Regulation of Hemostasis

July 23, 2017 Anticoagulant Therapy, Cardiology, Hematology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , ,

Key events that initiate and propagate coagulation are the redistribution of negatively charged phospholipids to the cell surface and the exposure of tissue factor to the blood. The appropriate negatively charged phospholipids, primarily phosphatidylserine, can arise as a result of either cellular activation with strong agonists like thrombin together with collagen in the case of platelets or tissue damage or death. The negatively charged phospholipids promote the activation of factor X and IX by the tissue factor-factor VIIa pathway, the activation of prothrombin by factors Va and Xa, and the activation of factor X by factors VIIIa and IXa. In addition, it has been suggested that oxidation of a specific disulfide in tissue factor is important for expression of its procoagulant activity, a process that may be regulated by protein disulfide isomerase, although this concept remains controversial.

Normally tissue factor is not present on cells in contact with blood. Tissue factor is found on extravascular cells surrounding the blood vessel so that a potent procoagulant surface is exposed when the endothelium is breached. This helps to seal the breach. Intravascularly, inflammatory stimuli can induce tissue factor synthesis and expression on leukocytes, particularly monocytes, providing a mechanism for the initiation of coagulation. This response likely contributes to disseminated intravascular coagulation (DIC). Animal studies suggest that this coagulation response plays a role in innate immunity and prevents the dissemination of infectious agents.

Other key events that can play a major role in the pathogenesis of thrombosis, at least in animal models, involve the release of intracellular components, including ribonucleic acid (RNA) and polyphosphates. These can trigger activation of factor XII, which initiates coagulation via the contact pathway. Although factor XII does not appear to contribute to hemostasis, it drives several models of thrombosis, including pulmonary embolism and myocardial infarction.

Polyphosphates are stored in the dense granules of platelets and when released, contribute to the procoagulant potential of the platelet. In regions of cellular death or severe inflammation, histones released from the tissue can bind to these polyphosphates, increasing the procoagulant activity more than 20-fold. Heparin analogues can block polyphosphate stimulation of coagulation by histones. In addition, neutrophils in hyperinflammatory environments can release their nuclear contents to form neutrophil extracellular traps (NETs). These NETs are effective in killing bacteria and other pathogens and also provide a potent agonist for the activation of platelets and the development of thrombi. Interestingly, heparin, an anticoagulant often used in the setting of inflammation, can disrupt the NETs and diminish the activation of platelets by histones and NETs.

Inhibition of Coagulation

There are three major natural anticoagulant mechanisms that serve to limit the coagulation process. These are tissue factor pathway inhibitor (TFPI), which blocks the initiation of coagulation by tissue factor-factor VIIa; the antithrombin-heparin mechanism, which inhibits thrombin and factors VIIa, Xa, and IXa; and the protein C pathway, which inactivates factors Va and VIIIa.

  1. Tissue factor pathway inhibitor (TFPI)
  2. Antithrombin-heparin mechanism
  3. Protein C pathway

Tissue Factor Pathway Inhibitor

TFPI is a complex molecule composed of three similar domains related to a protease inhibitor type known as Kunitz inhibitor. To inhibitor the tissue factor-factor VIIa complex, the Kunitz-1 domain of TFPI binds factor VIIa, whereas the Kunitz-2 domain binds factor Xa, either because the factor X is activated on tissue factor or (probably less effectively) by first reacting with factor Xa in solution and then inhibiting factor VIIa bound to tissue factor, thus blocking the initiation of coagulation. The carboxy terminal portion of TFPI is very basic, potentially facilitating interaction with the endothelium. Protein S can augment the activity of TFPI by increasing the rate of TFPI inactivation of factor Xa. The physiologic importance of TFPI is highlighted by the fact that gene deletion results in embryonic lethality apparently because of thrombosis and subsequent hemorrhage.

  1. Inhibiting Xa (Xa-TFPI complex)
  2. Xa-TFPI complex Inhibits FVIIa-TF complex
  3. TFPI is necessary for life

Antithrombin and Heparin

Antithrombin is the major inhibitor of the coagulation proteases thrombin, factor VIIa, factor Xa, and factor IXa. Antithrombin is a member of a large class of protease inhibitors referred to as serine protease inhibitors and abbreviated sermons. Antithrombin forms a very tight complex with these proteases. This reaction is rather slow with a half-life in the order of 30 seconds in plasma. Heparin markedly accelerates the reaction, thus accounting for most of its anticoagulant activity. There is a “bait” region in antithrombin that is involved in its interaction with the proteases. In the absence of heparin, this bait region is only partially available to the protease, resulting in the slow inhibition. Heparin binding to antithrombin induces a conformational change in antithrombin that enhances protease access to the bait loop.

In addition to the conformational change in antithrombin, heparin has additional roles in the inhibition of coagulation proteases. High-molecular-weight heparin can bind to both antithrombin and the protease, creating a situation where both reactants are brought into close proximity, thus increasing the reaction rate. This function is of variable importance with different proteases of the cascade. It is essential for thrombin inhibition, but plays a less important role in the inhibition of factor Xa. High-molecular-weight heparins accelerate factor Xa inhibition somewhat better than low-molecular-weight forms, but in contrast to most of the other heparin-mediated inhibitory functions, the additional acceleration gained by the high-molecular-weight forms is dependent on calcium ions. It is of interest that as heparins become processed to generate lower-molecular-weight fractions, such as enoxaparin, the capacity to promote thrombin inhibition versus factor Xa inhibition decreases. With the smallest functional form of heparin, the synthetic pentasaccharide fondaparinux, the ability to augment thrombin inhibition is almost completely lost, while good inhibition of factor Xa is maintained. Although heparin is a potent antithrombin-dependent anticoagulant, it is not effective against clot-bound thrombin or the factor Va-factor Xa complex assembled on membrane surfaces.

The importance of antithrombin is documented by the clinical observation that antithrombin deficiency, even to 50% of normal, is associated with significant thrombotic problems in humans and mice. Deletion of the gene in mice causes embryonic lethality, apparently in a mechanism that involves thrombosis followed by hemorrhage. Although heparin-like proteoglycans have been proposed to be important in modulating antithrombin function, immunohistochemical analysis indicates that most of these are localized to the basolateral side of the endothelium. No definitive deletion of heparin sulfate proteoglycans has been reported, possibly because there are alternative mechanisms for its biosynthesis. However, deletion of ryudocan, another heparin-like proteoglycan, is associated with a thrombotic phenotype.

  1. Antithrombin is ineffective against clot-bound thrombin or the factor Va-factor Xa complex assembled on membrane surfaces
  2. Heparin itself has no anticoagulation effect
  3. Heparin accelerates the anticoagulation capacity of antithrombin
  4. Deficiency of heparin-like proteoglycan potentiates patients at risk of thrombosis

The Thrombomodulin and Protein C Anticoagulation Pathway

The protein C pathway serves many roles, probably the primary role being to work to generate activated protein C (APC) that in turn inactivates factors Va and VIIIa to inhibit coagulation. The importance of this anticoagulant activity is readily apparent because patients born without protein C die in infancy of massive thrombotic complication (purport fulminans) unless provided a protein concentrate.

The protein C anticoagulant pathway serves to alter the function of thrombin, converting it from a procoagulant enzyme into the initiator of an anticoagulant response. This occurs when thrombin binds to thrombomodulin, a proteoglycan receptor primarily on the surface of the endothelium. Thrombomodulin binds thrombin with high affinity, depending on the posttranslational modifications of thrombomodulin. Binding thrombin to thrombomodulin blocks most of thrombin’s procoagulant activity such as the ability to clot fibrinogen, activate platelets, and activate factor V but does not prevent thrombin inhibition by antithrombin. The thrombin-thrombomodulin complex gains the ability to rapidly activate protein C. In the microcirculation, where there is high ratio of endothelial surface to blood volume, it has been estimated that the thrombomodulin concentration is in the range of 100 to 500 nM. Thus a single pass through the microcirculation effectively strips thrombin from the blood, initiates protein C activation, and holds a coagulantly inactive thrombin molecule in place for inhibition by antithrombin or protein C inhibitor. Activation of protein C is augmented approximately 20-fold in vivo by the endothelial cell protein C receptor (EPCR). EPCR binds both protein C and APC with similar affinity. The EPCR-APC complex is capable of cytoprotective functions, but at least with soluble EPCR, this complex is not an effective anticoagulant. Instead, when APC dissociates from EPCR, it can interact with protein S to inactivate factors Va and VIIIa and thus inhibit coagulation. Factor V increases the rate at which the APC-protein S complex inactivates factor VIIIa.

Thrombomodulin also increases the rate at which thrombin activates thrombin-activatable fibrinolysis inhibitor (TAFI) to a similar extent as it dose protein C. Once activated, TAFI releases C-terminal lysine and arginine residues of fibrin chains. C-terminal lysine residues on fibrin enhance fibrin degradation by serving as plasminogen- and tissue plasminogen activator-binding sites. Consequently, their removal by activated TAFI (TAFIa) attenuates clot lysis.

More than any other regulatory pathway except tissue factor, the protein C pathway is sensitive to regulation by inflammatory mediators. Tumor necrosis factor-alpha and IL-1beta downregulate thrombomodulin both in cell culture and in at least some patients with sepsis. Downregulation of thrombomodulin has been observed in animal models of diabetes, inflammatory bowel disease, reperfusion injury in the heart, over human atheroma, and in villitis, in addition to sepsis.

  1. Protein C, thrombomodulin, and EPCR are essential for life
  2. Protein C targets against factors Va and VIIIa
  3. EPCR increases the protein C activation by thrombin-thormbomodulin complex by about 20-fold
  4. Protein C’s anticoagulation function needs the help of protein S
  5. Thrombin-thrombomodulin complex removes the C-terminal lysine residues of fibrin, which attenuates clot fibrinolysis.

Regulation of Fibrinolysis

Fibrinolysis is the process by which fibrin clots are dissolved, either through natural mechanisms or with the aid of pharmaceutical interventions. Plasmin is the serine protease that solubilizes fibrin. Plasmin is generated by the activation of its precursor plasminogen either by natural activators, tissue plasminogen activator (tPA), the major activator in the circulation, or urokinase plasminogen activator (uPA), or by administration of recombinant tPA or streptokinase, a bacterial protein that promotes plasmin generation and aids in dissemination of the bacteria. Staphylokinase, a protein from Staphylococcus aureus, is similar to streptokinase and also has been examined as a potential therapeutic.

Fibrin plays an active role in its own degradation because it binds plasminogen and tPA, thereby concentrating them on the fibrin surface and promoting their interaction. The resultant plasmin cleaves fibrin and exposes C-terminal lysine residues that serve as additional plasminogen and tPA binding sites. TAFIa attenuates fibrinolysis by releasing these C-terminal lysine residues. Furthermore, lysine analogues, such as ε-aminocaproic acid or tranexamic acid, bind to tPA and plasminogen. Consequently, these lysine analogues can be used to treat patients with hyperfibrinolysis and can reduce bleeding complications.

Plasmin is not specific for fibrin and degrades a variety of other proteins. Consequently, plasmin is tightly controlled. There are two major inhibitors of fibrinolysis: α2-antiplasmin, and serpin that inactivates plasmin, and plasminogen activator inhibitor 1 (PAI-1), which inhibits tPA and uPA. α2-Antiplasmin is cross-linked to fibrin by activator factor XIII. PAI-1 is an intrinsically unstable serpin that can be stabilized by interaction with vitronectin. Because of its instability, the antigen and functional levels of PAI-1 are often quite different and can vary among individuals. PAI-1 is upregulated by lipopolysaccharide, tumor necrosis factor, and other inflammatory cytokines. PAI-1 levels are increased in vascular diseases such as atherosclerosis and in metabolic syndrome, sepsis, and obesity. Increased levels of PAI-1 result in decreased fibrinolytic activity, which increases the risk for thrombosis. PAI-1 is also stored in platelets and is released with platelet activation. Platelet-derived PAI-1 may limit the degradation of platelet-rich thrombi, such as those that trigger acute coronary syndromes.

Overall the fibrinolytic system is dynamic and responsive to local phenomena, such as platelet-derived PAI-1, as well as to systemic alterations like obesity and inflammation. In this sense, the fibrinolytic control mechanisms share many similarities with the control of coagulation, in which similar considerations affect their function.

EKG Findings Related to Myocardial Infarction

July 15, 2017 Cardiology, EKG/ECG No comments , , , , , ,

In most infarctions, the EKG will reveal the correct diagnosis. An EKG should be performed immediately on anyone in whom an infarction is even remotely suspected. However, the initial EKG may not always be diagnostic, and the evolution of electrocardiographic changes varies from person to person; therefore, it is necessary to obtain serial cardiograms once the patient is admitted to the hospital. During an acute myocardial infarction, the EKG evolves through three stages: 1) T-wave peaking followed by T-wave inversion, 2) ST-segment elevation, 3) the appearance of new Q waves.

T Wave

With the onset of infarction, the T waves become tall and narrow, a phenomenon called peaking. These peaked T waves are often referred to as hyperacute T waves. Shortly afterward, usually a few hours later, the T waves invert. These T-wave changes reflect myocardial ischemia, the lack of adequate blood flow to the myocardium. Ischemia is potentially reversible: if blood flow is restored or the oxygen demands of the heart are eased, the T waves will revert to normal. On the other hand, if actual myocardial cell death (true infarction) has occurred, T-wave inversion will persist for months to years. T-wave inversion by itself is indicative only of ischemia and is not diagnostic of myocardial infarction. T-wave inversion is a very nonspecific finding. Many things can cause a T wave to flip. One helpful diagnostic feature is that the T waves of myocardial ischemia are inverted symmetrically, whereas in most other circumstances, they are asymmetric, with a gentle downslope and rapid upslope. In patients whose T waves are already inverted, ischemia may cause them to revert to normal, a phenomenon called pseudonormalization. Recognition of pseudonormalization requires comparing the current EKG with a previous tracing. In young persons without any cardiac-related symptoms, T-wave inversion isolated to one geographic region of the heart, particularly one or two midprecordial leads, for example, V3 and V4, is usually a normal variant.

  • Peak and inversion
  • Only reflecting ischemia
  • Symmetrical
  • Pseudonormalization

ST Segment

ST-segment elevation is the second change that occurs acutely in the evolution of an infarction. ST-segment elevation signifies myocardial injury. Injury probably reflects a degree of cellular damage beyond that of mere ischemia, but it, too, is potentially reversible, and in some cases the ST segments may rapidly return to normal. In most instances, however, ST-segment elevation is a reliable sign that true infarction has occurred and that the complete electrocardiographic picture of infarction will evolve unless there is immediate and aggressive therapeutic intervention.

Even in the setting of a true infarction, the ST segments usually return to baseline within a few hours. Persistent ST-segment elevation often indicates the formation of a ventricular aneurysm, a weakening and bulging out of the ventricular wall. Like T-wave inversion, ST-segment elevation can be seen in a number of other conditions in addition to an evolving myocardial infarction. There is even a type of ST-segment elevation that can be seen in normal hearts. This phenomenon has been referred to as early depolarization or J point elevation.

The J point, or junction point, is the place where the ST segment takes off from the QRS complex. J point elevation is very common in young, healthy individuals. The ST segment usually returns to baseline with exercise. J point elevation has long been thought to have no pathologic implications. However, some research has reported a slightly increased risk of death from cardiac causes in patients with J point elevation in the inferior leads. How can the ST-segment elevation of myocardial injury be distinguished from that of J point elevation? With myocardial injury, the elevated ST segment has a distinctive configuration. It is bowed upward and tends to merge imperceptibly with the T wave. In J point elevation, the T wave maintains its independent waveform.

  • Elevation
  • Reflecting true infarction
  • Return to baseline within a few hours
  • J point elevation

Q Waves

The appearance of new Q waves indicates that irreversible myocardial cell death has occurred. The presence of Q waves is diagnostic of myocardial infarction. Q waves usually appear within several hours of the onset of infarction, but in some patients they may take several days to evolve. The ST segment usually has returned to baseline by the time Q waves have appeared. Q waves usually persist for the lifetime of the patient.

Other leads, located some distance from the site of infarction, will see an appear increase in the electrical forces moving toward them. They will record tall positive R waves. These opposing changes seen by distant leads are called reciprocal changes. The concept of reciprocity applies not only to Q waves but also to ST-segment and T-wave changes. Thus, a lead distant from an infarct may record ST-segment depression.

Small Q waves can be seen in the left lateral leads (I, aVL, V5, and V6) and occasionally in the inferior leads (especially II and III) of perfectly normal hearts. These Q waves are caused by the early left-to-right depolarization of the interventricular septum. Pathologic Q waves signifying infarction are wider and deeper. They are often referred to as significant Q waves. The criteria fro significance include: 1) The wave must be greater than 0.04 seconds in duration, 2) the depth of the Q wave must be at least one-third the height of the R wave in the same QRS complex. Because lead aVR occupies a unique position on the frontal plane, it normally has a very deep Q wave. Lead aVR should not be considered when using Q waves to look for possible infarction.

Acute Potassium Disorders

July 15, 2017 Cardiology, Clinical Skills, Critical Care, Differential Diagnosis, EKG/ECG No comments , , , , ,

Disorders of potassium homeostasis are common in hospitalized patients and may be associated with severe adverse clinical outcomes, including death. Prevention and proper treatment of hyper- and hypokalemia depend on an understanding of the underlying physiology.

The total body potassium content of a 70-kg adult is about 3500 mmol (136.5 g), of which only 2% (about 70 mmol / 2.73 g) is extracellular. It is not surprising that the extracellular potassium concentration is tightly regulated. In fact, two separate and cooperative systems participate in potassium homeostasis. One system regulates external potassium balance: the total body parity of potassium elimination with potassium intake. The other system regulates internal potassium balance: the distribution of potassium between the intracellular and extracellular fluid compartments. This latter system provides a short-term defense against changes in the plasma potassium concentration that might otherwise result from total body potassium losses or gains.

Disorders of Potassium Homeostasis

Disorders of potassium homeostasis may be conveniently divided according to the duration of the disturbance: acute (<48 hours’ duration) or chronic.

Acute Hyperkalemia

Excessive potassium intake. Given an acute potassium load, a normal individual will excrete about 50% in the urine and transport about 90% of the remainder into cells over 4 to 6 hours. It is possible to overwhelm this adaptive mechanism such that if too much potassium is taken in too quickly, significant hyperkalemia will result. Such events are almost always iatrogenic. One’s ability to tolerate a potassium load declines with disordered internal balance and impaired renal potassium excretory capacity. In such circumstances, an otherwise tolerable increase in potassium intake may cause clinically significant hyperkalemia: Doses of oral potassium supplements as small as 30 to 45 mmol have resulted in severe hyperkalemia in patients with impaired external or internal potassium homeostasis.

KCl, used as a supplement, is the drug most commonly implicated in acute hyperkalemia. Banked blood represents a trivial potassium load under most circumstances, because a unit of fresh banked blood, either whole or packed cells, contains only 7 mmol (273 mg) of potassium. Thus, severe hyperkalemia would result only from massive transfusion of compatible blood. However, the potassium concentration in banked blood does increase substantially as the blood ages.

Patients undergoing open heart surgery are exposed to cardioplegic, solutions containing KCl typically at about 16 mmol/L, which may lead to clinically significant hyperkalemia in the postoperative period, especially in patients with diabetes mellitus with or without renal failure.

Abnormal potassium distribution. Acute hyperkalemia may result from sudden redistribution of intracellular potassium to the extracellular space. If only 2% of intracellular potassium were to leak unopposed from cells, serum potassium level would immediately double. Fortunately, such dramatic circumstances are rarely encountered. Nevertheless, smaller degrees of potassium redistribution commonly result in clinically significant hyperkalemia.

Among the most impressive syndromes associated with acute hyperkalemia are those involving rapid cell lysis. The tumor lysis syndrome results from treatment of chemosensitive bulky tumors with release of intracellular contents, including potassium, into the ECF. Extreme hyperkalemia even causing sudden death has featured prominently in some series of patients. Most of such patients were in renal failure from acute uric acid nephropathy, thus impairing their ability to excrete the potassium load. Rhabdomylosis, either traumatic or nontraumatic, may result in sudden massive influx of potassium to the extracellular space. Other circumstances that may result in redistributive hyperkalemia include severe extensive burns, hemolytic transfusion reactions, and mesenteric ischemia or infarction.

Pharmacologic agents. Two drugs may rarely cause acute hyperkalemia by redistribution: digitalis glycosides and succinylcholine. Massive digitalis overdose has been associated with extreme hyperkalemia. Succinylcholine depolarizes the motor end plate and in normal individuals causes a trivial amount of potassium leak from muscle, resulting in an increase in serum potassium level by about 0.5 mmol/L. In patients with neuromuscular disorders, muscle damage, or prolonged immobilization, however, muscle depolarization may be more widespread, causing severe hyperkalemia. Prolonged use of nondepolarizing non depolarizing neuromuscular blockers in critically ill patients may predispose to succinylcholine-induced hyperkalemia.

Hyperkalemic periodic paralysis. This rare syndrome of episodic hyperkalemia and paralysis is caused by a mutation of the skeletal muscle sodium channel, inherited in an autosomal dominant pattern. Attacks may be precipitated by exercise, fasting, exposure to cold, and potassium administration, and prevented by frequent carbohydrate snacks. Attacks are usually brief and treatment consists of carbohydrate ingestion. Severe attacks may require intravenous glucose infusion.

Acute renal failure. Hyperkalemia accompanies acute renal failure in 30% to 50% of cases. It is seen most commonly in oliguric renal failure. Contributing factors include tissue destruction and increased catabolism.

Pseudohyperkalemia. It refers to a measured potassium level that is higher than that circulating in the patient’s blood. It has a number of possible causes. First, it may be caused by efflux of potassium out of blood cells in the test tube after phlebotomy. This may be seen in a serum specimen in cases of thrombocytosis or leukocytosis, when the clot causes cell lysis in vitro. These days, many clinical laboratories measure electrolytes in plasma (unclotted) specimens. Even under these conditions, extreme leukocytosis may cause pseudohyperkalemia if the specimen is chilled for a long time before the plasma is separated, leading to passive potassium leak from cells. Hemolysis during specimen collection with false raise [K+] or plasma potassium concentration by liberating intraerythrocyte to potassium. Second, if the patient’s arm is exercised by fist clenching with a tourniquet in place before the specimen is drawn, the sampled blood potassium concentration will rise significantly as a result of local muscle release of intracellular potassium.

Acute Hypokalemia

Treatment of diabetic ketoacidosis. It is well recognized that patients presenting in DKA are always severely depleted in total body potassium as a result of glucose-driven osmotic diuresis, poor nutrition, and vomiting during the development of DKA. Paradoxically, most patients in DKA have a normal serum potassium level upon admission. Insulin deficiency and hyperglycemia appear to account for the preservation of a normal [K+] despite severe total body potassium depletion. Once therapy for DKA is instituted, however, [K+] typically plummets as potassium is rapidly taken up by cells. Potassium replacement at rates up to 120 mmol (4.68 g) per hour have been reported, with total potassium supplementation of 600 to 800 mmol (23.5 to 31.2 g) within the first 24 hours of treatment. Hypokalemia in this setting may lead to respiratory arrest.

Refeeding. A situation analogous to DKA arises during aggressive refeeding after prolonged starvation or with aggressive “hyperalimentation” of chronically ill patients. The glucose-stimulated hyperinsulinemia and tissue anabolism shift potassium into cells, rapidly depleting extracellular potassium.

Pharmacologic agents. Specific beta2-adrenergic receptor agonists may cause electrophysiologically significant hypokalemia, especially when given to patients who are potassium depleted from the use of diuretic drugs. Epinephrine, given intravenously in a dose about 5% of that recommended for cardiac resuscitation, cause a fall in [K+] by about 1 mmol/L. A rare cause of severe hypokalemia is poisoning with soluble barium salts such as chloride, carbonate, hydroxide, and sulfide. Soluble barium salts are used in pesticides and some depilatories, which may be ingested accidentally or intentionally. Thiopentone, a barbiturate used to induce coma for refractory intracranial hypertension, is associated with redistributive hypokalemia in the majority of treated patients within 12 hours of initiating therapy.

Hypokalemic periodic paralysis. Three forms of this rare syndrome have been described: familial, sporadic, and thyrotoxic. All have in common attacks of muscle weakness accompanied by acute hypokalemia caused by cellular potassium uptake.

Pseudohypokalemia. Severe leukocytosis may cause spuriously low plasma potassium concentrations if blood cells are left in contact with the plasma for a long time at room temperature or higher. This phenomenon results from ongoing cell metabolism in vitro with glucose and potassium uptake. Unexpected hypokalemia and hypoglycemia in the setting of leukocytosis should alert the clinician to this phenomenon.


Potassium exchange between ECF and ICF: insulin, epinephrine, and [H+]

Potassium renal secretion: [K+], dietary intake of potassium, AngII, aldosterone, tubular sodium delivered to principal cells (at distal nephron).

EKG Changes of Potassium Disturbances



Hyperkalemia produces a progressive evaluation of changes in the EKG that can culminate in ventricular fibrillation and death. The presence of electrocardiographic changes is a better measure of clinically significant potassium toxicity than the serum potassium level. As the potassium begins to rise, the T waves across the entire 12-lead EKG begin to peak. This effect can easily be confused with the peaked T waves of an acute myocardial infarction. One difference is that the changes in an infarction are confined to those leads overlying the area of the infarct, whereas in hyperkalemia, the changes are diffuse. With a further increase in the serum potassium, the PR interval becomes prolonged, and the P wave gradually flattens and then disappears. Ultimately, the QRS complex widens until it merges with the T wave, forming a sine wave pattern. Ventricular fibrillation may eventually develop.

It is important to note that whereas these changes frequently do occur in the order described as the serum potassium rises, they do not always do so. Progression to ventricular fibrillation can occur with devastating suddenness. Any change in the EKG due to hyperkalemia mandates immediate clinical attention.


With hypokalemia, the EKG may again be a better measure of serious toxicity than the serum potassium level. Three changes can be seen, occurring in no particular order, including: ST-segment depression, flattening of the T wave with prolongation of the QT interval, and appearance of a U wave. The term U wave is given to a wave appearing after T wave in the cardiac cycle. It is usually has the same axis as the T wave and is often best seen in the anterior leads. Its precise physiologic meaning is not fully understood. Although U waves are the most characteristic feature of hypokalemia, they are not in and of themselves diagnostic. Other conditions can produce prominent U waves, and U waves can sometimes be seen in patients with normal hearts and normal serum potassium levels. Rarely, severe hypokalemia can cause ST-segment elevation. Whenever you see ST-segment elevation or depression on an EKG, you first instinct should always be to suspect some form of cardiac ischemia, but always keep hypokalemia in your differential diagnosis.

Evaluation of Chronic Heart Failure

July 12, 2017 Cardiology, Critical Care, Differential Diagnosis, Laboratory Medicine No comments , , , ,

Table 28-3 and 28-4, taken from the European Society of Cardiology heart failure guideline, recommend a routine assessment to establish the diagnosis and likely cause of heart failure. Once the diagnosis of heart failure has been made, the first step in evaluating heart failure is to determine the severity and type of cardiac dysfunction, by measuring ejection fraction through two-dimensional echocardiography and/or radionuclide ventriculography. Measurement of ejection fraction is the gold standard for differentiating between the two forms of heart failure, systolic and diastolic, and is particularly important given that the approaches to therapy for each syndrome differ somewhat. The history and physical examination should include assessment of symptoms, functional capacity, and fluid retention.


Functional capacity is measured through history taking or preferably an exercise test. Analysis of expired air during exercise offers a precise measure of the patient’s physical limitations. However, this test is uncommonly performed outside of cardiac transplant centers. The NYHA has classified heart failure into four functional classes that may be determined by history taking. The NYHA functional classification should not be confused with the stages of heart failure described in the American College of Cardiology/American Heart Association heart failure guideline. The NYHA classification describes functional limitation and is applicable to stage B through stage D patients, whereas the staging system describes disease progression somewhat independently of functional status.

Assessment of fluid retention through measurement of jugular venous pressure, auscultation of the lungs, and examination for peripheral edema is central to the physical examination of heart failure patients.

Given the limitation of physical signs and symptoms in evaluating heart failure clinical status, a number of noninvasive and invasive tools are under development for the assessment of heart failure. One such tool that has proven useful in determining the diagnosis and prognosis of heart failure is the measurement of plasma B-type natriuretic peptide (BNP) levels. Multiple studies demonstrate the utility of BNP measurement in the diagnosis of heart failure. The diagnostic accuracy of BNP at a cutoff of 100 pg/mL was 83.4 percent. The negative predictive value of BNP was excellent. At levels less than 50 pg/mL, the negative predictive value of the assay was 96%.


Based largely on the findings of the BNP Multinational Study, clinicians were advised that a plasma BNP concentration below 100 pg/mL made the diagnosis of congestive heart failure unlikely, while a level above 500 pg/mL made it highly likely. For BNP levels between 100 pg/mL and 500 pg/mL, the use of clinical judgement and additional testing were encouraged.

Additionally, plasma BNP is useful in predicting prognosis in heart failure patients. However, serial measurement of plasma BNP as a guide to heart failure management has not yet been proven useful in the management of acute or chronic heart failure.

[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.