on the blood or plasma flow to the eliminating organ. To determine whether the clearance for a drug with significant plasma binding will be influenced primarily by blood flow or plasma protein binding, its extraction ratio is estimated and compared to its fu value.

The extraction ratio is the fraction of the drug presented to the eliminating organ that is cleared after a single pass through that organ. It can be estimated by dividing the blood or plasma clearance of a drug by the blood or plasma flow to the elimination organ. At rest, the blood flow to the liver via the portal vein is at a rate of 1300 mL/min, and the other 500 mL/min is suppled by the hepatic artery. If the extraction ratio exceeds the free fraction (fu), then the plasma proteins are acting as a transport system and clearance will not change in proportion to fu. If, however, the extraction ratio is less than fu, clearance is likely to increase by the same proportion that fu changes. This approach does not take into account other factors that may affect clearance such as red blood cell binding, elimination from red blood cells, or changes in metabolic function.

Renal and Hepatic Function

Drugs can be eliminated or cleared as unchanged drug through the kidney (renal clearance) and by metabolism in the liver (metabolic clearance). These two routes of clearance are assumed to be independent of one another and additive.

Clt = Clm + Clr (total Cl = metabolic CI + renal Cl)

Because the kidneys and liver function independently, it is assumed that a change in one does not affect the other. Thus, Clt can be estimated in the presence of renal or hepatic failure or both. Because metabolic function is difficult to quantitate, Clt is most commonly adjusted when there is decreased renal function:

A clearance that has been adjusted for renal function can be used to estimate the maintenance dose for a patient with diminished renal function. This adjusted clearance equation, however, is only valid if the drug’s metabolites are inactive and if the metabolic clearance is indeed unaffected by renal dysfunction as assumed. A decrease in the function of an organ of elimination is most significant when that organ serves as the primary route of drug elimination. However, as the major elimination pathway becomes increasingly compromised, the “minor” pathway becomes more significant because it assumes a greater proportion of the total clearance. For example, a drug that is usually 67% eliminated by the renal route and 33% by the metabolic route will be 100% metabolized in the event of complete renal failure; the total clearance, however, will only be one-third of the normal value.

As an alternative to adjusting Clt to calculate dosing rate, one can substitute fraction of the total clearance that is metabolic and renal for Clm and Clr. Using this technique the equation below can be derived.

The Dosing Rate Adjustment Factor can be used to adjust the maintenance dose for a patient with altered renal function.

Most pharmacokinetic adjustments for drug elimination are based on renal function because hepatic function is usually more difficult to quantitate. Elevated liver enzymes do reflect liver damage but are not a good measure of function. Hepatic function is often evaluated using the prothrombin time (or INR), serum albumin concentration, and serum bilirubin concentration. Unfortunately, each of these laboratory tests is affected by variables other than altered hepatic function. For example, the serum albumin may be low due to decreased protein intake or increased renal or GI loss, as well as decreased hepatic function. Although liver function tests do not provide quantitative data, pharmacokinetic adjustments must still take into consideration liver function because this route of elimination is important for a significant number of drugs.

Cardiac Output

Cardiac output also affects drug metabolism. Hepatic or metabolic clearances for some drugs can be decreased by 25% to 50% in patients with congestive heart failure. For example, the metabolic clearances of theophylline and digoxin are reduced by approximately one-half in patients with congestive heart failure. Since the metabolic clearance for both of these drugs is much lower than the hepatic blood or plasma flow (low extraction ratio), it would not have been predicted that their clearances would have been influenced by cardiac output or hepatic blood flow to this extent. The decreased cardiac output and resultant hepatic congestion must, in some way, decrease the intrinsic metabolic capacity of the liver.

## ASH Guideline for RBC Transfusion

The Guideline

The development of clinical practice guidelines for RBC transfusion has been challenged by a limited availability of high-quanlity evidence to support practice recommendations. There is general agreement that RBC transfusion is typically not indicated for hemoglobin (Hgb) levels of >10 g/dL and that transfusion of RBCs should be considered when Hb is <7 to 8 g/dL depending on patient characteristics. The decision to transfuse RBCs should be based on a clinical assessment of the patient that weighs the risks associated with transfusion aganist the anticipated benefit. As more studies addressing RBC transfusion become available, it becomes increasely clear that liberal transfusion strategies are not necessarily associated with superior outcomes and may expose patients to unnecessary risks.

The most recently published guidelines from the AABB (formerly the American Association of Blood Bank) are based on a systematic review of randomized, controlled trials evaluating transfusion thresholds. These guidelines recommend adhering to a restrictive transfusion stratety and consider transfusion when Hb is 7 to 8 g/dL in hospitalized, stable patients. This strong recommendation is based on high-quality evidence from clinical trials comparing outcomes in liberal versus restrictive transfusion strategies in this patient population. A restrictive transfusion strategy is also recommended for patients with preexisting cardiovascular disease. In this population, transfusion should be considered when Hb levels are <8 g/dL or for symptoms such as chest pain, orthostatic hypotension, tachycardia unresponsive to fluid resuscitation, or congestive heart failure. This weak recommendation is based on moderate-quality evidence due to limited clinical trial data directly addressing this population of patients. Additional clinical practice guidelines exist that specify Hb targets for critical care patients with conditions including sepsis, ischemic stroke, and acute coronary syndrome.

RBC transfusion is indicated in patients who are actively bleeding and should be based on clinical assessment of the patient in addition to laboratory testing. Much remains to be learned about the optimal resuscitation of the bleeding patient. However, a recent study examining transfusion in patients with active upper gastrointestinal bleeding showed superior outcomes in patients treated with a restrictive transfusion strategy (<7 g/dL).

The Physiologic Response to Anemia

The initial response to anemia is a shift in the oxygen dissociation curve to the right as modulated by an increase in production of 2,3-DPG in RBCs. This shift allows for the unloading of oxygen to the tissues at higher partial pressures of oxygen, ensuring adequate oxygen delivery despite the reduction in RBC mass.

As anemia progresses, the cardiac output will increase by an increase in the heart rate to preserve the delivery of oxygen in the setting of decreased oxygen content. As RBC mass is reduced in anemia, the viscosity of the blood decreases. This reduction in viscosity leads to an increase in regional blood flow at the tissue and organ level, driving up local perfusion area and pressures leading to increased oxygen extraction. While a change in viscosity may be the trigger for increased regional blood flow, there has been suggestion that local blood vessel dilatation may be mediated by the release of nitric oxide (NO) from the RBCs. In order for these mechanisms to work properly, the patient must be at or near a euvolemic state. In considering these regulatory mechanisms, it is important to understand that the transfusion of RBCs will incease viscosity by adding stored RBCs that may not have the same vasoactive capabilities of native RBCs. As such, a transfusion of RBCs may inhibit compensatory mechanisms for low oxygen states, without significiantly increasing oxygen delivery.

There is evidence that low levels of Hb can be tolerated in healthy subjects. Hematocrits of 10% to 20% have been achieved in experimental studies using normovolemic hemodilution without untoward effects. Weiskopf and colleagues studied patients who underwent isovolemic reduction of Hb to 7, 6, and 5 g/dL. No evidence of reduced oxygen delivery was detected at any of the tested values of Hb; however, there was a subtle reversible reduction in reaction time and impaired immediate and delayed memory observed at Hb below 6 g/dL. An important source of data regarding the impact of anemia on surgical outcome comes from studies of Jehovah's Witness patients. Carson has demonstrated that the risk of death in these pateints at Hb between 7 and 8 g/dL is low. However, the odds of death increase by 2.5 for each gram decrease in Hb below 8 g/dL. The mortality is very high at Hb levels below 5 g/dL. It should be noted that these data are from patients who refuse all RBC transfusions. There is time to intervene between a low Hb and resulting morbidity or mortality in most patients.

## [Physiology] Vascular Control in Specific Organs

In General

Basal tone, local metabolic vasodilator factors, and sympathetic vasoconstrictor nerves acting through alpha1-receptors are the major factors controlling arteriolar tone and therefore the blood flow rate through peripheral organs. Sympathetic vasoconstrictor nerves, internal pressure, and external compressional forces are the most important influences on venous diameter and therefore on peripheral-central distribution of blood volume. Compared with arterioles, veins normally have little basal tone. Thus, veins are normally in a dilated state. One important consequence of the lack of basal venous tone is that vasodilator metabolites that may accumulate in the tissue have little effect on vein.

• Arteriolar Tone

• Basal tone
• ANS
• Local

• Metabolic substances
• Endothelial cells secretion
• Other local chemical influences
• Transmural pressure (myogenic response)
• Venous Tone

• Basal tone (little)
• ANS
• Internal pressure (recall deltaV/deltaP = C)
• External compression

Coronary Blood Flow

• 4% of cardiac output (at rest)
• Vasodilation – local metabolic mechanisms (to outweight sympathetic vasoconstriction)
• Systolic compression (left ventricle)
• Local O2ER 70-75% (at rest)

The major right and left coronary arteries that serve the heart tissue are the first vessels to branch off the aorta. Thus, the driving force for myocardial blood flow is the systemic arterial pressure, just as it is for other systemic organs. Most of the blood that flows through the myocardial tissue returns to the right atrium by way of a large cardiac vein called the coronary sinus.

Coronary blood flow is controlled primarily by local metabolic mechanisms. It responds rapidly and accurately to changes in myocardial oxygen consumption. The issue of which metabolic vasodilator factors play the dominant role in modulating the tone of coronary arterioles is unresolved at present. Many suspect that adenosine, released from myocardial muscle cells in response to increased metabolic rate, may be an important coronary metabolic vasodilator influence. Regardless of the specific details, myocardial oxygen consumption is the most important influence on coronary blood flow.

In a resting individual, the myocardium extracts 70% to 75% of the oxygen in the blood that passes through it. Because of this high extraction rate, coronary sinus blood normally has a lower oxygen content than blood at any other place in the cardiovascular system. Because myocardial oxygen extraction cannot increase significantly from its high resting value, increases in myocardial oxygen consumption must be accompanied by appropriate increases in coronary blood flow.

Large forces and/or pressures are generated within the myocardial tissue during cardiac muscle contraction. Such intramyocardial forces press on the outside of coronary vessels and cause them to collapse during systole. Because of this systolic compression and the associated collapse of coronary vessels, coronary vascular resistance is greatly increased during systole. The result, at least for much of the left ventricular myocardium, is that coronary flow is lower during systole than during diastole, even though systemic arterial pressure (i.e., coronary perfusion pressure) is highest during systole. Systolic compression has much less effect on flow through the right ventricular myocardium. This is because the peak systolic intraventricular pressure is much lower for the right heart than for the left heart, and the systolic compressional forces in the right ventricular wall are correspondinly less than those in the left ventricular wall.

Systolic compressional forces on coronary vessels are greater in the endocardial layers of the left ventricular wall than in the epicardial layers. Thus, the flow to the endocardial layers of the left ventricle is impeded more than the flow to the epicardial layers by systolic compression. Normally, the endocardial region of the myocardium can make up for the lack of flow during systole by a high flow in the diastolic interval. However, when coronary blood flow is limited the endocardial layers of the left ventricle are often the first regions of the heart to have difficulty maintaining a flow sufficient for their metabolic needs.

Coronary arterioles are densely innervated with sympathetic vasoconstrictor fibers, yet when the activity of the sympathetic nervous system increases, the coronary arterioles normally vasodilate rather than vasoconstrict. This is because an increase in sympathetic tone increases myocardial oxygen consumption by increasing the heart rate and contractility. The increased local metabolic vasodilator influence apparently outweighs the concurrent vasoconstrictor influence of an increase in the activity of sympathetic vasoconstrictor fibers that terminate on coronary arterioles.

Skeletal Muscle Blood Flow

• Important to overall cardiovascular hemodynamics (large mass; sympathetic vasoconstriction only has impact for cardiac output, not for blood volume [due to sparsely innervated with sympathetic vasoconstrictor fibers])
• Vasodilation – local metabolic mechanisms (countered by sympathetic vasoconstriction to prevent over-vasodilation which might result in not enough cardiac output to maintain arterial pressure)
• Skeletal muscle pump – enhance venous return
• 15% of the cardiac output (at rest)
• Local O2ER 25-30% (at rest)

Because of the large mass of the skeletal muscle, blood flow through it is an important factor in overall cardiovascular hemodynamics. Collectively, the skeletal muscles constitute 40% to 45% of body weight – more than any other single body organ. Even at rest, approximately 15% of the cardiac output goes to skeletal muscle, and during strenuous exercise, the skeletal muscle may receive more than 80% of the cardiac output.

Resting skeletal muscle has a high level of intrinsic vascular tone. Because of this high tone of the smooth muscle in resistance vessels of resting skeletal muscle, the blood flow per gram of tissue is quite low when compared with that of other organs. However, resting skeletal muscle blood flow is still substantially above that required to sustain its metabolic needs. Resting skeletal muscles normally extract only 25% to 30% of the oxygen delivered to them in arterial blood. Thus, changes in the activity of sympathetic vasoconstrictor fibers can reduce resting muscle blood flow without compromising resting tissue metabolic processes.

Local metabolic control of arteriolar tone is the most important influence on blood flow through exercising muscle. A particular important characteristic of skeletal muscle is its very wide range of metabolic rates. During heavy exercise, the oxygen consumption rate of and oxygen extraction by skeletal muscle tissue can reach the high values typical of the myocardium (70-75%). In most respects, the factors that control blood flow to exercising muscle are similar to those that control coronary blood flow (metabolic mechanisms). Local metabolic control of arteriolar tone is very strong in exercising skeletal muscle, and muscle oxygen consumption is the most important determinant of its blood flow.

Alterations in sympathetic neural activity can alter nonexercising skeletal muscle blood flow. For example, maximum sympathetic discharge rates can decrease blood flow in a resting muscle to less than one fourth its normal value, and conversely, if all neurogenic tone is removed, resting skeletal muscle blood flow may double. This is a modest increase in flow compared with what can occur in an exercising skeletal muscle. Nonetheless, because of the large mass of issue involved, changes in the vascular resistance of resting skeletal muscle brought about by changes in sympathetic activity are very important in the overall reflex regulation of arterial pressure. In exercising muscles, the increased sympathetic vasoconstrictor nerve acivity is not evident as outright vasoconstriction but does limit the degree of metabolic vasodilation, which seemingly is a counterproductive process that serves to prevent an excessive reduction in total peripheral resistance during exercise (over-vasodilation). This process is of very importance because if arterioles in most of the skeletal muscles in the body were allowed to dilate to their maximum capacity simultaneously, total peripheral resistance would be so low that the heart could not possibly supply enough cardiac output to maintain arterial pressure.

As in the heart, muscle contraction produces large compressional forces within the tissue, which can collapse vessels and impede blood flow. Strong, sustained (tetanic) skeletal muscle contractions may actually stop muscle blood flow. Approximately 10% of the total blood volume is normally contained within the veins of the skeletal muscle, and during rhythmic exercise, the "skeletal muscle pump" is very effective in displacing blood from skeletal muscle veins. Valves in the veins prevent reverse flow back into the muscles. Blood displaced from the skeletal muscle into the central venous pool is an important factor in the hemodynamics of strenuous whole body exercise.

Veins in skeletal muscle can constrict in response to increased sympathetic activity. However, veins in the skeletal muscle are rather sparsely innervated with sympathetic vasoconstrictor fibers, and the rather small volume of blood that can be mobilized from the skeletal muscle by sympathetic nerve activation is probably not of much significance to total body hemodynamics. This is in sharp contrast to the large displacement of blood from exercising muscle by the muscle pump mechanism.

Cerebral Blood Flow

• Interruption of flow more than a few seconds is dangerous
• Flow regulated by local mechanisms
• 12% of cardiac output (at rest)
• Brain metabolism rate is constant
• Brain flow starts to fall when arterial BP is under 60 mm Hg
• ANS's infuence on cerebral blood flow is minimal

Interruption of cerebral blood flow for more than a few seconds leads to unconsciousness and to brain damage within a very short period. One rule of overall cardiovascular system function is that, in all situations, measures are taken that are appropriate to preserve adequate blood flow to the brain.

Cerebral blood flow is regulated almost entirely by local mechanisms (by local metabolites and/or myogenic mechanisms?). The brain as a whole has nearly constant rate of metabolism that, on a per gram basis, is nearly as high as that of myocardial tissue. Flow through the cerebrum is autoregulated very strongly and is little affected by chagnes in arterial pressure unless it falls below approximately 60 mm Hg (brain blood flow starts to decrease below this level).

PS: Local mechanisms include: 1).autoregulation; 2).metabolites; and 3).local vasoconstriction (in the face of artery injuries). Detail: Arteriolar Tone and Its Regulation (local mechanisms) http://www.tomhsiung.com/wordpress/2015/07/arteriolar-tone-and-its-regulation-local-mechanisms/

Sympathetic and parasympathetic neural influences on cerebral blood flow are minimal. Although cerebral vessels receive both sympathetic vasoconstrictor and parasympathetic vasodilator fiber innervation, cerebral blood flow is influenced very little by changes in the activity of either under normal circumstances. Sympathetic vasoconstrictor responses may, however, be important in protecting cerebral vessels from excessive passive distention following large, abrupt increases in arterial pressure.

The "blood-brain barrier" refers to the tightly connected vascular endothelial cells that severely restrict transcapillary movement of all polar and many other substanes. Because of this blood-brain barrier, the extracellular space of the brain represents a special fluid compartment in which the chemical composition is regulated separately from that in the plasma and general body extracellular fluid compartment. The extracellular compartment of the brain encompasses both interstitial fluid and cerebrospinal fluid (CSF), which surround the brain and the spinal cord and fills the brain ventricles. These processes regulate the chemical composition of the CSF. The interstitial fluid of the brain takes on the chemical composition of CSF through free diffusional exchange. The blood-brain barrier serves to protect the cerebral cells from ionic disturbances in the plasma. Also, by exclusion and/or endothelial cell metabolism, it prevents many circulating hormones (and drugs) from influencing the parenchymal cells of the brain and the vascular smooth muscle in brain vessels.

Although many organs can tolerate some level of edema, edema in the brain represents a crisis situation (increased intracranial pressure). Cerebral edema increases intracranial pressure, which must be promptly relieved to avoid brain damage. Special mechanisms involving various specific ion channels and transporters precisely regualte the transport of solute and water across astrocytes and the endothelial barrier. These mechanisms contribute to normal maintenance of intracellular and extracellular fluid balance.

Splanchnic Blood Flow

• Splanchnic blood flow has big impact on overall hemodynamics (both blood flow and blood volume)
• Sympathetic activity has big impacts on splanchnic blood flow and volume
• 25% of cardiac output (at rest)
• 20% of circulating blood volume (at rest)
• Local O2ER 15% to 20% (at rest)

Because of the high blood flow through and the high blood volume in the splanchnic bed, its vascular control importantly influences over all cardiovascular hemodynamics. A number of abdominal organs, including the gastrointestinal tract, spleen, pancreas, and liver, are collectively supplied with what is called the splanchnic blood flow. Splanchnic blood flow is supplied to these abdominal organs through many arteries, but it all ultimately passes through the liver and returns to the inferior vena cava through the hepatic veins. The organs of the splanchnic region receive approximately 25% of the resting cardiac output and contain more than 20% of the circulating blood volume. Thus, adjustments in either the blood flow or the blood volume of this region have extremely important effects on the cardiovascular system.

Sympathetic neural activity plays an important role in vascular control of the splanchnic circulation. Collectively, the splanchnic organs have a relatively high blood flow and extract only 15% to 20% of the oxygen delivered to them in the arterial blood. The arteries and veins of all the organs involved in the splanchnic circulation are richly innervated with sympathetic vasoconstrictor nerves. Maximal activation of sympathetic vasoconstrictor nerves can produce an 80% reduction in flow to the splanchnic region and also cause a large shift of blood from the splanchnic organs to the central venous pool. Humans, a large fraction of the blood mobilized from the splanchnic circulation during periods of sympathetic activation comes from the constriction of veins in the liver.

Local metabolic activity associated wtih gastrointestinal motility, secretion, and absorption is associated with local increases in splanchnic blood flow. There is great diversity of vascular structure and function among indidiviual organs and even regions within organs in the splanchnic region. The mechanisms of vascular control in specific areas of the splanchnic region are not well understood but are likely to be quite varied. Nonetheless, because most splanchnic organs are involved in the digestion and absorption of food from the gastrointestinal tract, overall splanchnic blood flow increases after food ingestion. Parasympathetic neural activity is involved in many of these gastrointestinal functions, so it is indirectly involved in increasing splanchnic blood flow. A large meal can elicit a 30% to 100% increase in splanchnic flow, but individual organs in the splanchnic region probably have higher percentage increases in flow at certain times because they are involved sequentially in the digestion – absoprtion process.

Renal Blood Flow

• Renal function is itself of paramount important to overall cardiovascular function
• 20% of cardiac output (at rest)
• Changes in renal blood volume are of no signifance to overall cardiovascular hemodynamics
• Sympathetic activity has big impacts on renal blood flow
• Local metabolic mechanism may influence local vascular tone, but physiological roles are not clear

Renal blood flow plays a critical role in the kidney's main long-term job of regulating the body's water balance and therefore circulating blood volume. However, acute adjustments in renal blood flow also have important short-term hemodynamic consequences. The kidneys normally receive approximately 20% of the cardiac output of a resting individual. This flow can be reduced to practically zero during strong sympathetic activation. Thus, the control of renal blood flow is important to overall cardiovascular function. However, because the kidneys are such small organs, changes in renal blood volume are inconsequential to overall cardiovascular hemodynamics.

Renal blood flow is strongly influenced by sympathetic neural stimulation. Alterations in sympathetic neural activity can have marked effects on total renal blood flow by altering the neurogenic tone of renal resistance vessels. In fact, extreme situations involving intense and prolonged sympathetic vasoconstrictor activity can lead to dramatic reduction in renal blood flow, permanent kidney damage, and renal failure.

Local metabolic mechanism may influence local vascular tone, but physiological roles are not clear. It has long been known that experimentally isolated kidneys (i.e., kidneys deprived of their normal sympathetic input) autoregulate their flow quite strongly (for detail about seek threads THE AUTOREGULATION OF RENAL BLOOD FLOW at http://www.tomhsiung.com/wordpress/2014/06/the-autoregulation-of-renal-blood-flow/ and ARTERIOLAR TONE AND ITS REGULATION (LOCAL MECHANISMS) at http://www.tomhsiung.com/wordpress/2015/07/arteriolar-tone-and-its-regulation-local-mechanisms/). The mechanism responsible for this phenomenon has not been definitely established, but myogenic, tissue pressure, and metabolic hypotheses have been advanced. The real question is what purpose such a strong local mechanism plays in the intact organism where it seems to be largely overridden by reflex mechanisms. In an intact individual, renal blood flow is not constant but is highly variable, depending on the prevailing level of sympathetic vasoconstrictor nerve activity. (For how renal plasma flow affects drug clearance [pharmacokinetics] please see thread PHARMACOKINETICS SERIES – CLEARANCE AND MAINTENANCE DOSE at http://www.tomhsiung.com/wordpress/2015/03/pharmacokinetics-series-clearance-and-maintenance-dose/).

The mechanisms responsible for the intrinsic regulation of renal blood flow and kidney function have not been established. Although studies suggest that prostaglandins and some intrarenal renin-angiotensin system may be involved, the whole issue of local renal vascular  control remains quite obscure. Renal function is itself of paramount important to overall cardiovascular function.

Cutaneous Blood Flow

• Cutaneous blood flow is related to regulation of body temperature
• 6% of cardiac output (at rest)
• Cutaneous blood flow can increases up to 7-fold with vasodilation
• Venous constriction can shift a considerable volume of blood to central venous pool

The physiological role of skin blood flow is to help regulate body temperature. The metabolic activity of body cells produces heat, which must be lost in order for the body temperature to remain constant. The skin is the primary site of exchange of body heat with the external environment. Alterations in cutaneous blood flow in response to various metabolic states and environmental conditions provide the primary mechanism responsible for temperature homeostasis.

Decreases in body tempeature (core temperature) decrease skin blood flow and vice versa. Cutaneous blood flow, which is approximately 6% of resting cardiac output, can decrease to about one-twentieth of its normal value when heat is to be retained. In contrast, cutaneous blood flow can increase up to seven times its normal value when heat is to be lost.

Structural adaptations of the cutaneous vascular beds promote heat loss or heat conservation. An extensive system of interconnected veins called the venous plexus normally contains the largest fraction of cutaneous blood volume, which, individuals with hightly pigmented skin, gives the skin a reddish hue. To a large extent, heat transfer from the blood takes place across the large surface area of the venous plexus. The venous plexus is richy innervated with sympathetic vasoconstrictor nerves. When these fibers are activated, blood is displaced from the venous plexus, and this helps reduce heat loss and also lightens the skin color. Because the skin is one of the largest body organs, venous constriction can shift a considerable amount of blood into the central venous pool.

Reflex sympathetic neural activity has important but complex influences on skin blood flow. Cutaneous resistance vessels are richly innervated with sympathetic vasoconstrictor nerves, and because these fibers have a normal tonic activity, cutaneous resistance vessels normally have a high degree of neurogenic tone. When body temperature rises above normal, skin blood flow is increased by reflex mechanisms. In certain areas (such as the hands, ears, and nose), vasodilation appears to result entirely from the withdrawal of sympathetic vasoconstrictor tone. In other areas (such as the forearm, forehead, chin, neck, and chest), the cutaneous vasodilation that occurs with body heating greatly exceeds that which occurs with just the remvoal of sympathetic vasoconstrictor tone. This "active" vasodilation is closely linked to the onset of sweating in these areas. The sweat glands in human cutaneous tissue involved in thermoregulation are innervated by cholinergic sympathetic fibers that release acetylcholine. Activation of these nerves elicits sweating and an associated marked cutaneous vasodilation (see post Responses of Some Effector Organs to Autonomic Nerve Activity at http://forum.tomhsiung.com/pharmacy-research-study-and-policy/physiology-and-pathophysiology/916-responses-of-some-effector-organs-to-autonomic-nerve-activity.html).

Cutaneous vessels respond to changes in local skin temperature. In general, local cooling leads to local vasoconstriction and local heating causes local vasodilation. The mechanisms for this are unknown. If the hand is placed in ice water, there is initially a nearly complete cessation of hand blood flow accompanied by intense pain. After some minutes, hand blood flow begins to rise to reach values greately in excess of the normal value, hand temperature increases, and the pain disappears. This phenomenon is referred to as cold-induced vasodilation. With continued immersion, hand blood flow cycles every few minutes between periods of essentially no flow and periods of hyperemia. The mechanism responsible for cold vasodilation is unknown.

Cutaneous vessels respond to local damage with observable responses. Tissue damage from burns, ultravioler radiation, cold inury, caustic chemicals, and mechanical trauma produces reactions in the skin blood flow. A classical reaction called the triple response is evoked after vigorously stroking the skin with a blunt point. The first component of the triple response is a red line that develops along the direct path of the abrasion in approximately 15 s. Shortly thereafter, an irregular red flare appears that extends approximately 2 cm on either side of the red line. Finally, after a minute or two, a wheal appears along the line of the injury. The mechanisms involved in the triple response are not well understood, but it seems likely that histamine release from damage cells is at least partially responsible for the dilation evidenced by the red line and teh subsequent edema formation of the wheal. The red flare seems to involve nerves in some sort of a local axon reflex, because it can be evoked immediately after cutaneous nerves are sectioned but not after the peripheral portions of the sectioned nerves degenerate.

Pulmonary Blood Flow

• Pulmonary blood flow equals cardiac ouput
• Pulmonary veins serve a blood reservoir function for the cardiovascular system
• Pulmonary vascular resistance is one-seventh of total SVR
• An increase in pulmonary arterial pressure decrease pulmonary vascular resistance
• Pulmomary arterioles constrict in response to alveolar hypoxia
• Autonomic nerves play no major role in control of pulmonary vascular activity

Pulmonary blood flow equals cardiac output. Except for very transient adjustments, the rate of blood flow through the lungs is necessarily equal to cardiac output of the left venticle in all circumstances. When cardiac output to the systemic circulation increases threefold during exercise, for example, pulmonary blood flow must also increase threefold.

Pulmonary vascular resistance is about one-seventh of total systemic vascular resisrance. Pulmonary vessels do offer some vascular resistance. Although the level of pulmonary vascular resistance does not usually influence the pulmonary flow rate, it is important because it is one of the determinants of pulmonary arterial pressure. Recall that mean pulmonary arterial pressure is approximately 13 mm Hg (9-18 mm Hg), whereas mean systemic arterial pressure is approximately 100 mg Hg (70-105 mm Hg). The reason for the difference in pulmonary and systemic arterial pressures is not that the right side of the heart is weaker than the left side of the heart, but rather that pulmonary vascular resistrance is inherently much lower than systemic total peripheral resistance. The pulmonary bed has a low resistance because it has relatively large vessels throughout.

Pulmonary arteries and arterioles are less muscular and more compliant than systemic arteries and arterioles. When pulmonary arterial pressure increases, the pulmonary arteries and arterioles become larger in diameter. Thus, an increase in pulmonary arterial pressure decreases pulmonary resistance. This phenomenon is important because it tends to limit the increase in pulmonary arterial pressure that occurs with increases in cardiac output.

Pulmonary arterioles constrict in response to local alveolar hypoxia. One of the most important and unique active responses in pulmonary vasculature is hypoxic vasoconstriction of pulmonary arterioles in response to low oxygen levels within alveoli (Note: This is a response to alveolar hypoxia, not to low levels of oxygen in the blood – i.e., hypoxemia). This is exactly opposite to the vasodilation that occurs in systemic arterioles in response to low tissue PO2. The mechanisms that cause this unusual response in pulmonary vessels are unclear but seem to be dependent upon oxygen sensing by the pulmonary arterial smooth muscle cells. Current evidence suggests that local endothelin production or prostaglandin synthesis may be involved in pulmonary hypoxic vasoconstriction. Whatever the mechanism, hypoxic vasoconstriction is essential to efficient lung gas exchange because it diverts blood flow away from areas of the lung that are underventilated. Consequently, the best-ventilated areas of the lung also receive the most blood flow. As a consequence of hypoxic arteriolar vasoconstriction, general hypoxia causes an increase in pulmonary vascular resistance and pulmonary arterial hypertension.

Autonomic nerves play no major role in control of pulmonary vascular activity. Both pulmonary arteries and veins receive sympathetic vasoconstrictor fiber innervation, but reflex influences on pulmonary vessels appear to be much less important than the physical and local hypoxic influences. Pulmonary veins serve a blood reservoir function for the cardiovascular system, and sympathetic vasoconstriction of pulmonary veins may be imporant in mobilizing this blood during periods of general cardiovascular stress.

Low capillary hydrostatic pressure promotes fluid reabsorption and prevents fluid accumulation in pulmonary airways. A consequence of the low mean pulmonary arterial pressure is the low pulmonary capillary hydrostatic pressure of approximately 8 mm Hg (compared with approximately 25 mm Hg in systemic capillaries). Because the plasma oncotic pressure in lung capillaries is near 25 mm Hg, as it is in all capillaries, it is likely that the transcapillary forces in the lungs strongly favor continual fluid reabsorption. This cannot be the complete story, however, because the lungs, like other tissues, continually produce some lymph and some net capillary filtration is required to prodcue lymphatic fluid. This filtration is possible despite the unusually low pulmonary capillary hydrostatic pressure because pulmonary interstitial fluid has an unusually high protein concentration and thus oncotic pressure.

Other distribution of cardiac output (blood flow)

5% bone

2.5% lung

1.5% thyroid

3.3 others

## Vascular Resistances and Compliance, MAP and Pulse Pressure

Resistances In A Single Organ

In an organ, the consecutive vascular segments are arranged in series within an organ. Therefore, the overall vascular resistance of the organ must equal the sum of the resistances of its consecutive vascular segments,

Because arterioles have a large vascular resistance in comparison to the other vascular segments (see above), the overall vascular resistance of any organ is determined to a very large extent by the resistance of its arterioles. And according to its histologic characteristics, we can change the diameter of arterioles either spontaneously or with will (i.e., arterioles inside the penis). Thus, the blood flow through an organ is primarily regulated by adjustments in the internal diameter of arterioles caused by contraction or relaxation of their muscular arteriolar walls.

When the arterioles of an organ change diameter, not only does the flow (in general flow is decreased) to the organ change but also the manner in which the pressures drop within the organ is also modified. Arteriolar constriction causes a greater pressure drop  across the arterioles, and this tends to increase the arterial pressure while it decreases the pressure in capillaries and veins. Conversely, increased organ blood flow caused by arteriolar dilation is accompanied by decreased arterial pressure and increased capillary pressure. Because of the changes in capillary hydrostatic pressure, arteriolar constriction tends to cause transcapillary fluid reabsorption, whereas arteriolar dilation tends to promote transcapillary fluid filtration (see thread Transcapillary Transport at http://www.tomhsiung.com/wordpress/2015/07/transcapillary-transport/).

Resistances In A Whole Body

The overall resistance to flow through the entire systemic circulation is called the total peripheral resistance. Because the systemic organs are generally arranged in parallel, the vascular resistance of each organ contributes to the total peripheral resistance according to the following  parallel resistance equation:

According to the parallel vascular model, the TPR must always be less than that of any of the elements in the network (organ1, organ2, …, organn).

Compliance of Vassels

As indicated earlier, arteries and veins contribute only a small portion to the overall resistance to flow through a vascular bed. Therefore, changes in their diameters have no significant effect on the blood flow through systemic organs. The elastic behavior of arteries and veins is however every important to overall cardiovascular function because they can act as reservoirs and substantial amounts of blood can be stored in them.

Arteries or veins behave more like balloons with one pressure throughout rather than as resistive pipes with a flow-related pressure difference from end to end. Thus, we often think of an “arterial compartment” and a “venous compartment,” each with an internal pressure that is related to the volume of blood within it at any instant and how elastic its walls are.

The elastic nature of a vascular region is characterized by a parameter called compliance that describes how much its volume changes (ΔV) in response to a given change in distending pressure (ΔP): C = ΔV/ΔP. Distending pressure is the difference between the internal and external pressures on the vascular walls. The volume-pressure curves for the systemic arterial and venous compartments are shown in Figure 6-8. It is immediately apparent from the disparate slopes of the curve in this figure that the elastic properties of arteries and veins are very different. For the arterial compartment, the ΔV/ΔP measured near a normal operating pressure of 100 mm Hg indicates a compliance of approximately 2 mL/mm Hg. By contrast, the venous pool has a compliance of more than 100 mL/mm Hg near its normal operating pressure of 5 to 10 mm Hg.

Besides, arterial compliance also decreases with increasing MAP. Otherwise, arterial compliance is a relatively stable parameter.

Because veins are so compliant, even small changes in peripheral venous pressure can cause a significant amount of the circulation blood volume to shift into or out of the peripheral venous pool. Standing upright, for example, increases venous pressure in the lower extremities, distends the compliant veins, and promotes blood accumulation (pooling) in these vessels, as might be represented by as shift from point A to point B in Figure 6-8. Fortunately, this process can be counteracted by active venous constriction. The dashed line in Figure 6-8 shows the venous volume-pressure relationship that exists when veins are constricted by activation of venous smooth muscle. In constricted veins, volume may be normal (point C) or even below normal (point D) despite higher-than-normal venous pressure. Peripheral venous constriction tends to increase peripheral venous pressure and shift blood out of the peripheral venous compartment.

Mean Arterial Pressure

Mean arterial pressure is a critically important cardiovascular variable because it is the average effective pressure that drives blood through the systemic organs. One of the most fundamental equations of cardiovascular physiology is that which indicates how mean arterial pressure is related to cardiac output and total peripheral resistance:

This equation is simply a rearrangement of the basic flow equation (Q = ΔP/R) applied to the entire systemic circulation with the single assumption that central venous pressure is approximately zero so that ΔP = MAP. Of note is that all changes in MAP result from changes in either cardiac output or total peripheral resistance.

Arterial Pulse Pressure

The arterial pulse pressure (PP) is defined simply as systolic pressure minus diastolic pressure,

To be able to use pulse pressure to deduce something about how the cardiovascular system is operating, one must do more than just define it. It is important to understand what determines pulse pressure; that is, what causes it to be what it is and what can cause it to change. As a consequence of the compliance of the arterial vessels, arterial pressure increases as arterial blood volume is expanded during cardiac ejection. The magnitude of the pressure increase (ΔP) caused by an increase in arterial volume depends on how large the volume change (ΔV) is and on how compliant (CA) the arterial compartment is: ΔP = ΔV/CA. If, for the moment, the fact that some blood leaves the arterial compartment during cardiac eject is neglected, then the increase in arterial volume during each heartbeat is equal to the stroke volume (SV). Thus, pulse pressure is, to a first approximation, equal to stoke volume divided by arterial compliance:

If the stoke volume of a normal resting young man is approximately 80 mL and the arterial compliance is approximately 2 mL/mm Hg, arterial pulse should be approximately 40 mm Hg, according to the equation above. Because the compliance of arteries decrease as age grows, the arterial pulse pressure increases as age grows. Of note, arterial blood volume and mean arterial pressure tend to increase with age. The increase in mean arterial pressure is not caused by the decreased arterial compliance because compliance changes do not directly influence either cardiac output or total peripheral resistance, which are the sole determinants of MAP. And, the decrease in arterial compliance is sufficient to cause increased pulse pressure even through stroke volume tends to decrease with age.

In addition, MAP tends to increase with age because of an age-dependent increase in total peripheral resistance, which is controlled primarily by arterioles, not arteries.

The preceding equation for pulse pressure is a much-simplified description of some very complex hemodynamic processes. It correctly identifies stroke volume and arterial compliance as the major determinants of arterial pulse pressure but is based on the assumption that no blood leaves the aorta during systolic ejection. Obviously, this is not strictly correct. It is therefore not surprising that several factors other than arterial compliance and stroke volume have minor influences on pulse pressure. For example, because the arteries have viscous properties as well as elastic characteristics, faster cardiac ejection caused by increased myocardial contractility tends to increase pulse pressure somewhat even if stroke volume remains constant. Changes in peripheral resistance, however, have little or no effect on pulse pressure, because a change in total peripheral resistance causes parallel change in both systolic and diastolic pressures.