http://surgerybook.net/

complications, including the risk of central venous catheter insertion, endocarditis, and pulmonary

artery injury, which may outweigh any potential benefits. As the safety and utility of the PAC have not

yet been evaluated with prospective clinical trials in specific shock states, its usefulness in the

management of shock remains to be determined.

Newer versions of the PAC have been developed that provide additional hemodynamic information,

including continuous determination of cardiac output, ejection fraction, and calculated right ventricular

end-diastolic volume. The pulmonary artery wedge pressure is a proxy for preload. However, the

amount of precontractile stretch achieved with any given wedge or chamber pressure is modulated by

the compliance of the ventricle. Therefore, cardiac chamber pressure may not be an accurate indicator

of ventricular end-diastolic volume, just as end-diastolic volume may not be an accurate indicator of

pulmonary wedge pressure and/or risk of pulmonary edema. The combination of both wedge pressure

and end-diastolic volume may be optimal to maximize preload while avoiding excessive pulmonary

capillary pressure. The use, however, has been mainly supplanted with the use arterial wave contour

analysis and echocardiography.

A comparison of the pH and partial pressure of carbon dioxide (PCO2

) of mixed venous blood with a

matched arterial blood sample can provide evidence of shock with tissue hypoxia. Hypoxic cells

generate a hydrogen ion that is buffered by bicarbonate, resulting in increased production of H2O and

CO2

. An increase in venous PCO2

results in an abnormal gap between mixed venous and arterial PCO2

and pH and is a sign of anaerobic metabolism. With cessation of hydrogen ion production, this abnormal

gap is quickly eliminated, whereas base deficit and hyperlactatemia may persist for several hours.

Arterial Wave Contour Analysis

Analysis of the arterial wave contour in a mechanically ventilated patient has been shown to be a

marker of fluid responsiveness. This is a dynamic measurement, and as such, provides more information

than static measures such as CVP or PCWP. Inspiration during positive pressure ventilation increases

intrathoracic pressure and decreases venous return to the right heart. This, in turn, leads to a decrease

in left ventricular preload, a lower stroke volume, and a decreased cardiac output. This effect is more

pronounced in the hypovolemic patient, and calculation of PPV has been consistently shown to predict

fluid responsiveness in critically ill patients. PPV is a measure of percent-change in the pulse pressure

over the respiratory cycle, with a PPV greater than 12.5% being consistent with fluid responsiveness.101

Arterial wave contour analysis relies on patients having a sinus rhythm, no spontaneous respiratory

function, and a tidal volume of at least 8 mL/kg. Interpretation of PPV and other arterial wave contour

measurements should be cautioned outside of these parameters.

Bedside Ultrasound and Echocardiography

Improved ultrasound technology – better image quality and improved portability – over the past several

years has led to its frequent use in the emergency department and intensive care settings. Ultrasound

offers the benefits of being noninvasive, real-time, accurate, and reproducible. A focused cardiac

ultrasound can provide information on both left and right ventricular function as well as volume status.

Additionally, a pericardial effusion is easily identified and may be leading to tamponade physiology.

Valvular disease is much more difficult to identify and may require a formal transthoracic or

transesophageal echo.105

In addition to assessment of cardiac function, ultrasound has demonstrated use in assessment of

volume status and fluid responsiveness in shock states. Measurement of the superior vena cava (SVC),

IVC, and left ventricular stroke area (LVSA) have proved helpful in guiding resuscitation. Measurement

of the SVC and LVSA are performed via transesophageal echocardiography, which limits their routine

use in patient management. However, SVC and LVSA variation over the respiratory cycle has been

demonstrated to be predictive of fluid responsiveness.106–107 Measurement of the IVC is performed using

bedside ultrasound. The IVC is identified just caudal to the diaphragm, and an anterior–posterior

dimension is recorded at the end of expiration. In the setting of trauma and shock, an IVC diameter of

<1 cm is consistent with a transient responder and correlates with fluid responsiveness.108,109 The use

of ultrasound in critical care settings is growing and will continue to do so as technology and provider

experience improves.

PHARMACEUTICAL SUPPORT

286

http://surgerybook.net/

Therapeutic adjustments of preload and afterload form the basis of treatment strategies in all forms of

shock. Optimal volume resuscitation should always precede measures to augment the contractile

function of the heart. Inotropic augmentation of cardiac output may, therefore, be required when

restoration of venous preload fails to provide sufficient cardiac output to satisfy tissue oxygen demands.

The effect of inotropic agents depends on the specific adrenergic receptor affinity, chronotropic effects,

and demands placed on myocardial oxygen consumption of the individual agents (Table 9-7).

Vasodilators reduce demands on the myocardium and augment cardiac function via reduction in

systemic vascular resistance (SVR) or afterload or by dilating the venous system and reducing cardiac

preload. Afterload reduction may preserve stroke volume in the face of a failing myocardium, whereas

venodilation reduces pulmonary capillary wedge pressure and pressure-driven pulmonary edema.

Agents that increase afterload may be needed when blood pressure falls below the autoregulatory range

of the coronary, cerebral, and renal vascular beds.

Inotropes and Vasopressors

Dopamine

Dopamine is an endogenous sympathetic amine that is a biosynthetic precursor of epinephrine and

functions as a central and peripheral neurotransmitter. The effects of dopamine vary from individual to

individual, and are altered with increasing doses. The highest-affinity receptors are occupied at lowserum concentrations (infusions <2 to 3 μg/kg/min) and consist of dopaminergic receptors in the renal

and splanchnic beds that serve to augment regional blood flow, increase urine output, and cause

natriuresis. However, multiple studies, including prospective randomized trials, have failed to

demonstrate that low-dose dopamine prevents acute renal failure or decreases the need for dialysis in

critically ill patients. At modest concentrations (3 to 5 μg/kg/min), dopamine occupies cardiac β1

-

adrenergic receptors and increases myocardial contractility and heart rate. Higher doses (>5

μg/kg/min) cause an increase in heart rate and blood pressure. α-Adrenergic receptors are stimulated at

higher-dose ranges (>10 μg/kg/min), resulting in elevation of blood pressure and peripheral vascular

resistance. Dopamine is, therefore, an effective agent for increasing blood pressure in hypotensive

patients after appropriate fluid resuscitation. Because the relationship among a specific dose, receptor

affinity, and clinical effect is unique to each patient, individual titration is required to achieve the

desired effect.

Table 9-7 Pharmacodynamics of Inotropic/Vasoconstrictor Agents

Dobutamine

Dobutamine, a synthetic catecholamine, has a predominant affinity for β-adrenergic receptors. At

clinically relevant doses (5 to 20 μg/kg/min), dobutamine enhances myocardial contractility with mild

287

http://surgerybook.net/

to moderate changes in heart rate. It also induces peripheral vasodilation, which limits its utility in

patients with hypotension. It is an appropriate agent when cardiac output augmentation, not blood

pressure support, is required and when a drop in peripheral resistance and preload is clinically tolerable

or beneficial. Treatment of cardiogenic shock following myocardial infarction or cardiac dysfunction

following shock and reperfusion typically requires support of myocardial contractility and reduction of

peripheral resistance, which makes dobutamine an excellent choice in this setting.

Epinephrine

Epinephrine, the endogenous adrenal catecholamine, is released physiologically in response to stress. It

has a broad spectrum of systemic actions, including significant cardiovascular effects. When epinephrine

is administered as a pharmacologic agent (0.01 to 0.05 μg/kg/min), β1

-adrenergic effects predominate,

causing increased stroke volume, heart rate, and contractility, along with modest β2

-receptor

stimulation. At higher infusion rates, α-adrenergic receptors are stimulated, which overcome β2

-

mediated peripheral vasodilation, resulting in an increase in blood pressure and SVR. Renal and

splanchnic vasoconstriction, cardiac dysrhythmias, and increased myocardial oxygen demands limit the

prolonged use of high-dose epinephrine. Transient increases in serum lactate have also been noted,

possibly due to impaired regional blood flow. Epinephrine should be considered as a potential shortterm agent for use in patients with impaired cardiac function not responsive to other agents such as

dobutamine.

Norepinephrine

Norepinephrine, the sympathetic neurotransmitter, also has concentration-dependent cardiovascular

effects. It should be considered as a drug with predominantly α-constrictor effects and less pronounced

β-stimulation and is, therefore appropriate for use in patients who remain hypotensive despite

dopamine administration or as a dopamine alternative. Combined α- and β-stimulation typically results

in an increase in afterload and renal glomerular perfusion pressure, with preservation of cardiac output.

Despite the potential for renal vasoconstriction, as a result of its effects on mean arterial pressure,

norepinephrine is associated with an increase in urine output and creatinine clearance in hypotensive,

and particularly septic, patients. A primary concern is to ensure adequate volume resuscitation prior to

utilization due to risk of severe tissue damage from excessive vasoconstriction on the hypovolemic

patient.

Isoproterenol

Isoproterenol is a synthetic catecholamine with potent β-adrenergic effects. From a cardiovascular

standpoint, both cardiac and peripheral effects are significant. Stimulation of cardiac β1-receptors

prompts an increase in contractility, heart rate, and conduction velocity. The chronotropic response,

however, may predominate. These activities, in conjunction with peripheral vasodilation, generate

significant increases in cardiac output and pulse pressure. Isoproterenol greatly increases myocardial

oxygen demand and limits coronary filling due to tachycardia. As a result, indications for isoproterenol

are limited to patients with hemodynamically significant bradyarrhythmias while preparations are made

for electrical pacing.

Phenylephrine

Phenylephrine is a pure α-agonist and is an effective agent for increasing peripheral vascular resistance

and arterial blood pressure. Although it has no direct effect on the myocardium, the increase in

afterload increases left ventricular work and oxygen demand and may cause a decrease in stroke volume

and cardiac output. It is often used as a first-line agent in patients with neurogenic shock, but its use is

otherwise generally restricted to patients who remain hypotensive when the dosage of agents such as

dopamine or norepinephrine cannot be increased due to excessive tachycardia.

Vasopressin

Vasopressin acts directly on V1

receptors in vascular smooth muscle to cause vasoconstriction and

increases the reactivity of vascular smooth muscle to catecholamines. Release of endogenous

vasopressin is a normal physiologic response to shock. After septic or prolonged hemorrhagic shock,

circulating vasopressin levels are decreased, possibly due to depletion of hypophyseal secretory stores.

This relative deficiency may play a role in causing refractory hypotension. Vasopressin has minimal

effects on normotensive patients, but in patients with septic shock, it is effective in increasing SVR and

288

http://surgerybook.net/

mean arterial pressure. Vasopressin does not have inotropic properties but has potent splanchnic and

coronary vasoconstrictors. It has been associated with decreased cardiac output due to myocardial

ischemia and increased afterload and may worsen metabolic acidosis in patients in shock by causing

splanchnic ischemia. As a result, early use of vasopressin at only physiologic concentrations to minimize

associated other pressor use may be indicated in the event that other pressor agents are unable to

achieve optimal perfusion.110

Amrinone and Milrinone

Amrinone and milrinone are noncatecholamine inotropes with cardiovascular effects similar to

dobutamine, but with minimal chronotropic activity. As steroidlike phosphodiesterase antagonists, they

increase smooth muscle cyclic adenosine monophosphate (cAMP) and alter calcium metabolism. Cardiac

contractility, stroke volume, heart rate, and cardiac output are increased, while a concomitant reduction

in afterload offsets cardiac workload. The increase in cardiac performance with minimal demands on

myocardial oxygen consumption offers some utility in the treatment of cardiogenic shock or as a

potential alternative to dobutamine infusion. Both agents have a relatively long half-life of nearly 3

hours and should therefore be used with caution in patients at risk of developing hypotension, a major

risk in the critically ill patient.

Vasodilators

Vasodilators are used as a means to augment cardiac function through optimization of preload and

afterload, both of which reduce demands on the myocardium. The failing ventricle responds to afterload

reduction with significant increases in stroke volume. The reason for this is that the compromised

myocardium is working past the plateau and on the down slope of the Starling curve. As a result,

afterload reduction with vasodilator agents may allow cardiac output to increase, resulting in improved

oxygen delivery.

Nitroprusside

Nitroprusside is a balanced but potent arterial and venous smooth muscle vasodilator. It causes a

reduction in afterload that increases cardiac output and has a less prominent venodilatory effect that

reduces pulmonary venous pressure and preload. Hypotension may limit its use, particularly in the

presence of contractility deficits or inadequate preload. Infusions (>3 μg/kg/min) continued for greater

than 48 hours require monitoring of serum thiocyanate levels and arterial pH to detect complications of

cyanide toxicity.

Nitroglycerin

Nitroglycerin is primarily a venous smooth muscle vasodilator, with less significant arterial vasodilation

effects than nitroprusside. Thus, although nitroprusside predominantly decreases afterload, nitroglycerin

predominantly increases venous capacitance. It is an effective treatment for acute myocardial ischemia

because it reduces excessive preload and ventricular end-diastolic pressure, thereby diminishing

myocardial oxygen demand.

Miscellaneous Therapeutics

Corticosteroids

In septic shock, ACTH resistance may diminish the normal cortisol response. Also, peripheral tissue

resistance to corticosteroids may develop through proinflammatory-induced downregulation of normal

corticosteroid receptors. Initial clinical trials showed no reduction in mortality when short courses of

high-dose corticosteroids were used as adjuncts in the treatment of septic shock. However, recent

studies utilizing low or physiologic doses (<300 mg/day) of hydrocortisone for a longer duration (>5

days) of treatment have demonstrated a beneficial impact on mortality, particularly in septic patients.38

Currently, routine use of ACTH stimulation tests is not advocated since they provide little more than

prognostic information.40 Given that hypoadrenal shock complicates various shock states, routine use by

some experts is considered appropriate. However, this should only be based on patients who have

achieved adequate intravascular volume but remain in shock despite high vasopressor administration.

Thus use of corticosteroids at only physiologic doses with immediate tapering once hemodynamics have

improved should be used with caution.39

Metabolites and Electrolytes

289