17: Cardiologic Principles II: Hemodynamics

Adequate tissue perfusion depends on maintenance of volume status, vascular resistance, cardiac contractility, and cardiac rhythm. All of these components of the hemodynamic system are vulnerable to the effects of xenobiotics. Cardiovascular toxicity may therefore be manifested by the development of hemodynamic instability, heart failure, cardiac conduction abnormalities, or dysrhythmias. The presence of a specific pattern of cardiovascular anomalies (toxicologic syndrome or “toxidrome”) may suggest a particular class or type of xenobiotic.

In addition, an alteration in hemodynamic functioning may be the indirect result of metabolic abnormalities. Poisoning with a xenobiotic may lead to development of acid base disturbances, hypoxia, or electrolyte abnormalities with secondary hemodynamic changes. In these patients, supportive care with ventilation, oxygenation, and fluid and electrolyte repletion may improve the cardiovascular status. For example, salicylates may cause hypotension and cardiovascular collapse. These hemodynamic effects are primarily due to the systemic acidosis and electrolyte disturbances (Chap. 39).

Maintaining cardiac contractility, heart rate and rhythm, and vascular resistance requires complex modulation of the cardiac and vascular systems. Xenobiotics can cause hemodynamic abnormalities as a result of direct effects on the myocardial cells, on the cardiac conduction system, or on the arteriolar smooth muscle cells. These effects are frequently mediated by interactions with cellular ion channels or cell membrane neurohormonal receptors. These complex cellular systems provide multiple sites for xenobiotics to demonstrate their toxicologic effects. Xenobiotics and xenobiotic metabolites can interact with the cellular receptors, intracellular signal mechanisms, or with the effector enzymes and intracellular organelles.

Toxic effects of xenobiotics can obviously be due to direct poisoning from excessive amounts of a xenobiotic that follow an overdose. Additionally, slower accumulation of the xenobiotic or active metabolites (due to alterations in metabolism) can also lead to adverse effects. However, the toxic effects of a xenobiotic may be due largely to the properties and characteristics of the host subject. Underlying medical conditions, presence of other xenobiotics, electrolyte abnormalities, concurrent acid-base, and hydration status can all contribute to the potential adverse hemodynamic effects of a xenobiotic. Even with a usually non-harmful concentration of a xenobiotic, hemodynamic toxicity may occur due entirely to underlying genetic differences in the cellular receptors or the intracellular signal transducers in the particular patient.

This complex interaction between the xenobiotic and patient’s physiology and genetic diversity is exemplified by the cardiac disorder, ­Brugada syndrome. This congenital cardiac channelopathy (Chaps. 16 and 64) predisposes to sudden cardiac death due to polymorphic ventricular tachycardia or ventricular fibrillation. Brugada syndrome is characterized by an atypical right bundle branch pattern with a characteristic cove-shaped ST segment elevation in leads V1 to V3 of the electrocardiogram (ECG) in the absence or structural heart disease, ischemia, or electrolyte disturbances).^9,86 This typical type 1 Brugada ECG pattern is shown in Fig. 16–12. However, this distinctive ECG pattern may be concealed²⁶ and only unmasked by sleep, fever, bradycardia, or by xenobiotics such as vagotonic medications or class I antidysrhythmics (sodium channel blocking agents).^3,58 The reason for this variable and dynamic response to xenobiotics is the heterogeneous genetic basis of the disorder. Mutations in 10 different genes have been linked to the Brugada syndrome; more than 300 different mutations have been identified in the SCN5A gene alone (which encodes the α subunit of the cardiac sodium channel). Brugada syndrome is also associated with mutations in other ­cardiac ion channels and with mutations of the glycerol-3-phosphate 1-like (GDP1L) gene, which interacts with the cardiac sodium channel subunits at the cell membrane.⁴ The complexity of the potential xenobiotic interactions and variable potential for toxicity has lead to the establishment of a Web page (www.brugadadrugs.org) established by the Netherlands Heart Foundation and the University of Amsterdam to provide up-to-date classification of xenobiotics into those to avoid, those to preferably avoid, and those to potential use for treatment.^58,59

Autonomic Nervous System and Hemodynamics

In addition to the voltage-dependent ion channels, the cell membrane contains channels that open in response to receptor binding of neurotransmitters or neurohormones.^60-62 The hemodynamic effects of many xenobiotics are mediated by interactions with membrane receptors and by changes in the autonomic nervous system. The autonomic nervous system is functionally divided into the sympathetic (ie, adrenergic) and parasympathetic (ie, cholinergic) systems. The two systems, which share certain common features, function semi-independently of each other. Through complex feedback, the two systems provide the balance needed for existence under changing external conditions.

The sympathetic nervous system is primarily responsible for the maintenance of arteriolar tone and cardiac function. Norepinephrine is the primary postganglionic neurotransmitter of the sympathetic nervous system. On release into the synapse, norepinephrine binds to the postsynaptic adrenergic receptors to elicit an effect by the postsynaptic cell.

Cellular Physiology of Adrenergic Receptors

The effects of adrenergic xenobiotics on the cell are primarily mediated through a secondary messenger system of cyclic adenosine monophosphate (cAMP). The intracellular cAMP concentration is regulated by the membrane interaction of three components: the adrenergic receptor, a “G-protein” complex, and adenyl cyclase, the enzyme that synthesizes cAMP in the cell.^10,22,78,79 These receptors are described in detail in Chap. 14.

The G protein serves as a “signal transducer” between the receptor molecule in the cell membrane and the effector enzyme, adenyl cyclase, in the cytosol. The G proteins consist of three subunits: α, β, and γ.^14,52,53 The α subunit of the G protein complex binds to the adrenergic receptor in the cell membrane and to the adenyl cyclase enzyme. The G protein complex exists in several isomeric forms, depending on their interactions with the adenyl cyclase enzyme. These forms, G_s, G_i, and G_q have different functions in the regulation of cellular activity. The G_s protein complexes contain α_s subunits that stimulate adenyl cyclase when “activated” by adrenergic receptor interaction. These G_s complexes are primarily responsible for the stimulatory activity of β-adrenergic agonist agents. β₁- and β₂-adrenergic receptors interact primarily with β_s subunits in stimulatory G_s protein complexes. The α_i subunits of G_s proteins inhibit the activity of adenyl cyclase. Some β₂-adrenergic receptors and the α₂-adrenergic receptors interact with inhibitory G_i proteins to decrease the activity of adenyl cyclase. A third form, G_q, interacts with the α₁-adrenergic receptors, but does not interact directly with adenyl cyclase. Instead, the G_q interacts with phospholipase C to mediate the cell response to α₁-adrenergic stimulation.

The G protein complex is composed of the cellular receptor and the three subunits, α, β, and γ, which are involved in the cellular response to catecholamines. In the absence of a catecholamine at the receptor site, the receptor protein is bound to the β and β-γ–dimer of the G protein, and guanosine diphosphate (GDP) is bound to the α subunit. Catecholamine binding to the receptor causes a conformational change in the α subunit; GDP dissociates and guanosine triphosphate (GTP) binds to the α subunit. The α subunit (with GTP bound) then dissociates from the receptor and from the β-γ–dimer. This “activated” α subunit can now interact with adenyl cyclase or other effector enzymes. Interaction of the α_s subunit with adenyl cyclase increases the activity of the enzyme resulting in a rapid increase in the intracellular cAMP (Fig. 17–1).^{10,14,41,52,69}

cAMP acts as a secondary messenger in the cell. cAMP interacts with protein kinase A (PKA) and other cAMP-dependent protein kinases to increase their protein phosphorylating activity.⁴⁰ In the absence of cAMP, PKA is a tetramer of two regulatory and two catalytic subunits. cAMP binds to the regulatory subunits to release the active enzymatic units from the tetramer (Fig. 17–1). The activated protein kinases then transfer phosphate groups from ATP to serine (as well as to threonine and tyrosine amino acid groups) on enzymes that are involved in intracellular regulation and activities. Phosphorylation may increase or decrease the activity of specific enzymes, and specific protein kinases are highly selective in the proteins that they phosphorylate.^75,76

PKA phosphorylates a variety of cellular proteins involved in Ca²⁺ regulation, including the voltage-sensitive calcium channel, phospholamban, and troponin;^27,28,74 these are all involved in the regulation and control of cellular muscle fiber contraction. Phosphorylation of the l-type calcium channel increases the entry of calcium ions into the cell during membrane depolarization.⁵⁷ Phosphorylation of phospholamban decreases its ability to inhibit the calcium ATPase pump on the sarcoplasmic reticulum (SR). This decreased inhibition of the calcium ATPase pump increases the efficiency of Ca²⁺ storage in the SR. This enhances both the cellular contractility as the Ca²⁺ is released into the cell cytosol and the relaxation of muscle fibers as the Ca²⁺ is pumped back into the SR.⁵⁷

Physiologic Effects of Adrenergic Receptor Subclasses.

The existence of two types of adrenergic receptors, α and β, was first proposed in 1948 to explain both the excitatory and the inhibitory effects of catecholamines on different smooth muscle tissue.¹ The α receptor was subsequently subdivided into α₁ and α₂ when norepinephrine and other α-adrenergic agonists were found to inhibit the release of additional norepinephrine from neurons into the synapse. The α₁-adrenergic receptors are located on postsynaptic cells outside the central nervous system, primarily on blood ­vessels, and mediate arteriole constriction. The “autoregulatory” α₂-adrenergic receptors are primarily located on the presynaptic neuronal membrane and, when stimulated, decrease release of additional norepinephrine into the synapse. Additionally, some α₂-adrenergic receptors are also found on the postsynaptic membrane in the central nervous system. Activation of these postsynaptic α₂-receptors in the cardiovascular control center in the medulla and elsewhere in the central nervous system decreases sympathetic outflow from the brain. Thus, α₂-adrenergic agonists generally decrease peripheral vascular resistance, decrease heart rate, and decrease blood pressure. The α₁- and α₂-adrenergic receptors also interact with circulating catecholamines and other sympathomimetics. The effects of sympathomimetics vary in the different organ systems due to differences in the adrenergic receptors and in the cellular responses to the receptor interactions.

The β-adrenergic receptors are subclassified into three subtypes: β₁, β₂, and β₃ (Table 17–1). The most prevalent β-adrenergic subtype in the heart is β₁ (80%), although β₂ (20%) and β₃ (few) receptors are also present.^8,17,21,61 Stimulation of the β₁-adrenergic receptors increases heart rate, contractility, conduction velocity, and automaticity. The β₂-adrenergic receptors primarily cause relaxation of smooth muscle with resulting bronchodilation and arteriolar dilation. The β₃ receptors are located primarily on adipocytes where they play a role in lipolysis and thermogenesis.¹¹

The β₁-, β₂-, and α₂-adrenergic receptors all interact with G_s proteins and stimulate the adenyl cyclase enzyme. Differences in the resultant clinical effects are primarily related to the location and number of the different receptors in different tissues and to differences in the specificity of the tissue protein kinases activated by cAMP. Stimulation of the β₁-adrenergic receptor results in increased heart rate and increased contractility. β₂-Adrenergic receptor stimulation causes relaxation, as opposed to contraction, of smooth muscle. Because both β-adrenergic receptor subtypes interact with stimulatory G_s proteins, their clinical effects would appear to be paradoxical. However, there are two primary reasons for their different effects when G_s complexes are stimulated by β₁- or β₂-adrenergic agonists. First, PKA is not a single enzyme, but a group of related isoenzymes variably expressed in different tissues.^7,30,56 The actions and the substrates of the varied protein kinase isoenzymes differs between β₁- and β₂-adrenergic responsive tissues. Second, whereas β₁-adrenergic stimulation results in cAMP-mediated effects throughout the cytoplasm, β₂-adrenergic stimulation is compartmentalized within the cell. The effect of β₂-adrenergic stimulation of G_s type receptors is primarily localized phosphorylation of the L-type calcium channels, increasing their activity.^13,35,87,88 Additionally, some β₂-adrenergic receptors are also coupled to G_i-type receptors that inhibit adenyl cyclase and prevent the diffuse cytoplasmic increases in cAMP.^71,72,88 Also, β₂-adrenergic receptor stimulation does not result in phosphorylation of phospholamban³⁸ or troponins.¹³

The α₂-adrenergic receptor interacts with a G_i protein that has an inhibitory interaction with adenyl cyclase. Binding of α₂-adrenergic agonists to the receptor inhibits (not stimulates) adenyl cyclase and decreases intracellular cAMP.

The α₁-adrenergic receptors also are associated with G proteins. However, rather than being associated with G_s proteins and adenyl cyclase, the α₁-adrenergic receptors are associated with G_q proteins that are linked to phospholipase C.⁷⁷ Agonist binding to the receptor activates the hydrolysis of phosphatidyl inositol 4,5-bisphosphate (PIP₂) to 1,2-diacylglycerol (DAG) and inositol triphosphate (IP₃).²⁵ The IP₃ acts as an intracellular messenger, binds to receptors on the SR, and initiates the release of calcium ion.⁵ DAG activates protein kinase C, which phosphorylates slow calcium channels and other intracellular proteins, and increases the influx of calcium ion into the cell (Fig. 17–2).^63,70,91

Many xenobiotics interact with G-protein membrane receptors and alter the intracellular cAMP or Ca²⁺ concentration. β-Adrenergic antagonist overdose results in decreased stimulation of adenyl cyclase by G_s proteins, decreased production of cAMP, decreased activation of the cAMP-dependent kinases, and decreased Ca²⁺ release (Chap. 62). Similarly, by different mechanisms, calcium channel blocker overdose results in decreased cytoplasmic calcium concentration (Chap. 61).

Glucagon receptors, which are similar to the β-adrenergic receptors, are coupled to G_s proteins and stimulate adenyl cyclase activity.^{2,23,38,84,89} The ability of glucagon to increase cAMP is further enhanced by its inhibitory activity on phosphodiesterase (preventing cAMP breakdown).^18,48 Phosphodiesterase inhibitors, such as amrinone, milrinone, and enoximone, exert at least some of their inotropic activity by preventing the degradation of cAMP and enhancing calcium cycling.^42,81,85 In a canine model of propranolol poisoning, amrinone significantly increased inotropy, stroke volume, and cardiac output.⁴²

Intracellular Calcium, Calcium Channels, and Myocyte Contractility

The contraction and relaxation cycle of the myocyte is controlled by the flux of Ca²⁺ into and out of the SR into the cytoplasm of the cell.^15,39,66 Only a small proportion of the Ca²⁺ involved in myofibril contraction actually enters the cell through the exterior cell membrane during the action potential and membrane depolarization. The majority of the calcium is actually released from the SR of the cell invaginations of the myocyte membrane known as T-tubules place L-type calcium channels in close approximation to calcium release channels (ryanodine receptors {RyR}) on the sarcoplasmic reticulum. The local increase in Ca²⁺ concentration that follows the opening of a single L-type calcium channel triggers the opening of the associated RyR channels resulting in a large release of Ca²⁺ from the SR.¹² Myocytes contain tens of thousands of couplons, clusters of L-type calcium channels and RyR channels. The Ca²⁺ released from one couplon is not sufficient to trigger firing of neighboring couplons. Therefore, myocyte contraction requires synchronized release of Ca²⁺ from numerous couplons throughout the myocyte. The cell membrane depolarization synchronizes opening of L-type channels and subsequent Ca²⁺ release from the sarcoplasmic reticulum.^16,57 This phenomenon of calcium-induced calcium release results in a rapid increase in the intracellular Ca²⁺ concentration and initiates a rapid myosin and actin interaction.¹⁵

At the conclusion of cellular contraction, SR-associated Ca²⁺-adenosine triphosphatase (ATPase) pumps return the cytosolic Ca^2+-ATPase into the SR. This SR associated Ca²⁺-ATPase pump is regulated by phospholamban, a cellular protein. When phospholamban is bound to the Ca²⁺-ATPase pump, the activity of the pump is decreased and less Ca²⁺-ATPase is stored in the SR. Phosphorylation of phospholamban decreases its affinity for binding to the Ca²⁺-ATPase pump. Dissociation of the phosphorylated phospholamban increases the activity of the Ca²⁺-ATPase pump. β-Adrenergic stimulation increases protein kinase activity and leads to phosphorylation of phospholamban, dissociation of the phosphorylated phospholamban from the pump, and an increase in the total SR Ca²⁺ stores.^19,20 The increased activity of the SR associated Ca²⁺-ATPase pump enhances the contractility and increases the rate of relaxation of the myocytes.

Cellular contraction occurs when myosin filaments interact with the actin-tropomyosin helix. A complex of troponins T, I, and C binds to the actin helix near the myosin binding site and act as regulators of the interaction. Troponin T binds the regulatory complex to the actin helix, troponin I prevents myosin from accessing its binding site on the actin helix, and troponin C acts as a Ca²⁺ trigger to initiate contraction. When the intracellular Ca²⁺ concentration increases, 4 molecules of Ca²⁺ bind to troponin C and a conformational shift occurs in the troponin complex. Troponin I shifts away and the myosin-binding site is exposed. Myosin then binds to the exposed site and myofibril contraction occurs (Fig. 17–3).^31,32,67,68

Calcium transport through the cellular membrane ion channels is critical for normal cardiac muscle function and contractility and for maintenance of vascular smooth muscle tone. The physiologic response to calcium channel blockers and to xenobiotics that interact with the α- or β-adrenergic receptors is mediated through changes in the intracellular Ca²⁺. Calcium channel blockers in current clinical use primarily block the L-type calcium channel, although their specificity differs for the calcium channels on the vascular smooth muscle cells versus on the myocardial cells. This results in variable effects of the different calcium channel blockers on the vascular tone and peripheral vascular resistance, and on the contractility and electrical activity of the myocardial cells. Additionally, certain calcium channel blockers interact with the neuronal calcium channels, such as the P/Q type, and are used to treat neurologic disorders such as migraine headache.

Patients poisoned by calcium channel blockers have less Ca²⁺ entry into the cell during cardiac membrane depolarization. Administration of exogenous Ca²⁺ increases the concentration gradient across the cell membrane, enhances flow through available Ca²⁺ channels, and restores the triggered response of the RyR-2 channels to release Ca²⁺ from the sarcoplasmic reticulum (Antidotes in Depth: A29). Because β-adrenergic antagonists have negative effects on Ca²⁺ handling by the SR, similar effects occur in the myocyte affected by β-adrenergic antagonists.

In the vascular smooth muscle, the cytosolic Ca²⁺ concentration maintains the basal contraction of the vascular muscle. Any decrease of Ca²⁺ influx results in relaxation and arterial vasodilation.⁵⁵ Any influx of calcium binds calmodulin, and the resulting complex stimulates myosin light-chain kinase activity.⁴⁷ The myosin light-chain kinase phosphorylates myosin. The phosphorylated myosin has increased activity for binding to actin, which causes contraction (Fig. 61–1).^6,32

Xenobiotics may produce adverse effects on the cardiovascular system by acting on the myocardial cells or the autonomic nervous system to directly affect the heart rate, blood pressure, or cardiac contractility. Because metabolic abnormalities (especially acidemia, hypotension, hypoxia, and electrolyte abnormalities) can further exacerbate toxicity, or can be the sole cause of the cardiovascular abnormalities, correction of metabolic abnormalities must be a high priority in the treatment of patients with cardiovascular manifestations of poisoning. The terminal phase of any serious poisoning may include nonspecific hemodynamic abnormalities and ­cardiac dysrhythmias.

Heart Rate Abnormalities

Xenobiotics that directly cause dysrhythmias or cardiac conduction abnormalities usually affect the myocardial cell membrane. These abnormal rhythms, cardiac conduction abnormalities, and heart blocks are discussed in Chap. 16.

Bradycardia.

Sinus bradycardia is probably the most common xenobiotic-induced bradycardia. Xenobiotics (Table 17–2) produce bradycardia through different mechanisms. The xenobiotic may affect the central or peripheral nervous system or may affect rhythm generation or conduction in the heart. Most xenobiotics that cause central nervous system sedation, such as the sedative-hypnotics, opioids, and α₂-adrenergic receptor agonist (“centrally acting”) antihypertensives, will usually decrease sympathetic outflow to the heart and produce sinus bradycardia in the range of 40 to 60 beats/min. Digoxin, certain cholinergics, and α₁ agonists may produce bradycardia and heart block through the enhancement of vagal tone. Sodium channel activators, such as aconitine, cause bradycardia due to intracellular Na⁺ overload with a resultant alteration in Ca²⁺ handling. The most profound bradycardia results from overdoses of xenobiotics that have direct depressant effects on the cardiac pacemakers.⁷³ The inability to propagate an impulse within the cardiac conducting system may produce bradycardia or even asystole. Examples of xenobiotics that can produce pacemaker or conduction effects include calcium channel blockers and β-adrenergic antagonists.

Bradycardia, heart block, and asystole frequently are terminal events in patients with massive overdose of many noncardiotoxic xenobiotics. These dysrhythmias may occur as a result of direct effects on the myocardium or of indirect metabolic effects. For example, severe hyperkalemia or metabolic acidosis results in a wide complex, sinusoidal bradycardic rhythm.

Tachycardia.

Sinus tachycardia is the most common rhythm disturbance that occurs in poisoned patients. Parasympatholytic drugs, such as atropine, raise the heart rate by elimination of the inhibitory vagal influence. However, more rapid rates result from direct myocardial stimulatory effects, generally mediated by β-adrenergic agonism. For example, catecholamine excess (eg, cocaine, psychomotor agitation, methylxanthines, sedative-hypnotic withdrawal) may cause sinus tachycardia with rates faster than 150 beats/min. Tachycardia may also be an indirect effect in response to hypotension, hypoxia, acidemia, fever electrolyte abnormalities, and other metabolic derangements that may be present in poisoned patients (Table 17–3).

Decreased Cardiac Contractility and Congestive Heart Failure

Xenobiotics can reduce cardiac contractility with a resulting decrease in cardiac ejection fraction and cardiac output, a decrease in blood pressure, and development of congestive heart failure (CHF). Cardiogenic pulmonary edema generally occurs as a result of the direct effects of the xenobiotic on the contractility, or inotropy, of the heart, or through increases in the preload or afterload. Acute cardiogenic pulmonary edema, resulting from impaired left heart filling (which may be due to decreased cardiac output), occurs in patients poisoned by a nondihydropyridine calcium channel blocker or β-adrenergic receptor antagonist. Other xenobiotics that can exert direct depressant effects on cardiac contractility include antihistamines, phenothiazines, antidysrhythmics, and local anesthetics. Many of these xenobiotics reduce contractility through sodium channel blockade, which, by slowing intraventricular conduction, reduces the ability of the heart to contract efficiently. Pulmonary edema may also result from the fluid overload accompanying ingestion of large quantities of sodium-­containing xenobiotics (eg, sodium penicillin), the renal effects of medications such as nonsteroidal antiinflammatory drugs, or as a late consequence of xenobiotics that cause kidney failure (Chap. 28).

Xenobiotics can cause cardiomyopathy through chronic toxic effects directly on the myocardium or indirectly through effects on blood pressure or cardiac vasculature (Table 17–4). In most cases, the exact mechanism of the toxicity is not known. However, free radical generation, nitric oxide formation, acetaldehyde production, myocardial ischemia, mechanical overload, nutritional deficiency, and persistent tachycardia are each implicated in the cellular toxicity of the various xenobiotics and development of cardiomyopathy.

Blood Pressure Abnormalities

Blood pressure is dependent upon cardiac and vascular function. The blood pressure is directly related to the heart rate (HR), the stroke volume (SV), and the systemic vascular resistance (SVR): Blood pressure = HR × SV × SVR. The systolic component of the blood pressure measurement is a reflection of the inotropic state of the myocardium, whereas the diastolic component reflects the vascular tone. It is important to consider both components of the blood pressure. Blood pressure may be expressed also as the mean arterial pressure (MAP) during a single cardiac cycle. Since at normal heart rates the duration of diastole is approximately twice that of systole, the MAP is calculated as ({2 × diastolic} + {systolic}/3). Xenobiotics may affect either component, and compensatory mechanisms within the cardiovascular system may produce recognizable patterns of blood pressure alterations.

Many xenobiotics affect blood pressure by modulation of normal neurotransmission at the postganglionic sympathetic neurons. Through these interactions they may cause, for example, vasoconstriction with an α-adrenergic agonist or increased inotropy with a β₁-adrenergic agonist. Because of the functional similarity of most sympathomimetics, physical examination alone seldom identifies the specific causative xenobiotic in any tachycardic patient. However, often a clinical constellation of signs and symptoms can be identified that is associated with this general class. For example, patients who ingest sympathomimetic amines such as cocaine or amphetamines typically have central nervous system stimulation, hypertension, and tachycardia (Chap. 3).

Hypertension Caused by Xenobiotics.

Hypertension may be the result of an increase in either inotropy or vascular resistance or both. For example, stimulation of the α₁-adrenergic receptor causes hypertension through vasoconstriction, and stimulation of the β₁-adrenergic receptor causes hypertension through enhanced myocardial contractility (Table 17–5).

The hemodynamic results of a xenobiotic overdose depend on the specific xenobiotic ingested and the relative action on the various types of receptors. This suggests that, among β-adrenergic agonists, only those with a predominant β₁-adrenergic effect cause hypertension. ­Nonselective β-adrenergic agonists (those that agonize at both β₁ and β₂) produce β₁-mediated systolic hypertension (through inotropic effects) with β₂-mediated vascular vasodilation and diastolic hypotension. This may result in a widened pulse pressure, which is the numerical difference between the systolic and diastolic pressures. Exposure to selective β₂-adrenergic agonists (eg, albuterol) may also result in tachycardia and enhanced inotropy with a widened pulse pressure in a manner analogous to nonselective β agonists. The resulting blood pressure depends on the relative physiologic balance between inotropy and vasodilation.

Xenobiotics that interact only with the α₁-adrenergic receptor (such as phenylephrine) cause vasoconstriction and hypertension. Baroreceptors detect the increased blood pressure and signal the parasympathetic nervous system neurons of the vagus nerve to fire and slow the heart rate. In the absence of β-adrenergic stimulation, a “reflex” bradycardia results. Norepinephrine is an α₁-adrenergic agonist with additional β-adrenergic activity. Profound hypertension is the primary hemodynamic toxic effect due to the activity of norepinephrine as both a positive inotrope (β₁) and a vasoconstrictor (α₁). Reflex bradycardia does not occur as a result of stimulation of the cardiac β₁-adrenergic receptors.

Hypotension Caused by Xenobiotics.

Typically, hypotension in adults is arbitrarily defined as a systolic blood pressure of less than 90 mm Hg or a MAP of less than 70 mm Hg. However, this is not an adequate clinical parameter. Young children and adults with a small body habitus may have a normal systolic pressure less than 90 mm Hg (Chap. 3). Patients with hypothermia have decreased metabolic demands, and a lower blood pressure may be considered “normal” for these patients. Most importantly, patients with long-standing hypertension may have inadequate tissue perfusion even with a MAP of more than 70 mm Hg. The cerebral arterioles normally constrict or dilate to maintain a relatively constant cerebrovascular blood flow despite changes in the peripheral blood pressure. Chronically hypertensive patients lose this autoregulatory response as a consequence of atherosclerotic disease, arteriolar hypertrophy, or arteriolar smooth muscle constriction. These narrowed arterioles may require a higher peripheral blood pressure to properly perfuse the brain.

Clinically, hypotension is defined as blood pressure that is inadequate to perfuse tissues. The clinical assessment of tissue perfusion is based on the vital signs, skin color, capillary refill, mental status, urine output and concentration, and acid–base balance (eg, serum lactate concentration). However, if a xenobiotic directly affects one or more of these parameters, the clinical assessment of volume and hemodynamic status may be difficult. Measurement of central venous pressure is beneficial in the early treatment of the sepsis syndrome, and most likely would be beneficial in the treatment of other causes of hypotension, including those occurring in poisoned patients. Ultrasound of the inferior vena cava (IVC) has been shown to be useful for assessing volume status and estimating central venous pressure (CVP).^34,51,83,90 Invasive measurement of cardiac filling pressure, cardiac output, systemic vascular resistance, and arterial pressures may be necessary in critically ill patients with severe poisoning.^64,65

Poor tissue perfusion may result from hypovolemia, decreased peripheral vascular resistance, myocardial depression, or a dysrhythmia that reduces cardiac output. A single xenobiotic may exert several effects on the hemodynamic system, such as diltiazem, a calcium channel blocker that causes negative inotropy and vasodilation. Appropriate treatment of the hypotension requires an understanding of the pathophysiologic consequences of the xenobiotic and the resultant hemodynamic derangement (Table 17–6).

Hypotension in a poisoned patient may also be due to intravascular volume depletion. Intravascular volume may decrease due to gastrointestinal, urinary, or insensible losses; or fluid may redistribute from the intravascular space into the intracellular, interstitial, pleural, or peritoneal spaces. Xenobiotics can cause significant intravascular volume depletion through all of these mechanisms.

Hypotension may also be caused by xenobiotics that affect venous tone. These xenobiotics increase venous capacitance, decrease the central venous pressure, and result in relative hypovolemia. The effects may be mediated via central effects on the sympathetic nervous system or direct effects on the peripheral vasculature. Sedative hypnotics and central α₂-adrenergic agonists (eg, clonidine) decrease the central sympathetic outflow and may result in hypotension. Other xenobiotics directly block peripheral α₁-adrenergic receptors or stimulate β₂-adrenergic receptors on the blood vessels to produce vascular smooth muscle relaxation, venodilation, and hypotension. A large number of xenobiotics are reported to cause hypotension; however, the hypotension often is not a direct action of the xenobiotic. Rather, the cause of hypotension is coexisting hypoxia, acidemia, anaphylaxis, volume depletion, or dysrhythmias.

Identification of the specific xenobiotic causing hypotension requires the integration of a detailed history, complete physical examination, and laboratory studies. Often the identification of the specific xenobiotic responsible for hypotension is based on other physical findings associated with the xenobiotic or recognition of a specific toxic syndrome.

Assessment of volume status may be particularly difficult in the poisoned patient because of functional alterations in the patient’s autonomic nervous system and the pharmacologic effects of the xenobiotic. For example, the usual signs of salt and water depletion, such as dry mucous membranes, dry skin, low blood pressure, tachycardia, narrowed pulse pressure, clouded sensorium, and decreased urine output, can be mimicked by a number of xenobiotics, including tricyclic antidepressants. Additionally, hypovolemic patients may present with diaphoresis, flushed skin, hypertension, bradycardia, or increased urine output following exposure to a cholinergic xenobiotic such as an organic phosphorus compound. In most cases, clinical assessment of CVPs and neck vein distension or the hemodynamic response to a fluid bolus can assist in the determination of the patient’s volume status. A central venous or pulmonary artery pressure catheter may be required in some critically ill patients.

Additional information about the patient’s volume status can potentially be obtained with ultrasound measurements of the IVC. Ultrasound can noninvasively measure the IVC size and variation with respiration correlates with volume status.^34,90 Studies demonstrate that a decrease of more than 50% in the IVC diameter from expiration to inspiration correlates with a CVP of less than 8 mm Hg.⁵¹ However, other studies find that this index varies significantly by the chosen location for the ultrasound measurements.⁸³ Furthermore, there is a poor correlation between the ultrasound CVP determination and actual measured CVP.⁵⁴ Other ultrasound venous measurements have also been tested including the internal jugular vein³³ and compression ultrasound of a forearm vein, IVC collapsibility, and internal jugular vein collapsibility with only moderate correlation with the actual CVP.⁸² While ultrasound may not be absolutely predictive of the volume status, the information can be useful as an adjunct to clinical assessment of hydration status and end organ perfusion.

Additional information about the adequacy of the patient’s volume status may be obtained by orthostatic vital sign testing (Table 17–7).²¹ ­Normally, the cardiovascular system responds to sitting or standing with vasoconstriction and a slight increase in heart rate. Even with a 30% or greater volume loss, the supine blood pressure may remain normal in young, previously healthy patients. However, patients with hypovolemia are unable to maintain adequate intravascular pressure when upright and have either an exaggerated reflex increase in heart rate or a drop in blood pressure (ie, orthostasis).

A variety of xenobiotics can produce orthostatic blood pressure changes (Table 17–8).^24,44 Volume depletion is the most common cause of xenobiotic-induced orthostatic vital sign changes. However, xenobiotics may produce orthostatic vital sign changes even with a normal volume status. For instance, α₁-adrenergic antagonists or direct-acting vasodilators may prevent an adequate vasoconstrictor response or β-adrenergic antagonists may block the normal slight heart rate increase, and result in positive orthostatic vital sign testing. In these cases, cardiac output and blood pressure decrease when the patient is upright.

While various assessments can be useful for predicting the volume status, the most accurate immediate assessment is probably the demonstration or increased cardiac output after a fluid challenge. The passive leg-raising test may be used as a bedside test to evaluate the adequacy of fluid resuscitation. The test is performed by having the patient sit upright in a semi-recumbent position at about 45 degrees. The head is then lowered to the recumbent position and the legs are raised to about 45 degrees. This transiently increases the circulatory volume by around 130 to 300 mL, and it may result in changes in the arterial pressure and heart rate.^29,50 Several studies have shown that this simple maneuver is a good predictor of hemodynamic response to a fluid bolus especially in intensive care patients.^{36,37,43,45,46,49,80}

Definitive care of the poisoned patient with hemodynamic compromise or a dysrhythmia begins with recognition that a xenobiotic may be present. Infectious, cardiovascular disease, and other metabolic disorders must always be considered; however, the toxic effects of xenobiotics must be included in the differential diagnosis. A variety of clinical clues, when present, should heighten the clinician’s suspicion that a xenobiotic effect may be responsible for the hemodynamic or dysrhythmic problem (Table 17–9).

• Xenobiotics can interact with the heart or blood vessels to produce hypotension or hypertension, congestive heart failure, dysrhythmias (including bradycardias and tachycardias), or cardiac conduction delays.

• These toxic effects often occur through interactions with specific receptors or with the ion channels in the cell membrane.

• Disruption of the normal cellular regulation of metabolic processes or of the cellular ionic status leads to the cardiovascular and hemodynamic compromise.

• The occurrence of these abnormalities, individually or in combination, might suggest a particular xenobiotic or class of xenobiotics as the etiologic (toxic syndrome) and might dictate initial treatment. However, often significant abnormalities in vital signs must be corrected before the xenobiotic is identified.

  By understanding both the pharmacology of the xenobiotic and the physiology of the heart and vasculature, appropriately tailored treatment can be delivered.

References