Effect of Diabetes Mellitus on Intermittent Claudication

Outcomes After 5 Years11

Patients With

Diabetes (%)

Patients Without

Diabetes (%)

Mortality 49 23

Major amputation 21 3

Deterioration 35 19

who were at high risk for such events in the benazeprilamlodipine group with similar BP control.55

MANAGEMENT OF DIABETES

CASE 15-1, QUESTION 5: Will improving J.S.’s diabetes control or slow the progression of his PAD? What changes in his

diabetes management do you recommend?

Patients with type 2 diabetes mellitus (see Chapter 53, Diabetes Mellitus) are able to minimize macrovascular and microvascular complications of their disease with aggressive glucose

control.7,56,57 Insulin, sulfonylurea, or metformin therapies have

a beneficial effect on slowing the development of the microvascular complications of diabetes, such as retinopathy and nephropathy. Metformin has specifically been shown to further reduce the

occurrence of macrovascular complications such as stroke or MI

compared with insulin or sulfonylureas in obese patients with

type 2 diabetes.56

J.S.’s diabetes is a significant risk factor for progression to further ischemic events (Table 15-7). He has a twofold greater risk of

death and a sevenfold greater risk of amputation compared with

a patient without diabetes. Although a specific benefit for IC has

not been demonstrated, it seems prudent to initiate or continue

aggressive diabetes management in patients with type 2 diabetes

mellitus and IC. The addition of metformin to J.S.’s therapy could

improve his blood glucose control and decrease his risk of vascular complications. This agent will favorably affect hepatic glucose

production and insulin sensitivity and could result in weight loss.

It is hoped that J.S. can reach his Hgb A1c goal of less than 7%

and a fasting blood glucose of 70 to 130 mg/dL and 2-hour postprandial glucose of less than 180 mg/dL with diet, exercise, and

metformin therapy, in addition to his BID NPH standing dose

of insulin.58,59 It may be prudent to educate J.S. on the utility of

keeping a daily diary of his blood glucose results to enhance his

care. These data will assist his clinicians in modifying his insulin

regimen to improve outcomes.

J.S. also must take proper care of his feet to prevent ulcerative

complications of IC. He should be encouraged to keep his feet

warm, dry, and moisturized and to wear properly fitted shoes

and perform daily foot inspections.8 He should seek medical

attention immediately for minor trauma to his feet or legs.4 These

measures can reduce the incidence of amputation in patients with

diabetes.

PHARMACOLOGIC THERAPIES

ANTIPLATELET THERAPIES

CASE 15-1, QUESTION 6: Is the aspirin that J.S. is taking

beneficial for preventing further complications of IC? Would

an agent such as clopidogrel offer any advantage compared

with aspirin?

Aspirin is one of several antiplatelet agents that may be considered for indefinite use in patients such as J.S. with IC. A paucity of

studies has directly addressed the effects of aspirin on IC symptoms. For example, whether aspirin has any beneficial effects

on walking distance or claudication pain in patients with IC

has not been studied. Rather, most available data address the

impact of aspirin on overall cardiovascular morbidity and mortality. Aspirin exerts its antiplatelet effect by irreversibly inhibiting cyclo-oxygenase. This enzyme is essential for the production of thromboxane A2, a stimulus for platelet aggregation.

Although aspirin has no direct effect on plaque regression, it

does prevent and retard the role platelets play in the thrombogenic events that occur in the vicinity of atherosclerotic plaques.60

Aspirin is an effective antithrombotic agent at dosages ranging from 50 to 1,500 mg daily. The minimal dosages proved to

decrease cardiovascular events are 75 to 100 mg daily,61 with the

higher dosage showing benefit in active processes, such as acute

ischemic stroke62 and acute MI.63 A dosage of 75 mg daily has

demonstrated benefit in patients with hypertension64 and stable

angina.65 No evidence indicates that these “low doses” are any

more or any less effective than dosages of 900 to 1,500 mg daily.66

Aspirin is recommended in patients with vascular disease of

any origin (this includes stroke, MI, PAD, and ischemic heart disease). At dosages of 75 to 162 mg/day, it decreases vascular death

by approximately 15% and all serious vascular events (MI, stroke,

or vascular death) by approximately 20% in high-risk patients,

including those with PAD.58,61,66 In patients with PAD, aspirin

can delay the progression of established lesions as assessed by

angiography. When used for primary prevention of cardiovascular disease in men, aspirin decreased the need for arterial reconstructive surgery needed because of PAD.67 In a meta-analysis

of 5,269 subjects with PAD, aspirin was associated with a significant reduction in nonfatal stroke with a statistically insignificant

decrease of cardiovascular events.68 However, in a recent large

randomized, controlled trial in 3,350 patients 50 to 75 years of

age without clinically evident cardiovascular disease but with a

screening ABI of 0.95 or less, aspirin 100 mg/day was found to

be no more effective than placebo in reducing the primary end

point of fatal and nonfatal coronary events, stroke, or revascularization (13.7 events per 1,000 person-years in the aspirin group

vs. 13.3 in the placebo group; hazard ratio, 1.03; 95% confidence

interval, 0.84–1.27).69

Because all dosages of aspirin are similarly efficacious in

decreasing vascular events in this patient population, side effects

determine the dose chosen. Although few studies have directly

compared varying doses, side effects appear to be dose related.

Aspirin 30 mg daily results in less minor bleeding compared with

approximately 300 mg daily,70 and 300 mg daily results in fewer

gastrointestinal (GI) side effects compared with 1,200 mg daily.71

Therefore, J.S. should take the lowest effective dose of aspirin;

75 mg to 100 mg daily. Of note, J.S.’s hypertension should be

controlled before initiating aspirin therapy to decrease the small

increased incidence of cerebral hemorrhage associated with its

use.72

Ticlopidine is a thienopyridine derivative that blocks adenosine 5

-diphosphate (ADP) receptors on platelets and decreases

platelet-fibrinogen binding.73 Several studies document its efficacy in patients with PAD on end points such as walking distance, cardiovascular death, and the need for revascularization surgery.74,75 Diarrhea is a common side effect, however,

and hematologic toxicities (neutropenia and, rarely, thrombotic

thrombocytopenic purpura) further limit its use.76,77

Clopidogrel, an antiplatelet agent with the same mechanism

of action as ticlopidine but with an improved safety profile,

has largely replaced ticlopidine when thienopyridine therapy is

560 Section 2 Cardiac and Vascular Disorders

Vasopressin therapy significantly decreased the amount of norepinephrine required; however, there was no statistical difference in mortality between the treatment groups except when

the patients were stratified according to severity of sepsis. The

patients with less severe septic shock benefited from vasopressin

therapy. This study evaluated vasopressin as a catecholaminesparing drug rather than as rescue therapy for catecholamineunresponsive shock, which was how it was studied in previous

trials.

M.K. has decreased MAP despite the addition and increased

titration of norepinephrine. Because patients in septic shock

have decreased endogenous levels of vasopressin, it would be

reasonable to add vasopressin at 0.03 units/minute to the norepinephrine infusion to increase the MAP and renal perfusion.

INOTROPIC AGENTS

Although the use of inotropic agents is well established, controlled comparative studies have not clearly determined which

agent, or combination of agents, is most useful in the management of septic shock. Because differences among the inotropic

agents are significant, however, selection of the most appropriate

drug should be guided by careful consideration of the patient’s

hemodynamic status.

DOPAMINE

Dopamine has frequently been the initial pharmacologic agent

chosen for the treatment of septic shock. If the MAP is low

with a depressed CO and a low SVR, dopamine is an appropriate choice because its combined α-adrenergic vasoconstrictive actions and β-adrenergic inotropic effects will increase SVR

and CO, thereby effectively raising it. In situations in which the

PCWP is elevated or in patients with decreased ventricular compliance, the use of dopamine may be limited because it significantly increases venous return and ventricular filling pressure. In

addition, dopamine increases shunting of pulmonary blood flow,

leading to a decline in Pao2. This effect may worsen hypoxemia

in patients with pneumonia or ARDS.

DOBUTAMINE

Dobutamine is often advocated as the secondary inotropic agent

in the management of septic shock, particularly in patients with

low CO and high filling pressures. Dobutamine produces a

greater increase in CO than dopamine, but also lowers SVR.

In contrast to dopamine, dobutamine lowers PCWP, and causes

less pulmonary shunting. Because dobutamine can lower ventricular filling pressure, volume status must be monitored closely

to avoid the development of hypotension and reduced MAP.

Fluids should be administered as needed to maintain the PCWP

at maximal tolerated levels of 16 to 18 mm Hg. With the administration of greater amounts of fluid, CO, D˙ o2, and systemic

V˙ o2 are significantly increased. Dobutamine does increase D˙ o2

and CI when given concurrently with or after volume resuscitation. Decreases in Pao2 and increases in venous Po2, as well as

adverse effects on myocardium, may be evident at higher dosages

(>6 mcg/kg/minute).81

Combinations of vasopressors and inotropic agents can also

be used to achieve desired hemodynamic parameters. Because

GI perfusion can be compromised owing to the vasoconstricting

effects of catecholamines and may play a role in the pathogenesis of multiple organ dysfunction, the combination of norepinephrine and dobutamine has been studied to determine

whether an advantage exists to using norepinephrine alone,

epinephrine alone, or a combination.82,83 One prospective study

randomly assigned patients with an MAP less than 60 mm Hg

despite adequate fluid resuscitation and treatment with highdose dopamine to either dobutamine plus norepinephrine or

epinephrine monotherapy titrated to an MAP greater than 80

mm Hg.82 The variables were the MAP, metabolic effects as evidenced by lactate and pyruvate concentrations, and splanchnic

perfusion measured by the gap between gastric pH and Pco2.

This study showed that both therapies, norepinephrine plus

dobutamine and epinephrine monotherapy, were equally effective at achieving hemodynamic goals, but that treatment with

epinephrine alone could worsen splanchnic oxygen utilization

and potentially lead to ischemic injury. Currently, it is unknown

whether a specific catecholamine regimen provides a significant

benefit over others. There are conflicting data about which vasopressor can increase gastric perfusion and whether this increase

can alter progression to organ dysfunction.

CASE 22-4, QUESTION 5: Given M.K.’s history of cardiovascular disease, what factors should you consider before

initiating a vasopressor agent? Outline an overall approach

to maintaining adequate hemodynamic status.

M.K. has a history of coronary artery disease and is susceptible to myocardial ischemia. Therefore, a careful balance must

be achieved between myocardial V˙ o2 and coronary perfusion

pressure. Further attempts to optimize MAP and CI with norepinephrine alone could increase myocardialV˙ o2 and precipitate

ischemia. Evidence suggests that the goal of therapy in treating

patients with septic shock, or any form of shock for that matter,

is not to simply normalize BP, but to optimize D˙ o2 and V˙ o2.

Once anemia and hypoxia have been corrected, CO becomes the

remaining parameter that can be adjusted to increase oxygen supply, but raising arterial BP and CO with inotropic agents or vasopressors before restoring adequate blood volume actually can

worsen tissue perfusion. Therefore, the selection of an inotropic

agent must take into consideration the patient’s current hemodynamic status and the individual properties of those agents that

will most effectively maintain or increase the MAP and CO. In

many instances, because of individual variability and response,

more than one inotropic agent or addition of a vasopressor is

required to achieve these end points. These interventions must

be made with strict monitoring of the patients’ response to the

interventions to prevent any adverse consequences, especially

in those patients who are predisposed to an adverse event such

as M.K.

It is important to realize that the response to exogenous catecholamines in patients with septic shock is highly variable and a

successful regimen in one patient may be unsuccessful in another.

In addition, septic patients often require infusion rates in the

moderate-to-high range. Therefore, the goal is to use one or

more agents at the dosages necessary to achieve the desired end

points without unduly compromising the patient’s status. The

use of catecholamines, however, is only a stabilizing measure.

Strict attention to all other physiologic parameters—as well as

nutritional support, antibiotic modification, and ongoing surgical intervention—cannot be overemphasized.

OTHER THERAPIES

Therapies directed against the initiators and mediators of sepsis

are currently the focus of intense investigation. As previously

discussed, numerous exogenous and endogenous substances are

involved in the pathogenesis of sepsis. Strategies under development include antioxidants and free radical scavengers; antiendotoxin therapy; and inhibition of leukocytes, secondary

mediators (i.e., TNF-α, IL-1, cytokine pathway), coagulation and

arachidonic acid metabolites, complement, and NO. Although

several experimental therapies hold considerable promise for the

future, controlled human data are still lacking.

561Shock Chapter 22

CORTICOSTEROIDS

CASE 22-4, QUESTION 6: What is the rationale for the use

of glucocorticosteroids in the treatment of septic shock, and

is there evidence to support their use for this indication in

M.K.?

The use of corticosteroids in sepsis and septic shock has

been a controversial topic for many years. Corticosteroids were

originally proposed as a treatment option because of their antiinflammatory properties with the hope of attenuating the body’s

response to infection. More recently it has been shown that critically ill patients exhibit impaired cortisol secretion because of

a relative adrenocortical insufficiency, and it is suspected that

these patients display a glucocorticoid peripheral resistance syndrome. Almost 50% of patients with septic shock exhibit relative

adrenal insufficiency defined as a maximal change in cortisol

level of less than 9 mcg/dL after a 250-mcg IV dose of corticotropin.84

Several clinical trials have been performed during the past

few decades with varying results, and meta-analyses have recommended discontinuation of high-dose corticosteroid therapy

because of detrimental outcomes.85,86 End points that have been

studied include time to reversal of septic shock (defined by cessation of vasopressor support) and mortality. Older trials used

different definitions of septic shock, however, and the timing and

dosing of steroids were highly variable. Two recent trials have

shown that corticosteroid therapy may be beneficial in severe

septic shock at lower, physiologic doses. The trial by Annane

et al.87 showed a mortality benefit with the use of low doses of

hydrocortisone and fludrocortisones in patients with severe septic shock who exhibited a relative adrenocortical insufficiency. On

the other hand, the CORTICUS88 trial showed a faster resolution of shock for those patients on hydrocortisone as evidenced

by faster time to weaning from vasopressors; however, those

patients also had a higher incidence of superinfection and new

episodes of sepsis or septic shock. There was also no mortality

benefit seen with the use of corticosteroids. The CORTICUS

trial included patients with septic shock, whereas the study by

Annane et al. only enrolled patients with severe septic shock

unresponsive to vasopressor therapy. The results of these studies

demonstrate that corticosteroid therapy may not have a role in

the general population of patients with septic shock; however, it

may be beneficial for those patients unresponsive to vasopressors

who are treated early.

Because M.K. is refractory to increasing doses of norepinephrine and is in severe sepsis, it was decided to start hydrocortisone 50 mg IV every 6 hours.

STATINS

CASE 22-4, QUESTION 7: Is there any significance to the

fact that M.K. was on statin therapy before his episode of

sepsis? Should his statin therapy be continued?

Aside from their well-described lipid-lowering effects, statins

appear to have immunomodulatory and anti-inflammatory

effects. Statin therapy lowers C-reactive protein levels, inhibits

endothelial cell dysfunction, causes upregulation of endothelial

NO synthase, and blocks immune cell receptors.89 A growing

body of evidence shows that patients who are on a statin before

the inciting septic event may have a decreased likelihood of developing sepsis, and a mortality benefit may exist for those with sepsis or multiple organ dysfunction. All studies in humans thus far

have been retrospective and in patients who were previously on

a statin. One trial showed a significant survival benefit associated

with continuing statin therapy in patients who were bacteremic

compared with those who were never on statin therapy.90 Potentially more important is that the highest mortality was seen in

those patients who had been on statin therapy, but had been discontinued (result not statistically significant). These results may

lend credence to the idea of a rebound phenomenon that could

be detrimental if statins are not continued. Statins are often discontinued in septic patients because of concern for adverse effects

and further organ dysfunction. Presently, it is not clear whether

statins should always be continued in septic patients, and it is

unknown whether statins should be initiated in patients who

develop sepsis. Further evidence by means of prospective, randomized trials is needed to further define the role of statins in

sepsis.

DROTRECOGIN ALFA

CASE 22-4, QUESTION 8: What is the rationale for recombinant activated protein C in septic shock?

Activated protein C (APC) is an endogenous protein that acts

as one of the regulators of the coagulation cascade and also

interrupts the amplification cycle of inflammation.68 Protein C

is the inactive precursor to APC, and conversion to the active

form requires thrombin to complex with thrombomodulin. APC

enhances fibrinolysis and has potent inhibitory effects on thrombin, which possesses thrombotic as well as inflammatory effects.

Other anti-inflammatory effects of APC stem from suppression

of TNF-α, IL-6, and IL-1production.

Patients in septic shock exhibit microvascular thrombosis,

which leads to organ hypoperfusion, cell dysfunction, multiple

organ dysfunction, and death. The systemic response to infection

activates the coagulation pathway, leading to the generation of

thrombin and deposition of fibrin as well as initiating an inflammatory reaction via activation of cytokines. Adult and pediatric

septic patients have low levels of protein C, and a poor outcome

is expected for those patients with the lowest levels.91 The deficiency in protein C is probably caused by enhanced degradation

as well as impaired synthesis of protein C. It is also apparent that

patients in septic shock exhibit lower levels of thrombomodulin,

the protein necessary for the conversion of protein C to APC.

Thus, the use of APC would counter the anticoagulant deficiency

as well as suppress the inflammatory reaction that would normally take place owing to the infection.

The Protein C Worldwide Evaluation in Severe Sepsis

(PROWESS)69 trial was a phase III clinical trial to evaluate the

safety and efficacy of drotrecogin alfa (recombinant APC). It

was a randomized, double-blind, placebo-controlled, multicenter trial that was stopped early because of the statistically significant difference in the primary end point, 28-day all-cause

mortality, before enrollment was complete. Included in the

study were patients with a known or suspected infection plus

three or more signs of systemic inflammation and at least one

organ system dysfunction caused by sepsis. Patients also had

to begin treatment of drotrecogin alfa at 24 mcg/kg/hour for

96 hours within 24 hours of meeting inclusion criteria. The list of

exclusion criteria was extensive to ensure that patients who were

at higher risk for bleeding did not participate in the trial. No standardized protocol was established for the critical care provided to

the patient (e.g., antibiotics, vasopressors, inotropes). Treatment

with drotrecogin alfa reduced D-dimer and IL-6 levels, indicating attenuation of the procoagulant and inflammatory effects of

sepsis. Treatment with drotrecogin alfa was associated with a

6.1% absolute reduction in mortality at 28 days after the start

of infusion. The incidence of serious bleeding was higher in the

APC group, almost reaching statistical significance (p = 0.06). A

562 Section 2 Cardiac and Vascular Disorders

subgroup analysis showed that patients with higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (>25)

benefited the most from treatment with APC. A follow-up study

mandated by the US Food and Drug Administration showed

that APC use in septic patients with single organ failure or an

APACHE II score less than 25 was not effective in achieving a

decrease in mortality at 28 days and was actually associated with

an increase in bleeding complications.92 Based on the results of

these studies, drotrecogin alfa was generally limited to patients

with sepsis with an APACHE II score of more than 25 or with

two or more organ systems in failure.

More recently, on October 25, 2011, Eli Lilly and Company announced a worldwide voluntary market withdrawal

of drotrecogin. The decision stemmed from the results of a

recently completed clinical trial (PROWESS-SHOCK trial), in

which drotrecogin failed to show a survival benefit. In this trial

of 1696 patients, 851 patients were enrolled in the drotrecogin

arm and 845 patients were enrolled in the placebo arm. Results

showed a 28-day all cause mortality rate of 26.4% (223/846) in

drotrecogin-treated patients compared to 24.2% (202/834) in

placebo-treated patients, for a relative risk of 1.09 (95% CI :

0.92–1.28; p = 0.31). For more information, see http://www.

fda.gov/Drugs/DrugSafety/ucm277114.htm

DISSEMINATED INTRAVASCULAR

COAGULATION

Pathophysiology

CASE 22-4, QUESTION 9: M.K. experiences the sudden

appearance of bright red blood per rectum and through his

nasogastric tube; thus, a coagulation screen was ordered.

Until this time, all coagulation parameters had been within

normal limits. Now the results show the following:

Platelets, 43,000/μL (normal, 150,000–350,000/μL)

PT, 24 seconds

Activated PTT, 76 seconds

Thrombin time, 48 seconds (normal, 16–27 seconds)

Fibrinogen, 60 mg/dL (normal, 150–400 mg/dL)

Fibrin degradation products, 580 ng/mL (normal,

<250 ng/mL)

The diagnosis of DIC is made. How does the pathophysiology of DIC explain these hematologic abnormalities?

Thrombosis in response to endothelial damage or the presence of an altered surface in contact with blood components is

a localized phenomenon. Thrombus formation occurs at the

site of injury or abnormality, where procoagulant and anticoagulant mechanisms, as well as fibrinolytic and antifibrinolytic

mechanisms, are regulated. The term localized extravascular coagulation describes the site-specific nature of venous and arterial

thrombosis.

In contrast, DIC is a diffuse response to systemic activation of

the coagulation system (Fig. 22-5).93 Circulating thrombin converts fibrinogen to fibrin, resulting in fibrin deposition within

the microcirculation. Clinical manifestations of microvascular

thrombosis are the result of tissue ischemia resulting from thrombotic occlusion of small and midsize vessels.

The presence of systemic circulating thrombin causes simultaneous systemic activation of the fibrinolytic system, resulting

in circulating plasmin within the systemic circulation. Plasmin

causes systemic lysis of fibrin to fibrin degradation products and

results in hemorrhagic complications.

Trigger

Systemic Activation

of Clotting Cascade

Systemic Circulating

Thrombin

Systemic Circulating

Plasmin

Hemorrhage Microvascular

Thrombosis

Thrombocytopenia

Clotting

Factor

Degradation

Fibrin

Degradation

Formation

of Fibrin

Degradation

Products

Platelet

Dysfunction

Systemic Activation

of Fibrinolytic System

Platelet

Aggregation

Microvascular

Fibrin Deposition

FIGURE 22-5 Pathophysiology of disseminated intravascular

coagulation.

Bleeding manifestations of DIC occur not only as a result of

systemic fibrinolysis, but also secondary to thrombocytopenia,

clotting factor deficiency, and platelet dysfunction. Circulating

thrombin promotes platelet aggregation, resulting in thrombocytopenia as platelet aggregates deposit in the microcirculation.

Circulating plasmin degrades clotting factors as well as fibrin,

and the presence of fibrinogen degradation products from fibrinolysis inhibits platelet function. Normal mechanisms of platelet

and clotting factor synthesis are unable to compensate for this

consumption. In essence, the patient shows paradoxical bleeding secondary to overactivation and eventual consumption of

available clotting factors and platelets.

Clinical Presentation

CASE 22-4, QUESTION 10: What subjective and objective

evidence in M.K. is consistent with the diagnosis of acute

DIC?

563Shock Chapter 22

LABORATORY FINDINGS

Many coagulation laboratory abnormalities occur in DIC.94 The

ratio of PT to international normalized ratio, the activated PTT,

and the thrombin time are increased because clotting factors,

as well as antithrombin and proteins C and S, are consumed

more quickly than they can be replenished by hepatic synthesis.

Platelet count is diminished secondary to thrombin-mediated

platelet aggregation. Fibrinogen is reduced as a result of plasminmediated fibrinolysis, with an elevation in fibrinogen degradation products including D-dimer, indicative of a fibrinolytic state.

A peripheral smear will often show thrombocytopenia and red

blood cells fragmented by exposure to microcirculatory fibrin

(schistocytes).

The International Society of Thrombosis and Haemostasis

Overt DIC Scoring System, based on laboratory values observed

in patients suspected of having DIC, is used in the diagnosis of

DIC (Table 22-8).95 There is a strong correlation between increasing DIC score and 28-day mortality.96

HEMORRHAGIC MANIFESTATIONS

As illustrated by M.K., hemorrhagic manifestations are the predominant clinical finding in DIC.93 Bleeding can occur at sites of

injury, including surgical incisions, venipuncture sites, nasogastric tubes, or gastric ulcers. However, spontaneous bleeding also

occurs from intact sites or organ systems. Spontaneous ecchymosis, petechiae, epistaxis, hemoptysis, hematuria, and GI bleeding

are commonly encountered. Intracranial, intraperitoneal, and

pericardial bleeding may also occur.

THROMBOTIC MANIFESTATIONS

Thrombotic manifestations of DIC result in the obstruction of

blood flow to multiple organ systems. The resultant ischemic

damage to end organs, including the skin, kidneys, brain, lungs,

liver, eyes, and GI tract, can result in multisystem failure. Despite

the severity of hemorrhagic complications, microvascular thrombosis represents a significant cause of morbidity and mortality in

patients with acute DIC.

TABLE 22-8

International Society on Thrombosis and Haemostasis

Disseminated Intravascular Coagulation Scoring System

Does the patient have an underlying disorder known to be

associated with DIC? (If YES, continue with scoring.)

Laboratory Test Result Point Score

Platelet count >100,000 0

<100,000 1

<50,000 2

Fibrin-related

markers

No increase 0

Moderate increase 2

Strong increase 3

PT (vs. baseline) <3 seconds 0

3–6 seconds 1

>6 seconds 2

Fibrinogen >1 g/L 0

<1 g/L 1

TOTAL SCORE ≥5 Compatible with overt DIC

(repeat daily)

<5 Suggestive but not

affirmative for nonovert

DIC (repeat in 1–2 days)

DIC, disseminated intravascular coagulation; PT, prothrombin time.

Source: Taylor FB Jr et al. Towards definition, clinical and laboratory criteria,

and a scoring system for disseminated intravascular coagulation. Thromb Haemost

2001;86:1327.

Precipitating Events

CASE 22-4, QUESTION 11: What events may have precipitated the development of DIC in M.K.?

DIC is a pathological syndrome triggered by disease states

or conditions that activate coagulation systemically rather than

locally.94 The presence of thrombin within the systemic circulation can be triggered by systemic endothelial damage (e.g.,

bacterial endotoxin), by systemic contact activation of the clotting cascade (e.g., cardiopulmonary bypass), or by the release of

procoagulants into the systemic circulation (e.g., malignancy).

Table 22-9 presents an abbreviated list of disorders associated

with the development of DIC. Although the most likely stimulus

for DIC in M.K. is sepsis, both hypoxia and acidosis associated

with respiratory compromise may also have contributed.

Treatment

CASE 22-4, QUESTION 12: In the course of several hours,

M.K. has exhibited more severe GI bleeding. His hematocrit

has fallen from 43% to 35%. What treatment course should

be pursued? Should heparin therapy be given?

The most important element of treatment in patients with

DIC is alleviation of the underlying cause to eliminate the stimulus for continued thrombosis and hemorrhage.96 For M.K.,

this involves appropriate source control, antibiotic therapy,

and supportive measures to correct or prevent the hemodynamic, respiratory, and metabolic manifestations of shock. Fluid

TABLE 22-9

Clinical Conditions Associated With Disseminated

Intravascular Coagulation

Infectious Diseases

Aspergillosis

Bacterial infections

Candidiasis

Cytomegalovirus

Fungal infections

Gram-negative sepsis

Gram-positive sepsis

Hepatitis

Histoplasmosis

Miscellaneous infections

Mycobacterial malaria

Mycoplasma

Psittacosis

Rocky Mountain spotted fever

Varicella

Viral infections

Intravascular Hemolysis

Hemolytic transfusion reactions

Massive transfusions

Minor hemolysis

Malignancy

Myeloproliferative diseases

Solid tumor

Obstetric States

Amniotic fluid embolism

Eclampsia

Obstetric States

(Continued )

Retained dead fetus

Septic or saline abortion

Tissue Injury

Burns

Crush injuries

Extensive surgery

Multiple trauma

Vascular Disorders

Aortic aneurysm

Giant hemangioma

Miscellaneous

Acidosis

Anaphylaxis

Acute respiratory distress

syndrome

Cardiopulmonary bypass

Hematologic disorders

Heat stroke

Hepatic disease

Hypoperfusion

Hypovolemia

Severe allergic reaction

Snake bites

Transplant rejection

564 Section 2 Cardiac and Vascular Disorders

replacement, maintenance of BP and CO, and adequate oxygenation are essential components of the treatment of patients with

DIC.

The selection of other therapies aimed at correcting the hemorrhagic or thrombotic manifestations of DIC are controversial

and to some extent depend on whether hemorrhagic manifestations or thrombotic complications predominate in the clinical presentation. Initial treatment in patients with hemorrhage

involves replacement of clotting components that have been consumed in DIC, guided by coagulation laboratory data.97 Transfusion of platelets, fresh-frozen plasma (containing all clotting

factors), or cryoprecipitate (containing factor VIII and fibrinogen) may be necessary, with close monitoring of platelet count

and fibrinogen level.

Several approaches to restoring the inherent anticoagulant

pathways that are disrupted in DIC have been attempted. Transfusion of antithrombin concentrates may improve survival in

DIC associated with sepsis.98 Recombinant thrombomodulin

was associated with a higher degree of resolution of DIC compared with heparin in a randomized clinical trial, but it is not yet

commercially available.99 Recombinant APC (drotrecogin alfa),

which lowered mortality in patients with sepsis in the PROWESS

Trial, had its most significant impact on mortality in the subgroup

of sepsis patients who had DIC.87,88

Anticoagulation with heparin in patients with DIC is controversial. In theory, because the initial pathological event in DIC is

activation of the clotting system with formation of intravascular

thrombin, the antithrombin activity of heparin should prevent

further fibrin deposition and subsequent activation of fibrinolysis. However, randomized trials have not been conducted to

confirm this potential benefit, and the role of heparin remains

controversial. Emerging anticoagulants that are targeted more

specifically at the underlying pathophysiology of thrombosis in

DIC, recombinant tissue factor pathway inhibitor, and recombinant nematode anticoagulant protein c2 are being studied in

phase II and phase III clinical trials, but are not yet part of routine

care of patients with DIC.100

Finally, the use of the antifibrinolytic agents tranexamic acid