The Use of Vasopressors and Inotropes in the Emergency Department for the Treatment of Shock

The Use of Vasopressors and Inotropes in the Emergency Department for the Treatment of Shock

Introduction

An estimated one million cases of shock and up to 5.6 million cases of hypotension present to U.S. emergency departments (ED) each year.¹ Mortality related to shock remains high — up to 40-50% in patients with either cardiogenic or septic shock.² Non-traumatic hypotension occurring in the ED is linked to increased inpatient mortality.^3,4 Accurate assessment and treatment of shock by the emergency provider are critical, as early intervention based on hemodynamic parameters improves outcomes.⁴

What Is Shock?

Shock is the condition in which perfusion to the tissues is not matched with the demand for oxygen; simply, oxygen delivery (DO₂) does not meet oxygen consumption (VO₂). Oxygen delivery is determined by the oxygen content in the blood (CaO₂) and the cardiac output (CO):

DO₂ = CO × CaO₂

CaO₂ = (1.34 × Hb × SaO₂) + (0.003 × PaO₂) and CO = SV × HR

(SV = stroke volume, HR = heart rate, and Hb = hemoglobin concentration).

The contribution by dissolved oxygen (0.003 × PaO₂) is negligible under normobaric conditions, so the delivery equation becomes:

DO₂ = SV × HR × (1.34 × Hb × SaO₂).

Stroke volume is dictated by three parameters: preload, afterload, and contractility. Cardiac output, mean arterial pressure (MAP), and systemic vascular resistance (SVR) are interconnected: MAP = CO × SVR.

Increasing oxygen delivery is the main goal in treating shock, utilizing hydraulic (intravenous fluid), pharmacologic, hematologic (red cell infusion), and mechanical techniques.

Pharmacologic treatment may involve both inotropic and vasopressor therapy. Inotropes are agents that increase CO without necessarily increasing blood pressure. Vasopressors alter vascular tone to increase SVR and, thus, increase blood pressure without necessarily affecting CO. Another class of vasoactive drugs, vasodilators, are sometimes used to decrease SVR and indirectly increase CO and oxygen delivery in select cases.

Shock is broadly categorized into four types: cardiogenic, distributive, hypovolemic, and obstructive. (See Table 1.) In some cases, more than one type of shock may be present. In general, shock is treated according to the pathophysiology present.

Cardiogenic Shock. Cardiogenic shock is characterized by a sudden severe decrease in cardiac output due to ischemia, valvular dysfunction, or arrhythmias. Cardiogenic shock is the most common cause of death among patients hospitalized for acute myocardial infarction.⁵ Treating cardiogenic shock may require multiple agents, but despite appropriate inotropic and vasopressor support, mechanical assistance or even cardiac transplant may be required.

Distributive Shock. Distributive shock is characterized by a mismatch in perfusion and oxygen demand. Three clinical syndromes may exhibit maldistribution of perfusion and produce shock: sepsis, anaphylaxis, and neurogenic (spinal cord) injury.

Septic shock is the type of distributive shock that is most commonly seen in the ED. Inflammatory mediators released by the body in response to an infection may have multiple deleterious effects — including inappropriate vasoconstriction and vasodilation, increased vascular permeability, and impaired cardiac contractility — that can lead to maldistribution of perfusion. Volume resuscitation is the initial therapy in the resuscitation of patients with septic shock. The inciting infection should be identified, with the early administration of antibiotics chosen according to expected pathogens. Surgical removal of infected tissue may be necessary for localized infections. Inotropic and vasopressor support is often necessary.

Anaphylaxis is a form of distributive shock caused by an immediate-type hypersensitivity response to an allergen, provoking a severe, systemic inflammatory response. This response leads to increased vascular permeability, with intravascular volume loss, decreased SVR, and impaired myocardial contractility. Bronchospasm with increased resistance to airflow is common in anaphylaxis. Epinephrine is the drug of choice in the treatment of anaphylactic shock due to its potent inotropic and vasopressor effects, as well as the ability to decrease bronchospasm.

Neurogenic shock, a third form of distributive shock, normally arises from injuries or damage to the cervical spinal cord. The incidence of neurogenic shock with spinal cord injury is low — less than 20% of all spinal cord injured patients who present to the ED.⁶ A unique feature of neurogenic shock is that tachycardia in response to hypotension is uncommon. Intravenous fluid is the first-line in therapy for neurogenic shock. Vasopressor support may be required. If bradycardia is present, dopamine or another vasopressor that will provide chronotropic (heart rate) stimulation as well as increased vascular resistance may be preferred.

Hypovolemic Shock. Hypovolemic shock is caused by inadequate circulating volume, either due to an absolute fluid loss or an increase in the body's vascular capacitance. Foremost, hypovolemic shock is treated with volume resuscitation using isotonic crystalloid. If hemorrhage was the cause of volume loss, red cell transfusion may be necessary to maintain adequate oxygen-carrying capacity in the blood. If the blood pressure is dangerously low, it is reasonable to use vasopressors to increase blood pressure during volume resuscitation and methods to prevent ongoing volume loss are performed. Vasopressors are no substitute for adequate fluid resuscitation and should be discontinued once blood pressure has normalized with sufficient volume resuscitation.

Obstructive Shock. Obstructive shock is caused by an external obstruction of blood flow through the heart. Disorders that may produce obstructive shock are tension pneumothorax, pericardial tamponade, pulmonary embolism, and superior vena cava syndrome.

Physiologic Response to Shock

A variety of biochemical and hemodynamic responses can occur in shock. Some responses may produce a temporary increase in perfusion to some vascular beds, sometimes termed compensatory and helpful. However, the responses cannot be maintained and may lead to further harm if sustained. The hemodynamic responses observed in shock and during treatment are connected to the sympathetic nervous system and the adrenergic receptors.

Adrenergic Receptor Physiology

Humans have a closely regulated set of receptors that maintain blood flow and oxygen delivery throughout the body. These receptors exist as both chemo- and baroreceptors within the major arteries and also as monitors of pH and PaCO₂ at the tissue level. When activated, these receptors send signals to the central nervous system, producing changes in sympathetic activity and, subsequently, vascular tone and cardiac output. The key end-reaction is the release of norepinephrine to stimulate post-synaptic receptors. Severing the sympathetic response will lead to complete collapse of the system, such as is seen with complete transection of the spinal cord at a high level producing neurogenic shock.

Sympathomimetic receptors are located on the cell membrane. (See Figure 1.) When a receptor is stimulated, the adjacent adenylate cyclase in the cell membrane is activated to convert adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Increased intracellular cAMP stimulates the sarcoplasmic reticulum to release calcium, which complexes with the actin-myosin component of the muscle unit, causing contraction.

Figure 1: Beta-adrenergic Receptor

Phosphodiesterase enzymes convert cAMP back to ATP. When this enzyme is inhibited, there is a buildup of cAMP and a related increase in the intra-cellular calcium concentration. This is the main pharmacologic mechanism of phosphodiesterase inhibitors such as milrinone.

The individual adrenergic receptors and their subtypes are:

• α1-adrenergic receptors: These receptors exist within the peripheral vasculature, and activation leads to vasoconstriction. The blood-brain barrier potentially protects the brain from exogenous α-1 activation. These receptors are sparse within cardiac tissues. The overall effect of α-1 activation is increased peripheral vascular resistance leading to increased mean arterial pressure. This increased pressure may sometimes lead to reflex bradycardia.
• α2-adrenergic receptors: These receptors are more predominantly located at the pre-synaptic junction. Activation of these receptors causes inhibition of the release of norepinephrine, thereby acting as a negative-feedback loop for further norepinephrine release (autoregulation). Also, small quantities of the α2-adrenergic receptor are found in the peripheral vasculature at post-synaptic junctions, but their effect is small.
• β1-adrenergic receptors: Most β1-adrenergic receptors exist within the heart. When activated, there is increased inotropy and chronotropy, as well as increased conduction and automaticity of the heart's electrical signals. There is minimal effect on the peripheral vasculature.
• β2-adrenergic receptors: These receptors are located in bronchial, vascular, gastrointestinal, and genitourinary smooth muscle. The effect on the peripheral vasculature due to simulation of these receptors is primarily vasodilation. Although activation of these receptors within cardiac tissue may cause increased inotropy and chronotropy, there are much fewer β2-receptors in heart tissue than in the peripheral vasculature, minimizing the increase in CO. In patients with chronic heart failure, the ratio of cardiac to peripheral receptors increases, potentiating the effects of these receptors.
• Dopaminergic receptors (DA): These receptors exist mainly in the splanchnic circulation and lead to vasodilation. Renal dopaminergic receptors will lead to an increase in renal blood flow.
• Vasopressin receptors (V): These receptors are separate from the adrenergic system. There are three subtypes of this receptor, but V1 receptors located on vascular smooth muscle cells, producing arterial vasoconstriction when activated, are the most important subtype. V1 receptors also exist on platelets, hepatocytes, and the myometrium, with actions that vary based on location.

Other receptor types have been implicated in the control of blood pressure, but the aforementioned receptors appear to be the most understood and critical to increasing CO or MAP.

Regardless of which receptors influence blood flow during normal conditions, disease may cause alterations in this normal pattern by affecting the amount of receptors available, either quantitatively or functionally. For example, chronic hypoxia may lead to the down-regulation of receptors,⁷ and acidosis may affect the functional activity of receptors.⁸ Certain disease entities may affect receptor kinetics. In chronic congestive heart failure, the cardiac adrenergic receptors may be desensitized and down-regulated.⁹ These interactions may potentially reduce the body's response to the usual treatment doses of vasopressors. Meanwhile, endogenous mediators, such as vasopressin and epinephrine, may have concentration alterations in various types of shock, potentially affecting response to exogenous agents and outcomes.^10,11

Inotropes and vasopressors usually possess agonistic activity at multiple receptors, with the overall effect determined by the intensity of the individual interactions. (See Table 2.) Also, disease-induced alterations in receptor numbers, distribution, and responsiveness may alter the pharmacologic response.

Specific Pharmacologic Agents

Adrenergic Agents. As discussed previously, many vasopressors and inotropes function at either α- , β-, or DA receptors. These medications are known as adrenergic agents or sympathomimetics because they mimic the action of endogenous substances released from the adrenal gland, such as epinephrine. The various medications possess a range of agonistic activity at the different adrenergic receptors. (See Table 2.) There is a spectrum of β-adrenergic activity among the various agents.

The adrenergic agents are further divided into catecholamines and non-catecholamines, referring to the chemical structure of the compound as a monoamine side-chain attached to a catechol group, or not. The practical aspect of this distinction is that catecholamines are inactivated in acidic environments, and this knowledge will potentially alter whether or not bicarbonate is given or the location of bicarbonate administration. Also, catecholamines are metabolized by the catechol-O-methyltransferase (COMT) enzyme system in the liver. Other substances that alter COMT activity can affect catecholamine duration of action. Vasopressors and inotropes may further be labeled as endogenous or synthetic.

Phenylephrine. Phenylephrine is a rapid-acting, selective α1-adrenergic agonist. It is a non-catecholamine, and differs from epinephrine with its chemical structure lacking a hydroxyl (OH) group. It causes significant vasoconstriction that increases SVR and blood pressure. Due to its rapid-onset and half-life, a bolus of phenylephrine is an effective "quick fix" during procedures if hypotension develops due to the direct vasodilatory effects of the medications administered. If bradycardia accompanies the procedural drop in blood pressure, then a medication with both α- and β-effects should be used to help increase HR as well. Phenylephrine is commonly given through peripheral venous access since the risk of extravasation injury seems minimal.

Its onset of action is approximately two minutes. With continuous intravenous (IV) infusion, the initial dose is usually 10 mcg/min with the infusion rate titrated up to 200 mcg/min, but some practitioners will use up to 9 mcg/kg per min. As an alternative to continuous infusion, IV bolus doses of 50100 mcg may be given for severe hypotension. Once the blood pressure is stabilized, the rate should be decreased to 40-60 mcg/min if adequate to maintain blood pressure. It is metabolized by monoamine oxidase (MAO) in the liver. Elimination occurs mostly in the kidneys, and the elimination half-life is about two to three hours.¹²

There are few studies on the efficacy of phenylephrine in septic shock. One small study analyzed phenylephrine use in 13 patients with refractory hypotension despite fluid resuscitation and dopamine or dobutamine.¹³ Phenylephrine increased MAP, cardiac index, and urine output without changing heart rate or serum creatinine. While phenylephrine is not a first-line recommendation in the treatment of septic shock,¹⁴ it may be of therapeutic benefit when tachyarrhythmias are a significant concern.

Because phenylephrine has little β-receptor activity, the increase in afterload may lead to a reflex bradycardia and a decreased cardiac output in patients with active cardiac disease, including myocardial ischemia and cardiogenic shock. Phenylephrine should be avoided in these circumstances.

Norepinephrine. Norepinephrine is also a potent α-adrenergic agonist with some β1-adrenergic effects. It is identical to the endogenous norepinephrine that is released by the adrenal glands and sympathetic nervous system. Its receptor actions are dose-dependent and cause vasoconstriction and a slight increase in cardiac output by increasing heart rate and contractility. At lower doses, norepinephrine will have greater stimulation of β1-adrenergic receptors, while at higher doses norepinephrine has more α-adrenergic effect, increasing SVR and MAP. There is also a vasoconstrictor effect that occurs in the veins, leading to increased preload, which probably equalizes any effect on cardiac function. Overall, norepinephrine's ability to increase MAP is more directly related to increasing SVR than any effect on cardiac output.

The onset of action is one to two minutes, while duration of action is approximately five to 10 minutes. Norepinephrine is metabolized in the liver by both MAO and COMT. Renal excretion occurs, as well as reuptake by neural tissue. Dosing recommendations are variable, with initiation doses starting at approximately 2 mcg/min via IV infusion, with incremental increases every three to five minutes by 1-2 mcg/min to achieve blood pressure goal.¹ The maximal infusion rate is not well-defined, but most practitioners will go up to a maximum of 200 mcg/min; above that, little benefit has been observed.

Historically, norepinephrine was used as a last-ditch measure in the profoundly hypotensive patient who was refractory to other therapeutic measures. This hesitancy to utilize norepinephrine earlier in shock therapy mostly stemmed from fear of ischemic events, including bowel and limb ischemia. The current experience is that norepinephrine is safe to use in patients who have been adequately volume resuscitated, which appears to mitigate ischemic potential. The most common use of norepinephrine is probably septic shock, as it is now the first-line recommendation for treatment in the current Surviving Sepsis Campaign Guidelines.¹⁴ Norepinephrine is commonly used in neurogenic shock, severe cardiogenic shock, and obstructive shock due to pulmonary embolism.

Norepinephrine should be used with caution in patients who are taking MAO inhibitors and tricyclic antidepressants, as this may cause significant hypertension due to reduced metabolism. Norepinephrine should not be used in patients who are not adequately volume resuscitated, as this may lead to profound ischemia. It is important to frequently check the peripheral intravenous infusion site for signs of extravasation, as significant soft-tissue injury can occur. When possible, norepinephrine should be infused through a central line.

Epinephrine. Epinephrine is an endogenous catecholamine that is produced and released from the adrenal gland. It is produced in a methylation reaction of norepinephrine, but unlike norepinephrine, epinephrine also has effects on β2-adrenergic receptors. It is considered the most potent inotrope, and its actions are dose-dependent. Usual dosing is 1 mcg/min IV, with titration to desired effect, with a maximal infusion rate of 20 mcg/min. At low doses (< 5-10 mcg/min), predominantly β-adrenergic effects prevail, leading to increased inotropy, chronotropy, bronchodilation, and peripheral vasodilation. At higher doses, increasing α-adrenergic effects take over, leading to an increase in vasoconstriction. Epinephrine does not work as well in an acidic environment.¹⁵ It may be necessary to correct severe acidosis or increase the dose to have a beneficial effect. Onset, duration, and half-life are very short. Metabolism is via MAO and COMT enzymes, and excretion is through the kidneys.

Epinephrine is the primary vasopressor used in anaphylaxis. For patients with anaphylactic shock unresponsive to intramuscular or subcutaneous epinephrine treatment, dosing guidelines recommend epinephrine infused at a rate of 1 to 15 mcg/min,^12,16 although some practitioners have no maximum dose. Epinephrine is considered the second-choice agent for septic shock.¹⁴ Epinephrine is used for the treatment of patients in cardiac arrest.¹⁷

Adverse reactions and side effects include increased afterload, wall tension, and heart rate that lead to increased coronary oxygen demand and potential ischemia. There is an increase in the incidence of tachyarrhythmias. Epinephrine may reduce splanchnic and renal blood flow and may also cause lactic acidosis.¹⁸ It is unclear whether this reflects actual tissue ischemia in septic shock.¹⁹ As discussed later, epinephrine infusions may make it difficult to use lactate clearance as a marker of resuscitation.

Epinephrine increases glycogenolysis and triglyceride breakdown, leading to hyperglycemia.¹⁸ Since significant hyperglycemia increases morbidity in critically ill patients, it is important to reasonably control glucose to a range of 70 to 180 mg/dL.^20,21 Despite these adverse effects of epinephrine, a randomized, controlled trial of patients receiving norepinephrine plus dobutamine versus epinephrine for the treatment of septic shock showed no difference in efficacy and safety.²²

Dopamine. Dopamine is an endogenous catecholamine that acts as a precursor to other catecholamines. Depending on the dose, the intensity of the agonist effect varies on the dopaminergic, α-, and β1-adrenergic receptors. The common teaching is that low-dose dopamine (< 5 mcg/kg per min) activates dopaminergic receptors, leading to vasodilation of the splanchnic and renal circulations, while medium-dose dopamine (5-10 mcg/kg per min) causes β1 stimulation, and higher doses (> 10 mcg/kg per min) cause primary α-adrenergic effects. While it is likely that dopamine effects are dose-dependent, extreme variability in plasma concentration curves among healthy subjects given the same dose of dopamine has been observed.²³ Also, despite the preferential dopaminergic effects at small doses, low-dose dopamine infusion does not have a significant effect on clinical renal parameters or outcomes, specifically peak creatinine, change in creatinine, or need for renal-replacement therapy.²⁴

The typical initial dose for a patient in shock is 5 mg/kg per minute IV infusion, titrated according to the blood pressure goal, with a maximal dose of 20-50 mcg/kg per minute. Time of onset is approximately five minutes, and half-life is two minutes. Dopamine has tachyphylactic properties due to down-regulation of receptors, which may complicate dosing requirements during prolonged infusion. Partial metabolism of dopamine is via MAO and COMT in the liver and by degradation into metabolites such as norepinephrine.

It is important to monitor for adverse effects, including hypotension at low doses and limb ischemia or gangrene in high-risk populations, such as those with peripheral vascular disease, diabetics, or those on prolonged dopamine infusions. Use caution when administering dopamine to patients on MAO-inhibitors, as these may inhibit its metabolism, thereby prolonging its effects. Other potential side effects include dopamine-induced pituitary dysfunction in critically ill patients and immunosuppression in patients with sepsis.²⁵

Tachyarrhythmias are common with the use of dopamine. A meta-analysis of patients with septic shock showed that dopamine administration is associated with increased mortality and increased incidence of arrhythmias when compared to norepinephrine administration,²⁶ and a subgroup analysis of a large randomized, controlled trial showed increased 28-day mortality in patients receiving dopamine for cardiogenic shock.²⁷

Dobutamine. Dobutamine is a synthetic catecholamine that acts as a potent β1-adrenergic agonist with some weak β2-receptor activation. This leads to an overall positive inotropic effect with variable chronotropic effects and mild peripheral vasodilation.

The effects of dobutamine are dose-dependent. The initial dose is 0.5 to 1 mcg/kg per minute IV infusion, titrating every few minutes to desired response, with usual maintenance doses of 2 to 20 mcg/kg per minute. It is reported that titration to levels as high as 40 mcg/kg per minute may be required, but this is seldom seen in practice.¹² Doses up to 15 mcg/kg per minute increase cardiac contractility without greatly affecting peripheral resistance, but vasoconstriction becomes important at higher doses.²⁸ Its time of onset is approximately one to two minutes, while peak action occurs at 10 minutes. Elimination half-life is one to two minutes. It is metabolized by COMT in the liver. Excretion is via kidneys and feces. Tachyphylaxis does occur with prolonged infusion of dobutamine.²⁹

Dobutamine may lead to tachyarrhythmias and ventricular ectopic beats. Similar to epinephrine and dopamine, the incidence of tachyarrhythmias may be worse in patients who are already experiencing atrial fibrillation or already receiving other adrenergic medications or who are receiving infusion rates greater than 20 mcg/kg per minute. The primary β1-effects caused by dobutamine may also lead to an increase in cardiac work that will increase myocardial oxygen demand. The mild peripheral vasodilation caused by dobutamine may potentially reduce afterload such that in patients with intravascular volume depletion, this mild peripheral vasodilation may lead to profound hypotension. It is not recommended to administer dobutamine to hypotensive patients.³⁰ Dobutamine may cause hypokalemia; therefore, monitoring of potassium levels is recommended.

Isoproterenol. Isoproterenol is a synthetic catecholamine produced from norepinephrine. Isoproterenol is purely a β-agonist, which causes increased heart rate and cardiac output. In the peripheral vasculature, it will lead to vasodilation and decreased SVR. Its β2-agonist effects will relax smooth muscle, which may lead to bronchodilation. Isoproterenol is indicated for temporary treatment of symptomatic bradycardia or heart block and for treatment of refractory torsades de pointes. The effects are dose-dependent, with initial dosing starting at 2 mcg/min IV infusion, and titrated up to 20 mcg/min according to heart rate. The duration of action is approximately eight minutes with low doses and up to 50 minutes with larger doses. Isoproterenol is metabolized in the liver and excreted mostly in the kidney.

Myocardial ischemia is a major concern due to the significant increased cardiac oxygen demand; therefore, isoproterenol should be avoided in patients with coronary artery disease. Due to β-agonist effects, peripheral vasodilation will occur, and hypotension may develop in the patient with intravascular volume depletion. Isoproterenol should not be given to those with digitalis-induced tachycardia or heart block.

Non-Adrenergic Agents. These medications vary widely in mechanisms of action as well as overall hemodynamic effects. While these agents do not directly stimulate the adrenergic receptors, they may potentiate the effects of adrenergic agents.

Vasopressin. Vasopressin is a peptide hormone that is synthesized endogenously by the hypothalamus and stored in the posterior pituitary gland. It is released from the pituitary in response to increased plasma osmolality, decreased intravascular volume, and low blood pressure. Its major functions in the body are in water balance and blood pressure control. Stimulation of V1 receptors on arterial smooth muscles cause vasoconstriction, dramatically increasing SVR. Through actions at the V2 receptors in the kidney, vasopressin causes water reabsorption at the collecting ducts. The dose of vasopressin required to activate V2 receptors is much lower than the dose to cause vasoconstriction.

Doses depend on the clinical scenario. For cardiac arrest, the current American Heart Association (AHA) guidelines recommend a single, one-time dose of 40 units IV or intraosseously (IO) to replace the first or second dose of epinephrine.¹⁷ For septic shock, a dose of 0.01 to 0.04 units/min IV infusion is used.¹⁴ Duration of activity is 30-60 minutes, elimination half-life is 10-20 minutes, and metabolism occurs in both liver and kidneys.¹²

Vasopressin will increase responsiveness to catecholamines, and its use may also allow smaller doses of adrenergic drugs to be utilized.³¹ Endogenous vasopressin levels are lower in some patients with shock, which may explain hypotension refractory to adrenergic agents in these patients.^10,11 While vasopressin does not alter outcomes in all patients with septic shock, outcomes improve when low doses of vasopressin are added to norepinephrine treatment in patients with less severe septic shock.³²

The significant vasoconstriction caused by vasopressin may cause profound ischemic events in the coronary and peripheral vasculature. Cutaneous gangrene is a rare but feared complication. Vasopressin may also lead to platelet aggregation.

Milrinone. Milrinone is a phosphodiesterase inhibitor that causes an overall increase in intracellular cAMP, leading to an increase in intracellular calcium. This causes increased cardiac inotropy and vasodilation in vascular smooth muscle. Overall, the net effects are decrease in preload, decreased SVR, which leads to a decreased afterload, and positive inotropic effects. Milrinone also acts as a lusitrope, meaning it causes diastolic relaxation, thereby increasing the heart's ability to fill. Right atrial pressures and mean pulmonary artery pressures are reduced, and coronary arteries are dilated, making its use seem ideal for improving right heart function.

The hemodynamic effects of milrinone are dose-related. Milrinone may be given as a bolus of 50 mcg/kg loading dose over 10 minutes, followed by an infusion, or an infusion may be started without a bolus. The infusion dose is 0.25 to 0.75 mcg/kg per minute. Milrinone has a very long half-life of approximately two to four hours; therefore, its duration of action is also long (three to five hours). This long half-life may be a limiting factor when deciding to use milrinone, as it will often cause some degree of hypotension that is likely to be prolonged.

Because its action is independent of adrenergic receptor availability, milrinone is an important option when adrenergic receptors are unavailable due to down-regulation or desensitization, such as occurs in chronic heart failure or those patients using β-blocker medications.

Complications are related to hypotension from to decreased peripheral vascular resistance, as well as possible increased cardiac oxygen demand due to increased inotropy. Its use should be avoided in patients with hypertrophic cardiomyopathy and significant aortic or pulmonary valve disorders, since it may worsen outflow obstruction.^2,12 Drug-induced thrombocytopenia occurs rarely. Dosage adjustments for patients with renal failure may be required.

Specific Types of Shock and Recommended Treatment

Despite the availability of multiple vasopressors and inotropes, few randomized, controlled trials have compared the different agents in particular shock states. The existing consensus guidelines have been developed mostly for expert opinion and observational studies.

Septic Shock and Surviving Sepsis Campaign Guidelines

The Society of Critical Care Medicine updated their guidelines for the management of sepsis and septic shock in 2012.¹⁴ These guidelines focus on a "protocolized, quantitative resuscitation of patients with sepsis-induced hypoperfusion."¹⁴ The importance of early goal-directed therapy is stressed throughout the guidelines. As with any patient, the initial resuscitation should include an assessment of the airway, breathing, and circulation. The primary consideration is for immediate antibiotic delivery, fluid resuscitation, and source control when able. Isotonic crystalloids are the preferred fluid therapy, with an initial fluid bolus of 30 mL/kg. Normally, fluid administration should take place prior to the initiation of vasopressors, since end-organ ischemia may occur in volume-depleted patients; however, some patients may require vasopressor therapy on arrival in order to maintain adequate perfusion and oxygen delivery for survival. Regardless, norepinephrine is the first choice for a vasopressor. If an additional agent is required, the guidelines recommend epinephrine may be added to or replace standard norepinephrine treatment, as studies show no significant difference in mortality among patients with sepsis when given norepinephrine compared to epinephrine.³³ Low-dose vasopressin may be added in order to decrease requirements for other adrenergic agents or to augment blood pressure; however, vasopressin is not recommended as a single agent.

Unlike previous guidelines, dopamine is only recommended in certain patients with septic shock, such as patients with bradycardia or in patients without risk for or presence of tachyarrhythmias. Furthermore, phenylephrine may be considered in certain circumstances, specifically when serious tachyarrhythmias are a concern due to norepinephrine, when high cardiac output occurs with persistent hypotension, or when a salvage therapy is required. Finally, inotropic therapy may be administered in the known presence of myocardial dysfunction or when there are signs of ongoing hypoperfusion after fluid resuscitation and MAP goals are achieved. If intravascular volume is adequate and vasopressor therapy is not reversing signs of shock, corticosteroid therapy with IV hydrocortisone 200 mg per day is recommended.

Guidelines for Acute Cardiogenic Shock with MI

Cardiogenic shock is the most common cause of death among patients with acute myocardial infarction. While the incidence is only 6%, the mortality is greater than 50%.^34,35 Patients with cardiogenic shock have reduced stroke volume, leading to decreased cardiac output. The heart rate increases in an attempt to maintain cardiac output, but this tachycardia will increase myocardial oxygen demand, thereby increasing ischemia.

Patients with significant systemic hypotension or signs of vascular congestion due to low cardiac output may require inotropic or vasopressor support. Inotropic agents may improve cardiac function in patients with cardiogenic shock; however, all of these agents increase myocardial oxygen demand. This may lead to arrhythmias, increased ischemia, and extension of an acute infarct, if present. The risk of hypotension must be weighed against the risks of increased cardiac work.

The American College of Cardiology's (ACC) most recent guidelines state that "medical support with inotropes and vasopressor agents should be individualized and guided by invasive hemodynamic monitoring."³⁰ Patients with cardiogenic shock and severe hypotension (SBP < 70 mmHg) should be started on norepinephrine, while those with SBP between 70-100 mmHg should receive dopamine. The use of dopamine in the setting of cardiogenic shock has been commonplace, but this approach has come under some scrutiny after studies showing increased arrhythmias with patients in shock.^26,27 Dobutamine at a rate of 520 mcg/kg per minute IV infusion may be given to improve cardiac output.³⁶ Its use in patients with hypotension, however, is not recommended. Inotropic therapy may be used while a patient's own cardiac function recovers, but many times acts as a bridge or in concert with other therapies, such as intra-aortic balloon pump devices, ventricular assist devices, extracorporeal life support, or cardiac transplant.

Invasive hemodynamic monitoring is commonly used, especially in patients with an unclear picture regarding cardiac filling pressures and cardiac output. Pulmonary artery catheterization is appropriate in patients with: 1) presumed cardiogenic shock requiring escalating vasopressor therapy and consideration of mechanical support; 2) severe clinical decompensation in which therapy is limited by uncertainty regarding relative contributions of elevated filling pressures, hypoperfusion, and vascular tone; 3) apparent dependence on intravenous inotropic infusions after initial clinical improvement; or 4) persistent severe symptoms despite adjustment of recommended therapies.³⁰ Intra-arterial blood pressure monitoring for unstable patients requiring vasopressors is recommended.

Adult Cardiac Life Support (ACLS) and Use of Vasopressors and Inotropes

Current AHA guidelines for ACLS recommend epinephrine is 1 milligram (10 milliliters of 1:10,000 solution) IV or IO initially and repeated as necessary every three to five minutes in the cardiac arrest patient.¹⁷ Guidelines offer the option of a one-time dose of vasopressin (bolus of 40 units) in lieu of the first or second dose of epinephrine in patients without a pulse.

New evidence shows vasopressin given with epinephrine and steroids may offer improved survival and neurologic outcomes in adult cardiac arrest victims.³⁷ This approach has not been incorporated into ACLS guidelines or recommendations.

Practical Issues in the Emergency Department

The assessment and treatment of the patient in shock may present many practical issues for the ED. The pathophysiologic state may not be easily determined and, in a busy and chaotic ED, it may not be feasible to place intravascular monitoring devices in a timely, safe, and sterile manner.

End-Goals. One major issue in the treatment of shock is the issue of choosing a treatment goal. As noted previously, inpatient mortality correlates with the degree and length of hypotension measured in the ED.³ Therefore, it is crucial for the emergency provider to recognize hypotension and shock and intervene early, as multiple studies have illustrated the importance of early therapy in the treatment of shock.^4,38 A MAP greater than 65 mmHg is the typical goal for most patients in shock. Arguments regarding higher MAPs and improved outcomes are not currently substantiated, and there is no evidence that increasing MAP in order to increase renal perfusion will result in significant improvements or improved clinical outcomes.³⁹

There are recommendations for intra-arterial blood pressure measurements and monitoring,^14,30 based on significant discrepancies in systolic blood pressure measurements in hypotensive patients when measured non-invasively versus invasively.⁴⁰ However, MAP measurements are more consistent between invasive and non-invasive techniques; thus, using MAP to guide therapy is recommended.⁴⁰

While specific treatment strategies vary, well-founded strategies that ensure treatment guidance based on tissue perfusion and, therefore, oxygen delivery, are crucial to assure the intervention is adequately meeting the patient's oxygen demand. The physical exam may offer the first clues toward whether or not a patient is adequately resuscitated. Skin temperature, capillary refill, and mental status are all examples of easily obtainable exam findings that may be altered in the setting of shock. Heart rate, non-invasive blood pressure monitoring (NIBP), and urine output (UOP) are other non-invasive indicators of resuscitation. While these non-invasive measures are easily accessible, their sensitivity and specificity may be lower than more invasive monitoring methods and goals.

Central venous pressure (CVP) may be measured with an end-point of between 8-12 mmHg in non-ventilated patients.¹⁴ However, pressure does not always correlate with volume, and the CVP may not accurately identify volume status or ventricular filling, especially in patients with certain types of heart failure or pulmonary hypertension. Many emergency providers use measurement of inferior vena cava (IVC) diameter and variability with bedside ultrasound, which appears to correlate with low central venous pressures in some studies.⁴¹ Other studies have had less robust outcomes, however, illustrating that sonographic IVC measurement also has limitations and may have weaker associations with central venous pressures.^42,43

Pulmonary artery catheters (PAC) offer many measurements regarding the hemodynamic status of the patient in shock. The measurements obtained correlate closely with parameters involved in oxygen delivery. Left-sided heart filling pressures, pulmonary artery occlusion pressures, cardiac output, and mixed venous oxygen saturations are determined with a PAC. Much controversy still exists regarding the use of PAC. Recent studies and reviews illustrate that the use of a PAC does not affect mortality and has no clear evidence toward benefit or harm.^44,45

Lactate clearance is another marker of resuscitation from shock. Elevated lactate levels may occur in shock due to metabolic alterations or from decreased perfusion. Both the initial lactate and lactate clearance correlate to outcomes related to multiple shock types.^46,47 When compared to central venous oxygen goals, resuscitation guided by lactate clearance is not inferior.⁴⁸ Surviving Sepsis Guidelines recommend measuring and treating toward lactate clearance in the management of septic shock.¹⁴

Other end-goal and monitoring techniques include pulse-pressure variation, bedside echocardiography to determine cardiac indices, central and mixed venous oximetry, and near-infrared spectroscopy. All of the techniques have benefits and drawbacks.

Central Versus Peripheral Infusions. Historically, central infusion of vasopressor agents has been preferred, primarily due to the risk of infiltration and subsequent damage to surrounding tissue. The threat of tissue damage does not appear to be specific to one particular agent.⁴⁹⁵¹

Initially, peripheral infusion of vasopressors is often necessary, especially when no other access is available. The infusion site should be checked often for signs of extravasation. If this occurs, discontinue the vasopressor medication and leave the current vascular access in place in order to aspirate any remaining vasopressor medication from the area. If the extravasated drug was dopamine or norepinephrine, use the IV access to inject a small dose of phentolamine.^54,55 Early consultation with surgical specialists is recommended.

Risks, Complications, and Challenges

The drugs discussed, which act directly to increase afterload, contractility, or preload, may all cause unwanted hemodynamic variations and arrhythmias. Increased afterload may lead to increased myocardial oxygen consumption, causing myocardial ischemia and infarction. Increased peripheral vascular resistance may decrease in regional blood flow, leading to limb ischemia, necrosis, or impaired splanchnic perfusion.

Impaired blood flow to the splanchnic organs may ultimately cause complications such as bowel necrosis, renal injury, or gastric ulceration. The decrease in splanchnic blood flow during shock states, possibly exacerbated by the vasoconstriction caused by vasopressors, may also lead to decreased absorption of various medications. For example, patients on vasopressor therapy have decreased serum acetaminophen levels after enteral administration.⁵⁷ Decreases in subcutaneous blood flow may affect the efficacy of medications given subcutaneously, such as insulin. A decrease in anti-Xa levels in patients receiving vasopressors and low-molecular heparin has been observed.⁵⁹ Although plasma concentrations do not necessarily correlate with patient outcomes, IV medication administration remains the preferred route in patients on vasopressor therapy.⁶⁰

Conclusion

Shock is associated with high mortality. Morbidity and mortality are increased when episodes of hypotension persist in the ED. Understanding a patient's shock state and utilizing appropriate and early targeted therapy will improve outcomes. Choosing appropriate inotropic and/or vasopressor agents and evaluating the physiologic response is the most efficient approach to improve oxygen delivery and tissue perfusion.

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