65 J.S. already has

signs of acidosis (pH 7.28, HCO3

− 15 mEq/L), and increased lactic acid production

by epinephrine could be detrimental to his organ function. Epinephrine should be

reserved for patients with a markedly depressed CO in conjunction with severe

hypotension.

In summary, very few comparable studies of inotropic agents in this setting have

been conducted; thus, the selection of agent is often based on the expected clinical

benefit as well as individual experience with the drugs.

66 None of the choices are

without risk as they could adversely affect the myocardial oxygen supply to demand

ratio and could further extend the area of ischemia or necrosis. J.S. would benefit

from an increase in his CO, as well as in his MAP. The clinician elects to start J.S.

on dobutamine and dopamine infusions.

SELECTION AND INITIATION OF THERAPY

CASE 17-3, QUESTION 5: At what doses should you initiate a dobutamine and dopamine infusion in J.S.?

What therapeutic outcomes are anticipated at these doses and during what time? What adverse effects may be

encountered with these infusions?

J.S. has a MAP of 58 mm Hg, CI of 1.7 L/minute/m2

, PCWP of 24 mm Hg, and HR

of 105 beats/minute. Goals of therapy are to increase the CI to at least 2.5

L/minute/m2

, maintain a MAP of at least 70 mm Hg (preferably closer to 80 mm Hg,

depending on clinical signs of hypoperfusion), reduce the PCWP to 12 to 18 mm Hg,

and maintain an HR of less than 125 beats/minute. A urine output of at least 0.5

mL/kg/hour is desirable. Reasonable initial infusion rates would be dopamine 5

mcg/kg/minute and dobutamine 2 mcg/kg/minute. These doses should increase

cardiac contraction and CO, resulting in an increase in renal blood flow. The onset of

effect is rapid and the half-life short (approximately 2 minutes) for both agents, with

steady-state conditions generally achieved within 10 minutes of initiation of therapy.

This allows dose titration every 10 minutes based on patient tolerance.

Because the onsets of action are within minutes, J.S. can be reevaluated and the

infusion rates can be alternately titrated upward by 1 to 2 mcg/kg/minute every 10

minutes, depending on the hemodynamic data. The response to both agents is highly

variable among patients; thus, careful titration using the lowest effective infusion

rates is advised.

Adverse effects encountered with both infusions include increased HR, angina,

arrhythmias, headache, tremors, nausea, and vomiting. The increases in contractility

and HR caused by dobutamine and dopamine pose additive risk of tachyarrhythmias

and can increase myocardial O2

, leading to ischemia in patients with coronary

artery disease.

Dobutamine could lower the MAP, adversely affecting coronary perfusion

pressure. Another limiting factor to dobutamine is tolerance to its hemodynamic

effects with long-term continuous use. A decline in CO and HR has been seen after

prolonged infusion and is most likely caused by down-regulation of β1

-receptors. Of

concern, evidence suggests that inotropic agents can be associated with an increased

risk of mortality in patients with HF despite the improvement of symptoms and

hemodynamic indices.

67

Dopamine might elevate the PCWP, thereby decreasing coronary perfusion

pressure. Extravasation of large amounts of dopamine during infusion can cause

ischemic necrosis and sloughing. At higher dosages, α1

-adrenergic effects are more

prominent, causing peripheral arterial vasoconstriction and increases in afterload,

preload, and myocardial oxygen demand as well as ischemia.

CASE 17-3, QUESTION 6: Dobutamine and dopamine are titrated from 2 to 4 mcg/kg/minute and 5 to 6

mcg/kg/minute, respectively, in J.S. during the next 2 hours. A repeat chest radiograph shows slight worsening

of pulmonary edema. The following hemodynamic profile is obtained (previous values are in parentheses):

BP (S/D/M), 105/60/75 mm Hg (86/44/58 mm Hg)

HR, 140 beats/minute (105 beats/minute)

CO, 5.3 L/minute (3 L/minute)

CI, 3 L/minute/m

2

(1.7 L/minute/m

2

)

CVP, 11 mm Hg (14 mm Hg)

PCWP, 22 mm Hg (24 mm Hg)

SVR, 1,493 dyne·s·cm

−5

(1,570 dyne·s·cm

−5

)

Urine output, 0.4 mL/kg/hour (0.2 mL/kg/hour)

Hct, 33% (31%)

Do these data indicate a favorable or adverse hemodynamic effect from dobutamine and dopamine in J.S.?

Dobutamine at 4 mcg/kg/minute and dopamine at 6 mcg/kg/minute have established

a trend in the desired direction for CI; however, the HR has increased significantly.

The SVR and PCWP have not changed appreciably, and the urine flow has increased.

The SV (CO/HR) has only increased from 28 to 38 mL/beat; thus, the increase in CO

has resulted from both the chronotropic and the inotropic effects of these agents. As a

net response, the dobutamine and dopamine have most likely adversely affected the

myocardial oxygen supply to demand ratio; however, this cannot be established

definitively. J.S. should be monitored closely for signs of myocardial ischemia.

CHANGING THERAPY

CASE 17-3, QUESTION 7: The clinician decides that an HR of 140 beats/minute is unacceptable in J.S.,

who presented with an AMI. Subsequent attempts to taper the dobutamine to lessen the induced tachycardia

without dropping the CI and perfusion pressure are unsuccessful. Milrinone is suggested as an alternative to

dobutamine. What hemodynamic changes would you expect with milrinone in J.S.? Does milrinone offer any

advantages compared with dobutamine?

Milrinone increases intracellular AMP levels by inhibiting phosphodiesterase-3

within the sarcoplasmic reticulum of cardiac myocytes and vascular smooth muscle,

leading to increased contractility of the myocardium and vasodilation of vascular

smooth muscle. The increased CO and decreased SVR are accompanied by an

increased lusitropic effect. Milrinone produces fewer chronotropic and

arrhythmogenic effects than the catecholamines but, like dobutamine, can decrease

SVR and cause hypotension. Moreover, milrinone has a longer half-life than

dobutamine, making it difficult to use as monotherapy for cardiogenic shock. The

combination of

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p. 365

dopamine with milrinone would offset some of milrinone’s hypotensive effects.

Although milrinone has not been studied in patients who are post-AMI with

cardiogenic shock, it could be beneficial in patients with adequate BP, who have

down-regulated β receptors (chronic heart failure or beta agonist use), recently

received β-blockade, or with catecholamine dose-limiting arrhythmias.

Dobutamine has equivalent or greater inotropic action than dopamine and, as

mentioned above, dobutamine causes less tachycardia, so it may be better to remove

dopamine in this patient. A decrease of 20% of the current dopamine infusion rate (1

to 2 mcg/kg/minute) every 10 to 15 minutes is reasonable. Just as with upward

titration of therapy, steady state should be achieved within 10 minutes. When tapering

vasoactive agents, it is prudent, however, to let the patient stabilize hemodynamically

at new infusion rates for a period that exceeds the time to achieve a new steady-state

plasma concentration. After each reduction in the infusion rate, hemodynamic data

can be assessed. The major difference between the two agents is the effect of

dopamine on α1

-receptors. With dobutamine’s greater clinical effect on β2

-receptors

compared to α1

-receptors, J.S. may experience a decrease in the SVR. A decreased

SVR should allow for an increased CI, but J.S. should be monitored carefully as his

MAP is relatively low and any major reduction in SVR could lead to further BP

reduction.

CASE 17-3, QUESTION 8: Dopamine is tapered off and dobutamine is increased to 5 mcg/kg/minute for

J.S. His HR decreased to 105 to 110 beats/minute within the next hour. Despite these changes and initiation of

ventilatory support by tracheal intubation, J.S. continues to show signs of deterioration with progressive

obtundation and loss of bowelsounds. His systemic arterial pressure has continued to decline. Preload reduction

was attempted previously with nitroglycerin; however, the BP reduction was intolerable. A repeat

hemodynamic profile shows the following values (previous values in parentheses):

BP (S/D/M), 86/40/55 mm Hg (105/60/75 mm Hg)

HR, 132 beats/minute (105 to 110 beats/minute)

CO, 3.2 L/minute (5.3 L/minute)

CI, 1.8 L/minute/m

2

(3 L/minute/m

2

)

SvO2

, 42% (48%)

CVP, 16 mm Hg (11 mm Hg)

PCWP, 28 mm Hg (22 mm Hg)

SVR, 992 dyne·s·cm

−5

(1,493 dyne·s·cm

−5

)

Urine output, 0.1 mL/kg/hour (0.4 mL/kg/hour)

PaO2

, 75 mm Hg (90 mm Hg)

PaCO2

, 42 mm Hg (38 mm Hg)

pH, 7.24 (7.3)

HCO3

−

, 17 mEq/L (18 mEq/L)

The ECG shows atrial tachycardia with occasional premature ventricular contractions. What therapeutic

alternatives can be considered at this time?

J.S. is still in severe cardiogenic shock, and his tissue perfusion continues to

deteriorate as evidenced by a further reduction in urine output, a loss of bowel

sounds, continuing acidosis, and obtundation. Because his systemic arterial pressure

and tissue perfusion have declined, additional support with a potent vasopressor and

the insertion of an IABP or other percutaneous ventricular assist device are

indicated. The combination of dopamine and dobutamine previously resulted in

intolerable tachycardia, so other therapies should be considered.

Norepinephrine

Norepinephrine is a potent α-adrenergic agonist that vasoconstricts arterioles at all

infusion rates, thereby increasing SVR. Thus, systemic arterial and coronary

perfusion pressures both rise. Norepinephrine also stimulates β1

-adrenergic

receptors to a lesser extent, resulting in increased contractility and SV. However, HR

and CO usually remain constant or may decrease secondary to the increased

afterload, and baroreceptor-mediated reflex increases in vagal tone. Although

coronary perfusion pressure is enhanced as a result of the elevation in diastolic

pressure, myocardial O2 also is increased. Consequently, myocardial ischemia and

arrhythmias may be exacerbated and LV function further compromised.

Infusions of norepinephrine are begun at 0.01 to 0.05 mcg/kg/minute and titrated

upward to achieve a MAP of 65 to 70 mm Hg. Adverse effects of norepinephrine are

related mostly to excessive vasoconstriction and compromise of organ perfusion.

Administration should be through a central IV line because local subcutaneous

necrosis and sloughing can result from peripheral IV extravasation. Prolonged

infusion of larger doses will transiently exert a beneficial effect by diverting blood

flow from the peripheral and splanchnic vasculature to the heart and brain; however,

this ultimately can compromise capillary perfusion to the extent that end-organ

failure, particularly renal failure, ensues.

Again, it must be emphasized that pharmacologic support for J.S., particularly the

use of norepinephrine, is only an interim maneuver to temporarily maintain

hemodynamic function. J.S. should continue to be monitored for signs of myocardial

ischemia and the need for further revascularization procedures. Patients who cannot

be stabilized with pharmacologic intervention, and in whom systemic or myocardial

perfusion is becoming compromised, may require further support through insertion of

a mechanical circulatory assist device.

Mechanical Circulatory Support

When drug therapy is ineffective at stabilizing patients in cardiogenic shock,

mechanical intervention should be considered. Mechanical interventions can rapidly

stabilize patients with cardiogenic shock, especially those with global myocardial

ischemia or infarction complicated by mechanical defects, such as papillary muscle

rupture or ventricular septal rupture. Sometimes combined inotropic support and

intra-aortic balloon counterpulsation are required to maintain an acceptable BP

(MAP above 65 mm Hg) and CI (greater than 2.2 L/minute/m2

).

The IABP has been in use for more than 40 years and remains the most commonly

used mechanical assist device. It is designed to improve coronary arterial perfusion

pressure and reduce afterload, providing short-term reperfusion of the ischemic

myocardium.

68 A 20- to 50-mL balloon catheter is inserted into an artery (usually

femoral) and advanced to the proximal descending aorta. Balloon inflation and

deflation are synchronized with the ECG to inflate during diastole and deflate at the

onset of systole. The inflated balloon in diastole increases coronary perfusion by

elevating the mean aortic pressure. The rapid deflation of the balloon at the onset of

systole decreases afterload and modestly improving CO.

68 The enhanced myocardial

perfusion provided by IABP may reduce vasopressor requirements, thereby further

decreasing myocardial O2

. Occasionally, IABP augmentation is sufficient to allow

the institution of vasodilators (e.g., nitroprusside) or inodilators (e.g., milrinone).

IABP support should be discontinued as soon as the patient stabilizes or

complications develop. Complications associated with the IABP increase with

longer duration of use and include vascular injury, thrombocytopenia from the

mechanical destruction of platelets, and limb ischemia because of reduced blood

flow in the artery into which the IABP catheter is inserted. Heparin anticoagulation is

usually given with IABP because the device has a large, thrombogenic surface area.

Infectious complications are uncommon when the use is limited to less than 7 days.

Reviews of clinical studies investigating the use of the IABP in cardiogenic shock

have found no differences in 30-day mortality and an increase in the risk of bleeding

complications and stroke.

68,69 Despite the lack

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p. 366

of evidence, this device is recommended as reasonable to consider for patients

after ST-elevation MI and is commonly used to support patients with cardiogenic

shock.

50

Newer devices have been developed (TandemHeart, Impella) that augment CO

directly and decrease the load on the LV.

68 These small pumps are placed

percutaneously in the cardiac catheterization laboratory, avoiding major cardiac

surgery. They are best used for temporary circulatory support until more definitive

therapy is available. Systemic anticoagulation is required with these devices.

Complications of the TandemHeart include vascular injury, limb ischemia, cardiac

tamponade, thrombo- or air-embolism, and hemolysis. The most common adverse

effects of the Impella include vascular injury, thrombosis, thrombocytopenia,

bleeding, and hemolysis.

Advanced circulatory assist devices are evolving rapidly and are available in

centers with access to cardiac surgical procedures. Most patients currently receive

second- or third-generation, continuous flow devices (HeartMate II, Jarvik 2000,

HeartWare) because of their superior survival rates and lower incidence of adverse

events.

70 Mechanical assistance with these devices is used for patients with

cardiogenic shock who need support while awaiting definitive, corrective therapy or

as a bridging mechanism before cardiac transplantation. An improvement in survival

rates with newer generation devices has allowed their long-term use as destination

therapies in patients with severe cardiac failure despite optimal pharmacotherapy

that are not transplant candidates. The high cost of these devices and need for

experienced physicians will undoubtedly limit their use to only the most severely ill

patients.

In summary, J.S.’s condition has continued to deteriorate since his admission to the

ICU. Attempts at stabilizing his hemodynamic parameters with dopamine and

dobutamine have failed. This is evidenced by inadequate tissue perfusion, which is

reflected clinically by his continued lactic acidosis, decreased urine output, reduced

bowel sounds, and central nervous system obtundation. Norepinephrine and

epinephrine should be considered at this point to restore intra-arterial pressure and

tissue perfusion. Intra-aortic counterpulsation can provide synergistic temporary

support for J.S.

SEPTIC SHOCK

Distributive Shock

Distributive shock is characterized by an overt loss of vascular tone, causing acute

tissue hypoperfusion. Although numerous events such as anaphylaxis or neurogenic

causes can initiate distributive shock, most cases are readily reversed by supportive

measures and treatment or elimination of the underlying cause.

SEPTIC SHOCK

Distributive shock secondary to sepsis, or septic shock, is associated with a high

mortality rate, reflecting the limited therapeutic options available at this time. Over

1,500,000 cases of sepsis syndrome are seen annually in the United States. Mortality

rates are as high as 50%.

71 The combination of degree of organ dysfunction and

number of failing organs is the strongest predictor of death. Epidemiologic studies

show that approximately 25% of cases of sepsis syndrome eventually result in septic

shock. It has been projected that the incidence of sepsis will increase 1.5% per year

mainly because of the disproportionate growth of the elderly in the US population,

increasing burden of chronic health conditions, rising numbers of

immunocompromised patients, and multidrug-resistant infections.

3,4,71–73

The guidelines committee of the Surviving Sepsis Campaign—an international

consortium of professional societies involved in critical care, infectious diseases,

and emergency medicine—defines sepsis syndrome as life-threatening organ

dysfunction caused by a dysregulated host response to infection (see Table 17-8 for

definitions).

4 Organ dysfunction is identified as an acute change in total Sequential

Organ Failure Assessment (SOFA) score by at least 2 points consequent to the

infection (see Table 17-9 for SOFA calculation). In patients without preexisting

organ dysfunction, the baseline SOFA score is assumed to be zero. Persons with an

overall SOFA score of at least 2 may have a 25-times higher risk of mortality

compared to those with a score less than 2. A new bedside clinical score termed

quickSOFA (qSOFA) can easily identify persons that are more likely to have poor

outcomes. Adults with suspected infection are expected to fare worse if they have at

least two of three clinical criteria: RR of 22 breaths/minute or greater, altered

mentation (Glasgow Coma Scale score <15), or SBP of 100 mm Hg or less. When

hypotension persists despite adequate fluid resuscitation and requires vasopressor

support to maintain a MAP of at least 65 mm Hg while also having a serum lactate

level above 2 mmol/L, it is termed septic shock. Septic shock is associated with a

higher risk of mortality. Persons most at risk for septic shock are those who are

immunocompromised or have underlying conditions that render them susceptible to

bloodstream invasion. Groups at risk include neonates, the elderly, patients with

acquired immune deficiency syndrome, alcoholics, childbearing women, and those

undergoing surgery or who have experienced trauma. Other predisposing factors

include coexisting diseases such as diabetes mellitus, malignancies, chronic hepatic

or renal failure, and hyposplenism; exposure to immunosuppressant drugs and cancer

chemotherapy; and procedures such as insertion of urinary catheters, endotracheal

tubes, and IV lines.

Table 17-8

International Sepsis Definitions Task Force Definitions

Infection Pathologic process caused by the invasion of normally

sterile tissue or fluid or body cavity by pathogenic or

potentially pathogenic microorganisms. (Noted

exception: Clostridium difficile colitis does not occur in

a sterile colon)

Bacteremia The presence of viable bacteria in the blood.

Sepsis Life-threatening organ dysfunction caused by a

dysregulated host response to infection.

Organ dysfunction Identified as an acute change in total SOFA score ≥2

points consequent to the infection.

Septic shock A subset of sepsis in which underlying circulatory and

cellular/metabolic abnormalities are profound enough to

substantially increase mortality. Persistent sepsisinduced hypotension requiring vasopressors to maintain

MAP ≥65 mm Hg and having a serum lactate level >2

mmol/L despite adequate fluid resuscitation. Patients

who are on inotropic or vasopressor agents may not be

hypotensive at the time that perfusion abnormalities are

measured.