Pressors Scott Forman, D.O.

Adrenergic Receptor Physiology Alpha-1 Alpha-1 Beta-1 Beta-1 Beta-2 Beta-2 Dopamine Dopamine

Alpha Adrenergic Receptors Located in vascular walls Located in vascular walls –Induces significant vasoconstriction Present in heart Present in heart –Increase the duration of the contraction without increased chronotropy.

Beta Adrenergic Receptors Beta-1 adrenergic receptors are most common in the heart Beta-1 adrenergic receptors are most common in the heart –Mediate increases in inotropy and chronotropy with minimal vasoconstriction. Beta-2 adrenergic receptors in blood vessels induce vasodilation. Beta-2 adrenergic receptors in blood vessels induce vasodilation.

Dopamine Receptors Present in the renal, splanchnic, coronary, and cerebral vascular beds. Present in the renal, splanchnic, coronary, and cerebral vascular beds. Stimulation of these receptors leads to vasodilation. Stimulation of these receptors leads to vasodilation. Second subtype of dopamine receptors causes vasoconstriction by inducing norepinephrine release Second subtype of dopamine receptors causes vasoconstriction by inducing norepinephrine release

Principles Of Use Of Vasopressors and Inotropes Hypotension may result from: Hypotension may result from: –Hypovolemia –Pump failure –Pathologic maldistribution of blood flow Vasopressors are indicated for: Vasopressors are indicated for: –Decrease of >30 mmHg from baseline SBP or –MAP <60 mmHg and –Evidence of end-organ dysfunction due to hypoperfusion Hypovolemia must be corrected first Hypovolemia must be corrected first

Principles Of Use Of Vasopressors and Inotropes Use of vasopressors and inotropes is guided by three fundamental concepts: Use of vasopressors and inotropes is guided by three fundamental concepts: –One drug, many receptors –Dose-response curve –Direct versus reflex actions

Volume Resuscitation Repletion of adequate intravascular volume, when time permits, is crucial prior to the initiation of vasopressors. Repletion of adequate intravascular volume, when time permits, is crucial prior to the initiation of vasopressors. –Vasopressors will be ineffective or only partially effective in the setting of coexisting hypovolemia. Fluids may be withheld in patients with significant pulmonary edema due to ARDS or CHF. Fluids may be withheld in patients with significant pulmonary edema due to ARDS or CHF.

Selection and Titration Choice of an initial agent should be based upon the suspected underlying etiology of shock. Choice of an initial agent should be based upon the suspected underlying etiology of shock. Dose should be titrated up to achieve effective BP or end-organ perfusion. Dose should be titrated up to achieve effective BP or end-organ perfusion. If maximal doses of a first agent are inadequate, then a second drug should be added to the first. If maximal doses of a first agent are inadequate, then a second drug should be added to the first.

Tachyphylaxis Responsiveness to these drugs can decrease over time due to tachyphylaxis. Responsiveness to these drugs can decrease over time due to tachyphylaxis. Doses must be constantly titrated to adjust for this phenomenon and for changes in the patients clinical condition. Doses must be constantly titrated to adjust for this phenomenon and for changes in the patients clinical condition.

Subcutaneous Drug Delivery Bioavailability of subcutaneous heparin or insulin can be reduced during treatment with vasopressors due to cutaneous vasoconstriction. Bioavailability of subcutaneous heparin or insulin can be reduced during treatment with vasopressors due to cutaneous vasoconstriction.

Phenylephrine (Neosynephrine) Purely alpha-adrenergic agonist activity Purely alpha-adrenergic agonist activity –Vasoconstriction with minimal cardiac inotropy or chronotropy. Useful in settings of hypotension with SVR < 700 dynes x sec/cm5 Useful in settings of hypotension with SVR < 700 dynes x sec/cm5 –Hyperdynamic sepsis, neurologic disorders, anesthesia induced hypotension. Contraindicated if SVR > 1200 dynes x sec/cm5 Contraindicated if SVR > 1200 dynes x sec/cm5

Norepinephrine (Levophed) Acts on both alpha-1 and beta-1 receptors Acts on both alpha-1 and beta-1 receptors –Potent vasoconstriction as well as a less pronounced increase in cardiac output Reflex bradycardia usually occurs in response to the increased MAP Reflex bradycardia usually occurs in response to the increased MAP –Mild chronotropic effect is cancelled out and the HR remains unchanged or decreases slightly. Used most commonly to treat septic shock. Used most commonly to treat septic shock.

Epinephrine (Adrenalin) Potent beta-1 receptor activity and moderate beta- 2 and alpha-1 receptor effects. Potent beta-1 receptor activity and moderate beta- 2 and alpha-1 receptor effects. Result is an increased CO, with decreased SVR and variable effects on the MAP. Result is an increased CO, with decreased SVR and variable effects on the MAP. Beta-1 receptor stimulation may provoke dysrhythmias. Beta-1 receptor stimulation may provoke dysrhythmias. Greater degree of splanchnic vasoconstriction. Greater degree of splanchnic vasoconstriction. Most often used in treatment of anaphylaxis, as a second line agent in septic shock and for management of hypotension following CABG. Most often used in treatment of anaphylaxis, as a second line agent in septic shock and for management of hypotension following CABG.

Dopamine (Intropin) At low doses, dopamine acts predominately on dopamine-1 receptors in the renal mesenteric, cerebral, and coronary beds, resulting in selective vasodilation. At low doses, dopamine acts predominately on dopamine-1 receptors in the renal mesenteric, cerebral, and coronary beds, resulting in selective vasodilation. At moderate doses, dopamine also stimulates Beta-1 receptors and increases CO, predominately by increasing SV with variable effects on HR. At moderate doses, dopamine also stimulates Beta-1 receptors and increases CO, predominately by increasing SV with variable effects on HR. –Can result in dose-limiting dysrhythmias At higher doses, dopamine stimulates alpha receptors and produces vasoconstriction with an increased SVR. At higher doses, dopamine stimulates alpha receptors and produces vasoconstriction with an increased SVR.

Dopamine (Intropin) The dose-dependent effects of dopamine mean that increasing the dose of the drug is akin to switching vasopressors. The dose-dependent effects of dopamine mean that increasing the dose of the drug is akin to switching vasopressors. Most often used in hypotension due to sepsis or cardiac failure Most often used in hypotension due to sepsis or cardiac failure

Dobutamine (Dobutrex) Not a vasopressor but rather an inotrope that causes vasodilation. Not a vasopressor but rather an inotrope that causes vasodilation. Predominant beta-1 receptor effect increases inotropy and chronotropy and reduces LV filling pressures. Predominant beta-1 receptor effect increases inotropy and chronotropy and reduces LV filling pressures. Minimal alpha and beta-2 receptor effects result in overall vasodilation, complemented by reflex vasodilation to the increased CO. Minimal alpha and beta-2 receptor effects result in overall vasodilation, complemented by reflex vasodilation to the increased CO. Net effect is increased CO, with decreased SVR with or without a small reduction in BP. Net effect is increased CO, with decreased SVR with or without a small reduction in BP.

Dobutamine (Dobutrex) Frequently used in severe, medically refractory heart failure and cardiogenic shock. Frequently used in severe, medically refractory heart failure and cardiogenic shock. Should not be routinely used in sepsis because of the risk of hypotension. Should not be routinely used in sepsis because of the risk of hypotension. Does not selectively vasodilate the renal vascular bed. Does not selectively vasodilate the renal vascular bed.

Phosphodiesterase Inhibitors Amrinone and Milrinone Amrinone and Milrinone Nonadrenergic drugs with inotropic and vasodilatory actions. Nonadrenergic drugs with inotropic and vasodilatory actions. Effects are similar to dobutamine but with a lower incidence of dysrhythmias. Effects are similar to dobutamine but with a lower incidence of dysrhythmias. Used to treat patients with impaired cardiac function and medically refractory HF. Used to treat patients with impaired cardiac function and medically refractory HF. Vasodilatory properties limit their use in hypotensive patients. Vasodilatory properties limit their use in hypotensive patients.

Vasopressin Usually used in the setting of DI or esophageal variceal bleeding. Usually used in the setting of DI or esophageal variceal bleeding. May be useful in the treatment of refractory septic shock, particularly as a second pressor agent. May be useful in the treatment of refractory septic shock, particularly as a second pressor agent. Studies showed that the addition of vasopressin to norepinephrine was more effective in reversing late vasodilatory shock than norepinephrine alone. Studies showed that the addition of vasopressin to norepinephrine was more effective in reversing late vasodilatory shock than norepinephrine alone. Complications include coronary and mesenteric ischemia, hyponatremia, pulmonary vasoconstriction, and skin necrosis from peripheral infusion. Complications include coronary and mesenteric ischemia, hyponatremia, pulmonary vasoconstriction, and skin necrosis from peripheral infusion.

Complications Hypoperfusion Commonly occurs in the setting of inadequate cardiac output or inadequate volume resuscitation. Commonly occurs in the setting of inadequate cardiac output or inadequate volume resuscitation. Dusky skin changes at the tips of the fingers and toes, renal insufficiency and oliguria, and possible limb ischemia. Dusky skin changes at the tips of the fingers and toes, renal insufficiency and oliguria, and possible limb ischemia. Increase the risk of gastritis, shock liver, intestinal ischemia, or translocation of gut flora with resultant bacteremia. Increase the risk of gastritis, shock liver, intestinal ischemia, or translocation of gut flora with resultant bacteremia.

Complications Dysrhythmias Stimulation of beta-1 receptors. Stimulation of beta-1 receptors. Increases the risk of sinus tachycardia, atrial fibrillation, AVnRT, or ventricular tachyarrhythmias. Increases the risk of sinus tachycardia, atrial fibrillation, AVnRT, or ventricular tachyarrhythmias. Limit the maximal dose and necessitate switching to another agent with less prominent beta-1 effects. Limit the maximal dose and necessitate switching to another agent with less prominent beta-1 effects.

Complications Myocardial ischemia Beta receptor stimulation can increase myocardial oxygen consumption. Beta receptor stimulation can increase myocardial oxygen consumption. Excessive tachycardia should be avoided because of impaired diastolic filling of the coronary arteries. Excessive tachycardia should be avoided because of impaired diastolic filling of the coronary arteries.

Complications Local effects Peripheral extravasation of vasopressors into the surrounding connective tissue can lead to excessive local vasoconstriction with subsequent skin necrosis. Peripheral extravasation of vasopressors into the surrounding connective tissue can lead to excessive local vasoconstriction with subsequent skin necrosis. Vasopressors should be administered via a central line. Vasopressors should be administered via a central line. Local treatment with phentolamine (5 – 10mg) sub-Q can minimize local vasoconstriction. Local treatment with phentolamine (5 – 10mg) sub-Q can minimize local vasoconstriction.

Complications Hyperglycemia May occur due to inhibition of insulin secretion. May occur due to inhibition of insulin secretion. Magnitude of hyperglycemia generally is mild. Magnitude of hyperglycemia generally is mild. More pronounced with norepinephrine and epinephrine than dopamine. More pronounced with norepinephrine and epinephrine than dopamine.

Drug interactions/ Contraindications Patients with pheochromocytoma are at risk of excessive autonomic stimulation from pressors. Patients with pheochromocytoma are at risk of excessive autonomic stimulation from pressors. Dobutamine is contraindicated in the setting of IHSS. Dobutamine is contraindicated in the setting of IHSS. Patients receiving monoamine oxidase inhibitors are extremely sensitive to pressors, and require much lower doses. Patients receiving monoamine oxidase inhibitors are extremely sensitive to pressors, and require much lower doses.

Renal-dose Dopamine Dopamine selectively increases renal blood flow when administered at 1-3 mcg/kg/min Dopamine selectively increases renal blood flow when administered at 1-3 mcg/kg/min Currently, there is no data to support the routine use of low dose dopamine to prevent or treat acute renal failure or mesenteric ischemia. Currently, there is no data to support the routine use of low dose dopamine to prevent or treat acute renal failure or mesenteric ischemia.

Vasopressor Use in Septic Shock Patients with hyperdynamic septic shock (hypotension, low SVR, and high CI) tend to have warm extremities due to inappropriate hyperperfusion of the skin and soft tissues. Patients with hyperdynamic septic shock (hypotension, low SVR, and high CI) tend to have warm extremities due to inappropriate hyperperfusion of the skin and soft tissues. –Norepinephrine and phenylephrine appear more potent in hyperdynamic sepsis. Patients with hypodynamic septic shock (hypotension, low SVR, and low CI) manifest hypoperfusion of the extremities. Patients with hypodynamic septic shock (hypotension, low SVR, and low CI) manifest hypoperfusion of the extremities. –Dopamine may be preferable in patients with hypodynamic sepsis.

Management of Septic Shock Scott Forman, D.O.

Introduction Over 750,00 cases of sepsis occur in the U.S. each year Over 750,00 cases of sepsis occur in the U.S. each year Approximately 200,000 fatalities Approximately 200,000 fatalities Unfortunately, even with optimal treatment, the mortality rate from severe sepsis or septic shock is approximately 40%. Unfortunately, even with optimal treatment, the mortality rate from severe sepsis or septic shock is approximately 40%.

Therapeutic Priorities First priority is to employ supportive measures that counter physiologic abnormalities such as hypoxemia, hypotension, and impaired tissue oxygenation. First priority is to employ supportive measures that counter physiologic abnormalities such as hypoxemia, hypotension, and impaired tissue oxygenation. Early efforts must determine if SIRS is due to a noninfectious cause or is the result of an infection. Early efforts must determine if SIRS is due to a noninfectious cause or is the result of an infection. Identifying that infection is the cause of SIRS and finding the source are critical early priorities. Identifying that infection is the cause of SIRS and finding the source are critical early priorities. Patient must be assessed for adequate tissue perfusion. Patient must be assessed for adequate tissue perfusion.

Initial Management Resuscitation Resuscitation Supportive care Supportive care Monitoring Monitoring Targeted antimicrobial therapy Targeted antimicrobial therapy Drainage for infection Drainage for infection

Resuscitation The first step in the management of the patient with septic shack is to assess the ABCs. The first step in the management of the patient with septic shack is to assess the ABCs. Supplemental oxygen should be supplied to all patients with sepsis. Supplemental oxygen should be supplied to all patients with sepsis. The next priority is to assist ventilation and augment oxygenation. The next priority is to assist ventilation and augment oxygenation. Then, measures are taken to restore the BP to levels that perfuse vital organs. Then, measures are taken to restore the BP to levels that perfuse vital organs.

Monitoring of Tissue Perfusion Circulatory failure is present by definition in patients with septic shock. Circulatory failure is present by definition in patients with septic shock. The sphygmomanometer may be unreliable in hypotensive patients. The sphygmomanometer may be unreliable in hypotensive patients. An arterial catheter may be inserted if blood pressure is labile or if restoration of arterial perfusion pressures is expected to be a lengthy process. An arterial catheter may be inserted if blood pressure is labile or if restoration of arterial perfusion pressures is expected to be a lengthy process.

Monitoring of Tissue Perfusion Signs of impaired organ perfusion that occur in shock include: Signs of impaired organ perfusion that occur in shock include: –Cool, vasoconstricted skin –Obtundation or restlessness –Oliguria/anuria –Lactic Acidosis –Gastric intramucosal acidosis Clinical findings of shock may be modified by preexisting disease. Clinical findings of shock may be modified by preexisting disease.

Restoration of Tissue Perfusion Hypotension is sepsis results from: Hypotension is sepsis results from: –A loss of plasma volume into the interstitial space. –Decreases in vascular tone. –Myocardial depression. IV fluids, pRBCs, and pressors are often required, depending upon the patients volume status, cardiac status, and the severity of shock. IV fluids, pRBCs, and pressors are often required, depending upon the patients volume status, cardiac status, and the severity of shock.

Intravenous Fluids Rapid, large volume infusions of IVF are usually indicated as initial therapy in patients with septic shock. Rapid, large volume infusions of IVF are usually indicated as initial therapy in patients with septic shock. Fluid therapy should be administered in well-defined, rapidly infused boluses. Fluid therapy should be administered in well-defined, rapidly infused boluses. –Careful monitoring is essential in this approach because patients with sepsis can develop pulmonary edema at wedge pressures <18

Vasopressors Second line agents in the treatment of severe sepsis and septic shock Second line agents in the treatment of severe sepsis and septic shock –IVF are preferred so long as they increase CO and/or BP without seriously impairing gas exchange. Large trials comparing outcomes with different vasopressors have not been performed, and therefore there is no definitive evidence of the superiority of one pressor over another. Large trials comparing outcomes with different vasopressors have not been performed, and therefore there is no definitive evidence of the superiority of one pressor over another.

Identification of the Septic Focus A careful history and physical may yield clues to the source of sepsis and help guide subsequent microbiologic evaluation. A careful history and physical may yield clues to the source of sepsis and help guide subsequent microbiologic evaluation. Gram stain of suspicious fluids may give early clues to the etiology of infection while cultures are incubating. Gram stain of suspicious fluids may give early clues to the etiology of infection while cultures are incubating.

Eradication of Infection Essential to the successful treatment of septic shock. Essential to the successful treatment of septic shock. Source control should be undertaken when possible because undrained foci of infection may not respond to antibiotics alone. Source control should be undertaken when possible because undrained foci of infection may not respond to antibiotics alone. An empiric regimen of broad spectrum antibiotics should also be instituted as early as possible after appropriate cultures have been collected. An empiric regimen of broad spectrum antibiotics should also be instituted as early as possible after appropriate cultures have been collected.

Eradication of Infection Choice of antibiotics should be based upon clinical and Gram stain data and local resistance patterns, and then should be adjusted as culture results become available. Choice of antibiotics should be based upon clinical and Gram stain data and local resistance patterns, and then should be adjusted as culture results become available. Potential gram negative pathogens are generally covered with two effective agents from different antibiotic classes. Potential gram negative pathogens are generally covered with two effective agents from different antibiotic classes. Regardless of the antibiotic regimen, patients should be observed closely for toxicity, evidence of response, and for the development of superinfection. Regardless of the antibiotic regimen, patients should be observed closely for toxicity, evidence of response, and for the development of superinfection.

Recombinant Human Activated Protein C (Xigris) Dose 24 mcg/kg/hr for 96 hours Dose 24 mcg/kg/hr for 96 hours 28 day mortality rate was significantly lower. 28 day mortality rate was significantly lower. Increased incidence of serious bleeding, including fatal intracranial hemorrhage. Increased incidence of serious bleeding, including fatal intracranial hemorrhage. Treatment was of greater benefit in the most acutely ill patients. Treatment was of greater benefit in the most acutely ill patients. Analysis of secondary end points suggested that the incidence of MOD was lower in patients treated with Xigris, and that therapy was associated with more rapid recovery of cardiac and pulmonary function. Analysis of secondary end points suggested that the incidence of MOD was lower in patients treated with Xigris, and that therapy was associated with more rapid recovery of cardiac and pulmonary function.

Inclusion Criteria

Exclusion Criteria Pregnancy Pregnancy Age < 18 Age < 18 Weight > 135kg Weight > 135kg Platelet < 30,000 Platelet < 30,000 Known hypercoagulable conditions Known hypercoagulable conditions HIV with CD4<50 HIV with CD4<50 CKD requiring HD Conditions that increase the risk of bleeding Portal hypertension H/O bone marrow, lung, liver transplant. Acute pancreatitis

Corticosteroids Many patients with septic shock have a relative adrenal insufficiency. Many patients with septic shock have a relative adrenal insufficiency. Physiologic stress dose steroids were associated with a shorter duration of pressor dependence, as well as an improvement in 28-day mortality. Physiologic stress dose steroids were associated with a shorter duration of pressor dependence, as well as an improvement in 28-day mortality. Therapy was not associated with an increased incidence of adverse events. Therapy was not associated with an increased incidence of adverse events. Monitor for hyperglycemia in this setting. Monitor for hyperglycemia in this setting.

Nutrition Adequate nutritional support is essential for optimal immune function, and appears beneficial in both the prevention and the treatment of sepsis. Adequate nutritional support is essential for optimal immune function, and appears beneficial in both the prevention and the treatment of sepsis. –Improves wound healing and decreases susceptibility to infection. –Enteral nutrition may offer more benefit than parenteral nutrition. –Nutritional support results in higher lymphocyte counts and higher serum albumin levels. –Hyperglycemia and insulin resistance are common in critically ill patients. Evidence suggests that aggressive glucose control may improve outcome in these patients.

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