Vasoactive Drugs and Pharmacology Case File

Vasoactive Drugs and Pharmacology Case File

Eugene C. Toy, MD, Manuel Suarez, MD, FACCP, Terrence H. Liu, MD, MPH

Case 5

You are called to give orders for a  62-year-old woman admitted to the ICU in sep­tic shock. The patient is receiving intravenous (IV) vancomycin, levofloxacin, and gentamicin for suspected  urosepsis and potential pneumonia. The patient has been admitted from a  skilled nursing facility.  The vital  signs indicate the blood pressure  is 100/60 mm Hg, heart rate 120 beats/minute, respiratory rate (RR) 30 breaths/minute, with a  urinary output of 20 ml/h. Two liters of normal saline was given within 1 hour without a  noticeable improvement in BP or heart rate. A central  venous line recorded a venous O2 saturation of 60%.

⯈What is the next step in addressing the blood pressure?

⯈What other measures should be undertaken in this patient?

ANSWER TO CASE

Vasoactive Drugs and Pharmacology

Summary: A 62-year-old woman is in sepsis with decreased blood pressure as well as signs of decreased intravascular volume and cardiac output. 

• Next step in addressing blood pressure: Given the low mean arterial pressure and tachycardia, the first step should incorporate efforts to increase the BP is with IV fluids, mainly normal saline, followed by proper vasopressors if the BP does not improve. The blood pressure should be supported to ensure that the blood flow to target organs is sufficient with this combination. 
• Other measures: Appropriate maintenance of fluid and blood volume with adherence to goal-directed therapy. A pH of at least 7. 20 is   needed for vasopres­sors to be effective. 

ANALYSIS

Objectives

1. To describe the indications to the use of vasopressors. 
2. To understand the pharmacological mechanisms of vasopressors action. 

Considerations

This 62-year-old woman is admitted to the ICU with urosepsis and possible pneu­monia. The patient's hypotension and decreased urine output indicate profound septic shock. The  keys to treatment, and thereby improving survival include rapidly addressing the abnormal hemodynamic parameters, early correction of the  underly­ing cause of the  sepsis. This means administration and correct antibiotics in a timely fashion (within 1 hour for hospital inpatients and up to 6 hours for outpatients). 

Approach To:

Fluid and Vasopressor Use

IV FLUIDS 

IV fluids are usually the first therapy for hypotension. Fluid therapy is effective in increasing intravascular volume (IVC), which in turn increases the BP. An ideal fluid would maintain IVC without expanding the interstitial space (ISFV). Crystalloid solutions are universally used for initial volume resuscitation. In sepsis, significant tissue accumulation of resuscitation fluid occurs, which results in adverse effects. Crystalloid solutions may be isotonic, hypotonic, or hypertonic and are in universal use as   primary resuscitation fluids in critical illnesses. The determination of which crystalloid to use remains controversial. Aggressive resuscitation with crystalloids induces a dramatic increase in extracellular fluid (ECF), alterations in acid-base balance, electrolyte composition, colloid balance, and coagulation. Combinations of crystalloids and colloids given together have proven effective since significantly greater tissue perfusion occurs when compared with crystalloid alone. 

The volume distribution of 1L  of NaCl 0.9% would put 250 mL in   the IVC and 750 mL in the ISFV.  In contrast the administration of 5% albumin will increase plasma volume by 52% of the volume infused. Albumin increases the cardiac index significantly more than saline and has a significant effect on hemoglobin dilution. The tendency for crystalloids to extravasate may lead to relative hypoperfusion. There is emerging evidence that intravenous fluids may have an indigenous pro, inflammatory property. The findings in Iraq from studies on injured soldiers, who were resuscitated from a hypotensive state with low volume hypertonic saline, dem­onstrated an elevation in BP without an increase in inflammatory markers. Isotonic saline, when administered in  large volumes, is associated with hyperchloremic nongap acidosis. During sepsis, there is a dramatic increase in capillary permeabil­ity. In these circumstances, up to   80% of the crystalloid solutions used cause edema which varies linearly with the volume of crystalloid that is administered. 

Lactated Ringers 

Solution Infusion of lactated Ringers solution is associated with the expression of adhesion molecules in lung and spleen whether or not  hemorrhage has occurred. When pre­ceded by shock, the use of lactated Ringers solution for resuscitation is associated with histologic evidence of increased pulmonary edema and inflammation. Lactated Ringers solution and other isotonic crystalloid solutions may activate inflammatory cytokines and result in cellular apoptosis, possibly increasing lung injury

Ethyl Pyruvate 

Ketone buffered IV fluids such as ethyl pyruvate may have anti-inflammatory effects. In  animals, ethyl pyruvate versus lactated Ringers solution resulted in less cellular apoptosis in pulmonary tissues. 

Hypertonic Saline 

The osmolality of normal plasma is 280 to 295 mOsm/L. Any solution with   an osmolality exceeding 310 mOsm/L is considered to be a hypertonic fluid. Hypertonic saline (HS) and sodium bicarbonate are examples of hypertonic fluids. The most commonly used concentrations of HS are 1.8%, 3%, 7.5%, and 23.4%. The higher the concentration of Na in HS, the larger the amount that stays in the IVC. The two well-defined uses of hypertonic fluid are: first, to expand the IVC in patients in hypo­volemic shock, as a means of low-volume, high-impact resuscitation ( eg, war victims with closed trauma). The second use is a corollary of the  first use, namely for intracel­lular volume depletion. This second advantage is widely appreciated in neurosurgery and neuro critical care where the reduction of cerebral volume and intracranial pres­sure (ICP) is especially important. HS dramatically increases the osmotic pressure in the compartment into which it is injected. Water flows along the osmotic gradient into the compartment, expanding the compartment's fluid volume for several hours. HS may also increase myocardial contractility. The metabolic consequences of HS are hypematremia, hyperosmolality, and hyperchloremic nongap acidosis.

Some studies and case reports suggest that patients have better hemodynamic profiles when given HS than when given isotonic crystalloid. No study of the pre­hospital administration of HS has shown an overall statistically significant ben­efit. Survival benefit has been noted for patients requiring surgery and receiving pre-hospital administration of HS plus dextran (HSD) versus an equal volume of isotonic crystalloid. Wade and colleagues reported an improved survival in patients who had suffered penetrating trauma if they were given HS. The major controversy in trauma is not the utility of HS but in the timing of its use. There are no large prospective studies on the use of HS in   sepsis. Hypothetically, HS should improve overall systemic perfusion and presumably oxygen delivery, and in addition it may modulate the inflammatory response. 

Albumin 

Albumin is a volume expander in vials of 250 and 500 mL and is also used as a 25% solution in 50- and 100-mL vials. Albumin products contain 130 to 160 mEq of sodium per liter of solution. The 5% solution is iso-oncotic with respect to human plasma; the 25% solution is 4 to 5 times more oncotically active . Albumin solutions do not appear to alter blood coagulation. The administration of albumin is associated with a  rapid but unpredictable expansion of the plasma volume. There is no evidence that the injection of albumin reduces mortality. Concerns that albumin therapy may increase mortality appear to be unfounded. Albumin is safe to use, but it is costly. There is no evidence that the administration of albumin improves patient recovery from sepsis. 

Colloids 

High molecular-weight solutions (colloids)  are used widely as plasma substi­tutes. Colloid solutions remain in the intravascular space because of their large molecular size, which is associated with low membrane impermeability. Colloids may also plug leaky capillaries and increase colloid oncotic pressure (COP), thus expanding the intravascular volume (IVC). One can achieve a volume expansion equal to or   greater than the volume administered, which reduces tissue edema. There is a strong argument that colloid solutions are expensive, leak into the extracellular space, and affect blood coagulation. Blood products are discussed in another section.

VASOPRESSOR AGENTS 

Vasopressor therapy is used when hypotension, such as caused by sepsis, is unre­sponsive to  fluid therapy. Vasopressors are used to assist in the maintenance of mean arterial pressure (MAP), whereas inotropes are used to increase cardiac out­put, cardiac index, stroke volume, and Svo2. The exact MAP target in patients is uncertain because each patient autoregulates within their own individualized limits. Autoregulation in various vascular beds can be lost below a certain MAP. This could lead to conditions  in which tissue perfusion becomes linearly dependent on blood pressure. The titration of norepinephrine (NE) to an MAP of 65 mm Hg is known to preserve tissue perfusion. A patient with preexisting hypertension may well require a higher MAP to maintain adequate tissue perfusion. The ideal "pressor" would 

restore blood pressure while maintaining cardiac output and preferentially perfuse mainly the brain, heart, splanchnic organs, and kidneys. All vasopressors are associ­ated with adverse effects (Table 5-1).

Dobutamine

Dobutamine is a synthetic catecholamine with primarily β1 agonist activity, leading to increased cardiac contractility. The increase in heart rate caused by dobutamine is offset by its vasodilation effect with little net effect on blood pressure (BP) . The principal use of dobutamine is in patients with refractory CHF, hypotension, or septic patients with hypoperfusion in whom vasodilators cannot be used because of their effect on blood pressure (BP) . The onset of dobutamine action is 1 to 10 minutes after its administration with its peak effect being reached in 10 to 20 minutes. The usual drip rate for adults is at 2.5 to 20 μg/kg/min with a recommended maximum of 40 μg/ kg/min. It is important to titrate the dosage to achieve the desired target of increased cardiac output. Vasopressors should be administered into large veins preferably via a central line. Dobutamine has less effect on heart rate than dopamine. Dobutamine appears particularly effective in splanchnic resuscitation, increasing pH (gastric mucosal pH) , and improving mucosal perfusion when compared to dopamine. As part of an early goal-directed resuscitation protocol that combined close medical and nursing attention with aggressive fluid and blood administration, dobutamine was associated with a significant absolute reduction in the risk for mortality.

Dopamine

Dopamine has predominantly β-adrenergic effects in low-to-moderate dose ranges (up to 10 μg/kg/min). It is converted to NE in the myocardium and activates adrenergic receptors. In higher doses, its ability to sensitize α-adrenergic receptors causes vasoconstriction. Dopamine is a mixed inotrope and vasoconstrictor. At all dose ranges, dopamine is a potent chronotrope. Dopamine causes more tachycardia and is more arrhythmogenic than NE. Evidence suggests that dopamine does not have

a net substantial effect on the kidneys. It may interfere with thyroid and pituitary function and may have an immunosuppressive effect. The use of "renal-dose" dopamine has been proven false. Dopamine-resistant septic shock (DRSS) has been described, defined as MAP < 70 mm Hg despite administration of dopamine at 20 μg/kg/min. The incidence of DRSS was 60%, and those patients had a mortality rate of 78%, compared with 16% in the dopamine-sensitive group.

Norepinephrine

Norepinephrine (NE) has pharmacologic effects on both α1- and β1-adrenergic receptors.

NE is used to maintain BP in hypotensive states and is a more potent vasoconstrictor

than its relative phenylephrine. The usual maintenance dose is 2 to 4 μg/min.

Doses as high as 0.5 to 1.5 μg/kg/min for 1 to 1 0 days have been used in patients with

septic shock. The potential for extravasation is avoided when the administration is via

a large vein. Currently, NE is considered the agent of choice for the patient requiring

fluid resuscitation, although this is controversial. Both vasoconstriction and increased

MAP are evident when NE is used in the normal dosage range. NE does not increase

heart rate. The main beneficial effect of NE is to increase organ perfusion by increasing

vascular tone. Studies that have compared NE to dopamine have favored NE in terms

of overall improvement in oxygen delivery, organ perfusion, and oxygen consumption.

Oxygen delivery and oxygen consumption increased in both dopamine and NE

patient study groups. Norepinephrine is metabolically less active than epinephrine and

reduces serum lactate levels. Norepinephrine significantly improves renal perfusion

and splanchnic blood flow in sepsis, particularly when combined with dobutamine.

Epinephrine

Epinephrine has potent β1-, β2-,and α1-adrenergic activity, although the increase in MAP in sepsis is mainly from an increase in cardiac output (stroke volume). There are 3 major drawbacks to using this drug: (1) epinephrine increases myocardial oxy­gen demand; (2) it increases serum glucose and lactate, which is largely a calorigenic effect (increased release and anaerobic breakdown of glucose); and ( 3) epinephrine appears to have adverse effects on splanchnic blood flow, redirecting blood to periph­eral tissues as part of the  fight-and-flight response. A  combination of dopamine and norepinephrine enhanced gastric mucosal blood flow more than epinephrine alone. There are few data that distinguish epinephrine from norepinephrine in their abil­ity to achieve hemodynamic goals, and epinephrine is a superior inotrope. Concern about the impact of epinephrine on splanchnic perfusion needs to be considered. Concern about the effect of increased serum lactate and hyperglycemia has limited the use of epinephrine. Hypokalemia and arrhythmia are the result of the β2 agonist action of epinephrine, which drives potassium into the cell resulting in hypokalemia. 

Phenylephrine

Phenylephrine is an almost pure α1 -adrenergic agonist with moderate potency. Although widely used in anesthesia to treat iatrogenic hypotension, it is often an ineffective agent in treating sepsis. Phenylephrine is an adrenergic agent least likely to cause tachycardia. It is a less effective vasoconstrictor than norepinephrine or epinephrine. Compared with norepinephrine, phenylephrine is more effective in reducing splanchnic blood flow, oxygen delivery, and lactate uptake. Phenylephrine may be a good therapeutic option when tachyarrhythmias limit therapy with other vasopressors.

Vasopressin

Arginine-vasopressin is an endogenous hormone that is released in response to decreases in intravascular volume and increased plasma osmolality. Vasopressin constricts vascular smooth muscle directly through V1 receptors. It also increases the responsiveness of the vasculature to catecholamines. Vasopressin is a hormone ADH analog secreted from the posterior pituitary. It is now the first drug administered to adults in out-of-hospital asystole (cardiac arrest) with 40 units given IV as the standard dose. If spontaneous circulation is not restored in 3 minutes, then this dose is repeated or epinephrine therapy as a bolus is begun. If no IV access is available then 40 units diluted with NS to a total volume of 10 mL should be delivered endotracheally. An intra-osseous device can be used to gain IV access. Vasopressin may be used in patients with refractory shock where adequate fluid and pressor resuscitation has failed to increase BP. Vasopressin has emerged as an additive vasoconstrictor in septic patients who have become resistant to catecholamines. There appears to be a quantitative deficiency of this hormone in sepsis, and administration of vasopressin in addition to NE increases splanchnic blood flow and urinary output. Vasopressin does not increase myocardial oxygen demand significantly, and its receptors are unaffected by acidosis.

Neosynephrine

Phenylephrine and neosynephrine are selective a1-adrenergic receptor agonists used primarily as decongestants, to dilate the pupil, and to increase BP. MI originates from the frequent or overuse of these compounds in nasal sprays. The response of blood pressure and the emergence of side effects to these compounds render them inadequate for use in the ICU. NE and phenylephrine are used more commonly in situations involving anesthesia or critical care. Phenylephrine is especially useful in counteracting the hypotensive effect of epidural and subarachnoid anesthetics. With its pure a activity it lacks inotropic or chronotropic activity, and so it elevates the blood pressure without increasing the heart rate or contractility. Reflex bradycardia may result from the elevation of blood pressure, and this effect may be useful in hypotensive patients that present with a tachyarrhythmia.

Levosimendan

Levosimendan is a calcium sensitizer. It increases the sensitivity of the heart to calcium, thereby increasing cardiac contractility without forcing a rise in intracellular calcium. The combined inotropic and vasodilatory actions result in an increased power of contraction with decreased preload and decreased afterload.

Other Vasopressors

A variety of other vasopressors are available and some of these which are in use include phosphodiesterase inhibitors, such as milrinone and enoximone. These appear to be alternatives to dobutamine as a treatment for cardiomyopathy of critical illness while restoring splanchnic blood flow.

CLINICAL CASE CORRELATION

• See also Case 4 (Hemodynamic Monitoring) , Case 1 6 (Acute Cardiac Failure), Case 28 (Blunt Trauma), and Case 41 (Hemorrhage, Coagulopathy).

COMPREHENSION QUESTIONS

5.1 A 75-year-old man is brought to the ED from a nursing home because of confusion, fever, and flank pain. On physical examination, his temperature is 38.8°C (101.9°F), blood pressure is 78/46 mm Hg, heart rate is 117 beats/minute, and respiration rate is 29 breaths/minute. Dry mucous membranes, poor skin turgor, costovertebral angle tenderness but no edema is noted on physical examination.

The leukocyte count is 22,000/μL; urinalysis shows 3+ leukocytes. The patient has an anion-gap metabolic acidosis and high lactic acid level. Antibiotic therapy is started. Which of the following is most likely to improve survival for this patient?

A. Fluid resuscitation and correction of BP and lactic acidosis

B. Administration of 25% albumin infusion

C. Hemodynamic monitoring with a pulmonary artery catheter

D. Maintaining hemoglobin above 12 g/dL

E. Maintaining Pco2 below 50 mm Hg

5.2 You are paged by the ICU nurse at 3 AM to evaluate a 72-year-old man whose BP has dropped from 114/78 to 82/48 mm Hg in the past hour. His mucous membranes are dry. You see that the patient was admitted 6 hours ago with a temperature of 38.5°C (101.3°F) , BP 118/84 mm Hg, heart rate 104 beats/minute, and respiration rate of 28 breaths/minute. His WBC on admission was 18,000/μL The patient has been receiving normal saline at 200 mL/h for the past 6 hours. Which of the following is the best first-line pharmacological intervention most likely to improve the patient's blood pressure?

A. Epinephrine alone

B. Norepinephrine

C. Dobutamine

D. Vasopressin

E. Phenylephrine

ANSWERS TO QUESTIONS

5.1 A. Aggressive fluid resuscitation with IV antibiotics and resolution of lactic acidosis would have a beneficial effect on this patient's survival. The patient has severe sepsis presumptively from pyelonephritis. The timing of resuscitation matters relative to survival. Early goal-directed therapy includes interventions delivered within the first 6 hours of the patient's presentation to the hospital or within 1 hour if the patient has already been admitted. The goal is to maintain a central venous pressure of 8 to 12 cm H20 and an oxygen venous saturation of > 70%. This results in higher survival rates than more delayed resuscitation attempts. Reversal of the lactic acidosis is paramount.

5.2 B. This patient presents with hyperdynamic septic shock. Hyperdynamic septic shock is characterized by hypotension, low SVR, and high Cl. Norepinephrine (NE) and phenylephrine are the drugs of choice for the control of hyperdynamic septic shock. NE should be used initially followed by phenylephrine if no improvement is noted. NE is a more potent vasoconstrictor than phenylephrine. Epinephrine is not a first-line treatment as a vasopressor in sepsis. High-dose dopamine is more efficacious in treating hypodynamic septic shock, characterized by hypotension, low SVR, and low CI, resulting in cold extremities. Dobutamine is used in sepsis to reverse the cardiosuppressant effect induced by the gram-negative sepsis; it does not significantly elevate BP. Vasopressin as a supplementary agent in refractory hypotension has been effective.

CLINICAL PEARLS

⯈ Crystalloid solutions are universally used for initial volume resuscitation in sepsis and septic shock to compensate for fluid debt. 

⯈ Colloid solutions achieve  hemodynamic goals faster than crystalloids with lower volumes. 

⯈ Isotonic saline,  when administered in large volumes, is associated with hyperchloremic acidosis; this may affect splanchnic blood flow and may be nephrotoxic. 

⯈ Dobutamine is a potent inotrope that is a useful adjunct to fluid resusci­tation in early sepsis. 

⯈ Epinephrine is a  potent vasoconstrictor and inotrope. It causes an early lactic acidosis secondary to aerobic glycolysis and may reduce splanchnic blood flow. 

⯈ NE is a potent vasoconstrictor that maintains CO and restores blood flow to dependent organs. 

⯈ It is essential that  patients be fluid-resuscitated before  commencing vasopressor therapy. 

⯈ The goal of vasopressor support is to maintain BP in the autoregulation range of organs. 

⯈ Phenylephrine may be a  good therapeutic option when tachyarrhythmia limits therapy with other vasopressors. 

References

Loscalzo J. Harrison's Pulmonary and Critical Care Medicine. New York, NY: McGraw-Hill; 2 0 1 0 . 

Roberts I, Alderson P, Bunn F, et a l . Colloids versus crystalloids for fluid resuscitation i n critically ill patients. Cochrane Database Syst Rev. 2004;CD000567. 

Toy S, Takenaka, LR. Case Files Emergency Medicine. 2nd ed, New York, NY: McGraw-Hill, Lange, 2013.

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