results. MRC Working Party. BMJ. 1992;304:405.
antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43(5 Suppl 1):S1.
1992;267:2330]. JAMA. 1992;267:1213.
correction appears in N EnglJ Med. 1994;330:1689]. N EnglJ Med. 1993;328:914.
treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS). Hypertension.
Treatment of Mild Hypertension Study. Arch Intern Med. 1997;157:638.
Hypertension Study (TOMHS) Research Group. JAMA. 1996;275:1549.
pressures averaging 115 through 129 mm Hg. JAMA. 1967;202:1028.
SHEP Cooperative Research Group. JAMA. 1991;265:3255.
pressure: overview of randomised drug trials in their epidemiological context. Lancet. 1990;335:827.
Tobacco Use and Dependence Clinical Practice Guideline Panel, Staff, and Consortium Representatives.
Services Task Force recommendation statement. Ann Intern Med. 2009;150:396.
Research Group. JAMA. 1993;270:713.
network meta-analysis. JAMA. 2003;289:2534.
(CONVINCE) trial. JAMA. 2003;289:2073.
hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995.
diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
[published corrections appear in JAMA. 2004;291:2196; JAMA. 2003;289:178]. JAMA. 2002;288:2981.
Lancet. 2001;358:1556; Lancet. 2002;359:2120]. Lancet. 2001;358:1033.
cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet.
hypertension in the elderly. N EnglJ Med. 2003;348:583.
Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and
microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE
2000;356:860]. Lancet. 2000;355:253.
non-insulin-dependent diabetes and hypertension. N EnglJ Med. 1998;338:645.
(FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21:597.
microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ.
nephropathy. N EnglJ Med. 2001;345:861.
nephropathy due to type 2 diabetes. N EnglJ Med. 2001;345:851.
diabetes. N EnglJ Med. 2001;345:870.
myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with
Angiotensin II Antagonist Losartan. Lancet. 2002;360:752.
hypertensive kidney disease: results from the AASK trial [published correction appears in JAMA.
2006;295:2726]. JAMA. 2002;288:2421.
Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled
valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004; 363:2022.
Study Group [published correction appears in N EnglJ Med. 1993;330:152]. N EnglJ Med. 1993;329:1456.
outcomes:systematic review and meta-analysis. Lancet. 2005;366:2026.
angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148:30.
high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised
controlled trial. Lancet. 2010;375:1173.
management of patients with stable ischemic heart disease. Circulation. 2014;130:1749–1767.
angiotensin II-receptor blockers for ischemic heart disease. Ann Intern Med. 2009;151:861.
coronary syndromes: executive summary. Circulation. 2014;130:2354–2394.
O’Gara PT et al. 2013 ACCF/AHA Guideline for the management of ST-elevation myocardial infarction:
executive summary. Circulation. 2013;127:529–555.
Yancy CW et al. 2013 ACCF/AHA Guideline for the management of heart failure: executive summary.
Circulation. 2013;128:1810–1852.
correction appears in N EnglJ Med. 2005;352:1276]. N EnglJ Med. 2004;351:2049.
Agents. Arch Intern Med. 1995;155:1757.
diuretic therapies. JAMA. 2004;292:43.
and office blood pressure. Hypertension. 2006;47:352.
on systolic blood pressure and potassium. Am J Hypertens. 2010;23:440.
monitoring: a meta-analysis of randomized trials. J Am Coll Cardiol. 2011;57:590.
Dorsch MP et al. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a
retrospective cohort analysis. Hypertension. 2011;57:689.
Antihypertensive Agents. Arch Intern Med. 1999;159:551.
acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic
Hypertension in the Elderly Program. SHEP Cooperative Research Group. Arch Intern Med. 1998;158:741.
randomised trials. BMJ. 2003;326:1427.
metaanalysis. Hypertension. 2010;55:399.
for hypertension control (ACCELERATE): a randomised, parallel-group trial. Lancet. 2011;377:312.
—the Hypertension Control Program. JAMA. 1987;257:1484.
cause for concern? Arch Intern Med. 2000;160:685.
Hypertension in Blacks consensus statement. Hypertension. 2010;56:780.
Luque CA, Vazquez Ortiz M. Treatment of ACE inhibitor-induced cough. Pharmacotherapy. 1999;19:804.
Hypertens (Greenwich). 2008;10:707.
Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease
[published correction appears in Lancet. 2008;372:1384]. Lancet. 2008;372:1174.
systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet.
resistant hypertension. J Am Soc Hypertens. 2008;2:462.
and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens.
(ALLHAT). ALLHAT Collaborative Research Group [published correction appears in JAMA. 2002;288:2976].
with resistant hypertension. Hypertension. 2008;51:69.
dysfunction: the CAPRICORN randomised trial. Lancet. 2001;357:1385.
hypertension: a randomized controlled trial. JAMA. 2004;292:2227.
Am J Obstet Gynecol. 2000;183:S1.
Peripheral arterial disease (PAD) is stenosis or occlusion in the
peripheral arteries of the legs, usually caused by atherosclerosis. A
sometimes-painful complication called intermittent claudication (IC) can
be associated with PAD and is described as aching, cramping, tightness,
or weakness of the legs, which usually occurs during exertion.
Treatment for PAD should include therapeutic lifestyle changes and
pharmacologic intervention based on risk factors present. Specific
interventions may include smoking cessation; exercise; management of
dyslipidemia, hypertension, and diabetes; antiplatelet therapy; and
RP is an exaggerated vasospastic response to cold or emotion, likely
mediated through sympathetic response to the precipitating stimuli. RP
is classified as primary or secondary, in which secondary causes include
connective tissue diseases and occupational-related neural damage.
Treatment for RP should include therapeutic lifestyle changes and
pharmacologic intervention based on clinical presentation and underlying
etiology. First-line interventions may include avoidance of cold stimuli
and medications associated with vasoconstriction and treatment with
calcium-channel blockers (CCBs). Several other therapies may be
emerging as possible therapeutic options, including renin–angiotensin–
oral phosphodiesterase inhibitors.
Nocturnal leg muscle cramps are idiopathic, involuntary contractions
occurring at rest that cause a visible and palpable knot in the affected
muscle, usually occurring in the early hours of sleeping.
The primary treatment goal of nocturnal leg muscle cramps is the
prevention of episodes. Recommendations include stretching practices,
alteration of sleeping position, and treatment of modifiable causes (i.e.,
Peripheral arterial disease (PAD) is a common and sometimes painful complication
from stenosis or occlusion in the peripheral arteries of the legs, usually caused by
atherosclerosis. Similar to coronary artery disease (CAD) resulting in chest pain,
PAD pain can be classified as “angina” of the legs. When closely comparing the risk
factors and pathology of both diseases, the association with CAD and IC becomes
IC is described as aching, cramping, tightness, or weakness of the legs which
usually occurs in the calves during walking and is relieved at rest. Tissue ischemia,
resulting numbness or continuous pain in the toes or foot, may be present and can lead
to ulceration. IC is a painful condition that can severely limit mobility and lead to
tissue necrosis or amputation of the affected limb. Many patients with PAD,
however, are asymptomatic or have atypical lower limb symptoms, such as leg
fatigue, difficulty walking, or similar nonspecific complaints. Patients may not seek
medical attention until the condition is advanced because of the gradual onset of
Annual Incidence of Intermittent Claudication by Age
Age Group (years) Annual Incidence (%)
PAD is a relatively common condition that affects men and women equally, with a
1 although men have a twofold increased prevalence of
2 The annual incidence of IC increases dramatically with age (Table
10-1). Most patients with PAD are asymptomatic. In one study where the prevalence
of IC symptoms was 2%, only 11.7% of patients had detectable large vessel
atherosclerosis of the lower extremities.
3 This disparity between IC symptoms and
the presence of PAD contributes to the observation that 50% to 90% of patients with
IC do not mention PAD symptoms to their physician. Patients attribute the symptoms
of IC to normal walking difficulties associated with aging, not a medical condition
4 Public knowledge of the definition of PAD, risk factors for the
development of the disease, associated symptoms and disease states, and amputation
risk were evaluated in adults older than 50 years of age in a cross-sectional,
population-based telephone survey. Unfortunately, only 25% of the population
6 Each 1% increase in glycosylated hemoglobin is
associated with a 28% risk of incident PAD.
7 Other atherosclerotic risk factors
associated with PAD include cigarette smoking, hypertension, and dyslipidemia.
Hypertriglyceridemia is a more significant risk factor for PAD than for CAD, and
this may partially explain the increased prevalence of PAD in patients with diabetes.
Cigarette smoking is the strongest risk factor for PAD and the development of IC
pain than any other risk factors, and the risk increases dramatically with the duration
of smoking history and number of cigarettes smoked per day.
hypertension or diabetes, smoking further increases the rate of claudication
development. Smoking confers a sevenfold increase in risk for PAD compared with
Epidemiologic studies following PAD patients over 4 to 9 years show that IC is
nonprogressive in 75% of patients, whereas 25% of patients with IC will have
worsening painful ischemic episodes. Ischemic tissue changes, ulceration, and
gangrene can accompany advanced PAD. Amputation of the affected limb is rare, but
can occur in up to 5% of patients with claudication.
independent risk factors, such as diabetes and cigarette smoking, has an additive
effect on the risk for the development of progressive IC and serious limb
complications (Table 10-2). Finally, disease location in patients with severe disease
may be associated with prognosis. Proximal disease may be associated with poor
outcomes when compared with distal lesions, although further studies are needed to
Long-Term Incidence of Outcomes in Patients with Intermittent
Patient Population Abrupt Limb Ischemia (%) Amputation (%)
During a relatively short 2-year follow-up of patients with IC, 3.6% of patients
died, whereas 22% experienced a nonfatal cardiovascular event (defined as any
cardiac, cerebral, or peripheral vascular event). Walking capacity declined in 26%
during the same time frame, thus it is paramount to recognize that severe, short-term
morbidity is highly likely in this patient population.
IC is the predominant complication of occlusive PAD because of the resulting pain
and subsequent decreased mobility. The major cause of occlusive PAD is
arteriosclerosis obliterans, defined as the development of atherosclerotic plaques in
the peripheral vasculature. These plaques develop as a result of endothelial
activation in association with conditions such as dyslipidemia, diabetes mellitus,
hypertension, and smoking. Plaques also result from the proliferation of vascular
smooth muscle, with subsequent damage to the vascular structure. This damaged
endothelium has impaired vasodilatory capabilities because secretion of nitric oxide
is decreased and secretion of vasoconstrictive substances, such as endothelin, is
increased, impeding blood flow to the extremities. Further growth of atherosclerotic
lesions can physically limit blood flow. Exercise may induce IC symptoms in
patients who have lesions with greater than 50% stenosis, whereas patients with
lesions of greater than 80% stenosis can have pain at rest. The lesions themselves
can become unstable and rupture, or adjacent smaller vessels experiencing high
hemodynamic pressure caused by nearby plaques may rupture as well. Either
situation can lead to acute vascular occlusion, analogous to unstable angina or acute
myocardial infarction (MI) in coronary arteries.
Williams & Wilkins; 2012:452.)
Figure 10-1 illustrates the common sites of atherosclerosis. Plaques that develop
in central vessels (e.g., in the aorta and iliac artery) are primarily associated with
buttock pain and erectile dysfunction. Those confined to the more distal femoral and
popliteal arteries characteristically cause thigh and calf pain. Occlusion of the tibial
arteries will produce claudication pain in the foot. When more than one arterial bed
is affected by severe atherosclerosis, symptoms of IC will be diffuse. Symptoms of
IC indicate an inadequate supply of arterial blood to peripheral muscles. Exercise,
including walking, increases the metabolic demands of the muscles and can lead to
Erythrocyte deformability is an important factor for in vitro capillary perfusion.
In areas without compromised blood flow, normal red blood cells (RBCs) have the
ability to deform when passing through a small capillary. By aligning themselves in a
planar manner, RBCs reduce viscosity of the blood suspension, enabling them to pass
smoothly through capillaries. In many patients with IC, RBCs have a marked
decreased ability to deform, resulting in increased blood viscosity. This defect is
promoted by chronic tissue ischemia and hypoxia caused by increased intracapillary
leukocyte adherence, platelet aggregation, and activation of complement and clotting
16 The vascular responses to hypoxia are detrimental because this sequence of
events further inhibits blood flow and oxygen delivery to the tissues (Fig. 10-2).
The pain is relieved within minutes after he stops walking. R.L. smokes 2 packs of cigarettes a day.
His most recent laboratory results are significant for the following results:
Total cholesterol, 290 mg/dL (SI units, 7.49 mmol/L)
Fasting triglycerides, 350 mg/dL (SI units, 3.95 mmol/L)
Low-density lipoproteins (LDL), 188 mg/dL (SI units, 4.86 mmol/L)
High-density lipoproteins (HDL), 32 mg/dL (SI units, 0.83 mmol/L)
Serum creatinine (SCr), 0.8 mg/dL (SI units, 61 mmol/L)
Blood urea nitrogen (BUN), 18 mg/dL (SI units, 6.4 mmol/L)
, 10.5% (SI units, 91.3 mmol/mol)
Fasting glucose, 190 mg/dL (SI units, 10.5 mmol/L)
Blood pressure (BP), 170/95 mm Hg
Heart rate (HR), 89 beats/minute
R.L.’s medical history illustrates classic risk factors for vascular occlusion and
IC, including dyslipidemia, diabetes, hypertension, and smoking. His diabetes is not
adequately controlled based on elevated Hgb A1c and fasting glucose levels, and he
is obese. This constellation of disorders is known as the metabolic syndrome. These
factors, along with smoking, are commonly seen together and have been linked with
insulin resistance and accelerated atherosclerosis (Fig. 10-3).
angina indicates CAD, so it is not surprising that he has peripheral vascular
Figure 10-2 Erythrocyte inflexibility in intermittent claudication.
Figure 10-3 The metabolic syndrome in atherosclerosis.
The classic pain of IC described by R.L. is associated with exercise of the
affected muscle group(s) and subsides with a few minutes of rest. Other common
symptoms of extensive atherosclerosis include cold feet and persistent aching of the
feet during rest or sleep. Restricted blood flow to the feet along with pooling of
blood secondary to inadequate pressure needed to propel blood back up the leg can
lead to rubor (red or purple color of the foot). Other indicators of peripheral
atherosclerosis are the loss of hair from the top of the feet, thickening of the toenails,
and absence of sweating of the lower legs and feet, all caused by poor circulation.
The results of objective studies performed on R.L. are consistent with IC. Doppler
ultrasound of the spine is helpful in excluding pseudoclaudication caused by spinal
stenosis and other neurogenic or musculoskeletal causes of leg pain. Ultrasound is
also useful to measure BP of the lower extremities. An ABI of 0.7 means that the
ankle systolic BP reading is only 70% of the systolic pressure in the brachial artery
supplying blood to the arm. In patients with IC, this is caused by atherosclerotic
obstruction of blood flow in the lower limbs and subsequent decreased perfusion
pressures in the ankle compared with the arm (Table 10-3). As the ABI decreases,
blood flow to the extremities is reduced and the severity of symptoms is greater. An
ABI less than 0.9 is diagnostic for PAD. Loss of the posterior tibial pulse, as seen in
R.L., is common in those with peripheral vascular occlusion.
Severity of Arterial Obstruction as Assessed by Ankle-to-Brachial Index
Severity Ankle-to-Brachial Index
THERAPEUTIC OBJECTIVES AND NONPHARMACOLOGIC
CASE 10-1, QUESTION 2: What are the therapeutic goals in treating R.L.? What interventions should be
initiated to prevent claudication pain and arrest progression of his disease?
Specific treatment goals include preventing further claudication pain, lessening his
current pain, arresting the progression of underlying disease, and decreasing his risk
of cardiovascular events. Achieving these goals will provide R.L. with the best
chance of avoiding further mobility impairment, amputation, and cardiovascular
events. An important concept that should be stressed when explaining these treatment
goals to R.L. is that all his diseases are closely interrelated and that a beneficial
intervention for one disease is beneficial for all. Interventions that can be initiated
include diet modification; exercise and weight loss; and attainment of goal BP,
, and fasting and postprandial blood glucose levels. The American
College of Cardiology and American Heart Association (ACC/AHA) have published
guidelines that thoroughly evaluate the interventions and medications that have been
8 Table 10-4 summarizes these recommendations. The two
most important things that R.L. can do for his IC are summed up in five words: “Stop
The importance of smoking cessation cannot be overemphasized to patients with IC.
It is the most important modifiable factor in preventing the development of rest pain,
prolonged limb ischemia, need for amputation and reducing the risk for
cardiovascular events. Several studies document improved survival and decreased
amputation rates in patients with IC who stopped smoking compared with patients
24,25 Other benefits, such as improved treadmill walking
distance, decreased disease progression, and decreased complications after vascular
reconstructive surgery, have been shown in patients who quit smoking compared with
It is the one intervention that will decrease R.L.’s
claudication pain most rapidly. He will also decrease his risk of MI and mortality by
threefold and fivefold, respectively. Table 10-5 summarizes the risk of cigarette
smoking and the value of smoking cessation on cardiovascular complications.
Many pharmacologic products and strategies are available to aid R.L. to stop
smoking (see Chapter 91, Tobacco Use and Dependence). However, nicotine itself
has harmful effects on the vasculature via catecholamine release and
vasoconstriction; and it may play a role in endothelial damage and atherosclerosis
Medical Treatment of Peripheral Arterial Disease and Expected Outcomes
Intervention Improve Leg Symptoms?
Angiotensin-converting enzyme inhibitors Yes Yes
Patient Outcomes Based on Smoking Status After Intermittent Claudication
Current Smokers (%) Past Smokers(%)
Myocardial infarction 10 53 11
aQuit after intermittent claudication diagnosis.
An individualized and supervised exercise program is endorsed for patients with
PAD and will benefit most of R.L.’s other risk factors as well.
decreased mobility, and because of deconditioning from lack of exercise, patients
with IC may slowly become dependent on others for activities of daily living. An
exercise program is the most effective way to both preserve and increase mobility. It
is more effective than the best pharmacologic therapy currently available.
exercise program consists of walking for a minimum of 30 to 45 minutes at least 3
times a week, for a minimum of 12 weeks.
8 R.L. should walk as fast and far as he can
until the pain becomes severe; he should then wait until the pain subsides, and then
21 At first, R.L. may experience several painful episodes during each
exercise session, but these should gradually decrease as the beneficial effects of
exercise therapy begin to emerge. Studies have documented that this type of exercise
program can more than double the pain-free distance a patient with IC is able to
Comments
Post a Comment
اكتب تعليق حول الموضوع