Practice Essentials

Upper respiratory tract infection (URI) represents the most common acute
illness evaluated in the outpatient setting. URIs range from the common cold
typically a mild, self-limited, catarrhal syndrome of the nasopharynxto life-
threatening illnesses such as epiglottitis (see the image below).

Lateral neck radiograph demonstrates

epiglottitis. Courtesy of Marilyn Goske, MD, Cleveland Clinic Foundation.
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Signs and symptoms
Details of the patient's history aid in differentiating a common cold from
conditions that require targeted therapy, such as group A
streptococcal pharyngitis, bacterialsinusitis, and lower respiratory tract
infections. Clinical manifestations of these conditions, as well as allergy, show
significant overlap.
Viral nasopharyngitis
Patients with the common cold may have a paucity of clinical findings despite
notable subjective discomfort. Findings may include the following:
Nasal mucosal erythema and edema are common
Nasal discharge: Profuse discharge is more characteristic of viral
infections than bacterial infections; initially clear secretions typically
become cloudy white, yellow, or green over several days, even in viral
infections
 Foul breath
Fever: Less common in adults but may be present in children with
rhinoviral infections
Group A streptococcal pharyngitis The following physical findings suggest a
high risk for group A streptococcal disease [1] :
Erythema, swelling, or exudates of the tonsils or pharynx
Temperature of 38.3C (100.9F) or higher
Tender anterior cervical nodes (1 cm)
Absence of conjunctivitis, cough, and rhinorrhea, which are symptoms
that may suggest viral illness [2]
Acute bacterial rhinosinusitis In children, acute bacterial sinusitis is defined as
a URI with any of the following [3] :
Persistent nasal discharge (any type) or cough lasting 10 days or more
without improvement
Worsening course (new or worse nasal discharge, cough, fever) after
initial improvement
Severe onset (fever of 102 or greater with nasal discharge) for at least
3 consecutive days
In older children and adults, symptoms (eg, pain, pressure) tend to localize to
the affected sinus.
Epiglottitis
This condition is more often found in children aged 1-5 years, who present
with a sudden onset of the following symptoms:
Sore throat
Drooling, difficulty or pain during swallowing, globus sensation of a lump
in the throat
Muffled dysphonia or loss of voice
Dry cough or no cough, dyspnea
Fever, fatigue or malaise (may be seen with any URI)
Tripod or sniffing posture
Laryngotracheitis and laryngotracheobronchitis
Nasopharyngitis often precedes laryngitis and tracheitis by several days
Swallowing may be difficult or painful
Patients may experience a globus sensation of a lump in the throat
Hoarseness or loss of voice is a key manifestation of laryngeal
involvement
Features of whooping cough (pertussis) are as follows:
The classic whoop sound [4] is an inspiratory gasping squeak that rises in
pitch, typically interspersed between hacking coughs
 The whoop is more common in children
Coughing often comes in paroxysms of a dozen coughs or more at a
time and is often worst at night
The 3 classic phases of whooping cough are as follows:
Catarrhal (7-10 days) with predominantly URI symptoms
Paroxysmal (1-6 weeks) with episodic cough
Convalescent (7-10 days) of gradual recovery [5]
See Clinical Presentation for more detail.
Diagnosis
Tests of nasopharyngeal specimens for specific pathogens are helpful when
targeted therapy depends on the results (eg, group A streptococcal infection,
gonococcus, pertussis). Specific bacterial or viral testing is also warranted in
other selected situations, such as when patients are immunocompromised,
during certain outbreaks, or to provide specific therapy to contacts.
Diagnosis of specific disorders is based on the following:
Group A streptococcal infection: Clinical findings or a history of
exposure to a case, supported by results of rapid-detection assays and
cultures (positive rapid antigen detection tests do not necessitate a
backup culture)
Acute bacterial rhinosinusitis: Laboratory studies are generally not
indicated; Computed tomography (CT) scanning or other sinus imaging
may be appropriate if symptoms persist despite therapy or if
complications (eg, extension of disease into surrounding tissue) are
suspected
Influenza: Rapid tests have over 70% sensitivity and more than 90%
specificity
Mononucleosis: Heterophile antibody testing (eg, Monospot)
Herpes simplex virus infection: Cell culture or polymerase chain reaction
(PCR) assay
Pertussis: Rapid tests; culture of a nasopharyngeal aspirate (criterion
standard)
Epiglottitis: Direct visualization by laryngoscopy, performed by an
otorhinolaryngologist
Gonococcal pharyngitis: Throat culture for Neisseria gonorrhoeae
Blood cultures are typically appropriate only in hospitalized patients with
suspected systemic illness. Imaging studies are warranted in patients with
suspected mass lesions (eg, peritonsillar abscess, intracranial suppurative
lesions).
See Workup for more detail.
Management
Symptom-basedtherapy represents the mainstay of URI treatment in
immunocompetent adults. Antimicrobial or antiviral therapy is appropriate in
selected patients.
Epiglottitis
Immediately admit the patient to the nearest hospital
Avoid instrumentation; insertion of tongue depressors or other
instruments may provoke airway spasm and precipitate respiratory
compromise
Monitor for respiratory fatigue, visually and with continuous pulse
oximetry
Administer oxygen according to pulse oximetry results
Have equipment and personnel available for immediate intubation if
necessary
Start intravenous (IV) antibiotics after collecting culture specimens
Empiric coverage for Haemophilus influenzae is appropriate; common
choices include ceftriaxone or other third-generation cephalosporins,
cefuroxime, and cefamandole
Correct volume deficits with IV fluids; avoid sedatives
Laryngotracheitis
Hospitalization may be necessary, especially in infants and young
children who have hypoxemia, volume depletion, a risk of airway
compromise, or respiratory fatigue
Mild cases of croup (ie, laryngotracheobronchitis) may be managed at
home with moist air inhalation
Hospitalized patients require monitoring for respiratory fatigue, visually
and with continuous pulse oximetry
Expertise for immediate intubation and access to the necessary
equipment are required if respiratory failure is a possibility
Administer humidified oxygen to all hypoxemic patients. In patients who
do not require oxygen therapy, a cool-mist humidifier may be used
IV or oral glucocorticoids are commonly used to reduce symptoms and
shorten hospitalization in patients with moderate to severe croup
Inhaled racemic epinephrine may temporarily dilate the airways
Rhinosinusitis
Most cases of acute rhinosinusitis, including mild and moderate
bacterial sinusitis, resolve without antibiotics [6]
 Consider antibiotic treatment if symptoms persist without improving for
10 or more days, or if symptoms are severe or worsening during a period
of 3-4 days or longer [7]
Give first-line antibiotics for 5-7 days in most adults; for 10-14 days in
children
Begin treatment with an agent that most narrowly covers likely
pathogens, including Streptococcus pneumoniae, nontypeable H
influenzae, andMoraxella catarrhalis
Initial first-line options include amoxicillin/clavulanate
Alternatives in penicillin-allergic patients are doxycycline and respiratory
fluoroquinolones (eg, levofloxacin, moxifloxacin)
In patients who worsen or do not improve after 3-5 days of empirical
therapy, consider resistant pathogens, structural abnormality, or
noninfectious etiology
Adjunctive therapy for adults includes nasal saline irrigation and
intranasal steroids
Group A streptococcal disease
Oral penicillin or amoxicillin for 10 days for patients without an allergy to
penicillin
If compliance is a concern, consider a single IM injection of benzathine
penicillin G
A first-generation cephalosporin may be used in patients with non-
anaphylactic penicillin allergy
Options for penicillin-allergic patients include clindamycin or
clarithromycin for 10 days or azithromycin for 5 days [2]
See Treatment and Medication for more detail.
Background
Upper respiratory tract infection (URI) represents the most common acute
illness evaluated in the outpatient setting. URIs range from the common cold
typically a mild, self-limited, catarrhal syndrome of the nasopharynxto life-
threatening illnesses such as epiglottitis.
Viruses account for most URIs (see Etiology). Appropriate management in
these cases may consist of reassurance, education, and instructions for
symptomatic home treatment. Diagnostic tests for specific agents are helpful
when targeted URI therapy depends on the results (see Workup). Bacterial
primary infection or superinfection may require targeted therapy (see
Treatment).
The upper respiratory tract includes the sinuses, nasal passages, pharynx,
and larynx, which serve as gateways to the trachea, bronchi, and pulmonary
alveolar spaces. Rhinitis, pharyngitis, sinusitis, epiglottitis, laryngitis, and
tracheitis are specific manifestations of URIs. Further information can be
found in the Medscape Reference articles Acute Laryngitis, Acute
Sinusitis, Allergic Rhinitis, Bacterial Tracheitis, Croup, Epiglottitis, Pharyngitis,
and Viral Pharyngitis.
Common URI terms are defined as follows:
Rhinitis: Inflammation of the nasal mucosa
Rhinosinusitis or sinusitis: Inflammation of the nares and paranasal
sinuses, including frontal, ethmoid, maxillary, and sphenoid
Nasopharyngitis (rhinopharyngitis or the common cold): Inflammation of
the nares, pharynx, hypopharynx, uvula, and tonsils
Pharyngitis: Inflammation of the pharynx, hypopharynx, uvula, and
tonsils
Epiglottitis (supraglottitis): Inflammation of the superior portion of the
larynx and supraglottic area
Laryngitis: Inflammation of the larynx
Laryngotracheitis: Inflammation of the larynx, trachea, and subglottic
area
Tracheitis: Inflammation of the trachea and subglottic area
Pathophysiology
URIs involve direct invasion of the mucosa lining the upper airway. Inoculation
of bacteria or viruses occurs when a persons hand comes in contact with
pathogens and the person then touches the nose or mouth or when a person
directly inhales respiratory droplets from an infected person who is coughing
or sneezing.
After inoculation, viruses and bacteria encounter several barriers, including
physical, mechanical, humoral, and cellular immune defenses. Physical and
mechanical barriers include the following:
Hair lining the nose filters and traps some pathogens
Mucus coats much of the upper respiratory tract, trapping potential
invaders
The angle resulting from the junction of the posterior nose to the
pharynx causes large particles to impinge on the back of the throat
Ciliated cells lower in the respiratory tract trap and transport pathogens
up to the pharynx; from there they are swallowed into the stomach
Adenoids and tonsils contain immune cells that respond to pathogens.
Humoral immunity (immunoglobulin A) and cellular immunity act to reduce
infections throughout the entire respiratory tract. Resident and recruited
macrophages, monocytes, neutrophils, and eosinophils coordinate to engulf
and destroy invaders.
A host of inflammatory cytokines mediates the immune response to invading
pathogens. Normal nasopharyngeal flora, including various staphylococcal
and streptococcal species, help to defend against potential pathogens.
Patients with suboptimal humoral and phagocytic immune function are at
increased risk for contracting a URI, and they are at increased risk for a
severe or prolonged course of disease.
Inflammation (chronic or acute) from allergy predisposes to URI. Children with
allergy are particularly subject to frequent URIs.
Infection
Person-to-person spread of viruses accounts for most URIs. Household and
child care settings can serve as reservoirs for infection. Bacterial infections
may develop de novo or as a superinfection of a viral URI.
Viral agents occurring in URIs include a vast number of serotypes, which
undergo frequent changes in antigenicity, posing challenges to immune
defense. Pathogens resist destruction by a variety of mechanisms, including
the production of toxins, proteases, and bacterial adherence factors, as well
as the formation of capsules that resist phagocytosis.
Incubation times before the appearance of symptoms vary among pathogens.
Rhinoviruses and group A streptococci may incubate for 1-5 days, influenza
and parainfluenza may incubate for 1-4 days, and respiratory syncytial virus
(RSV) may incubate for a week. Pertussis typically incubates for 7-10 days, or
even as long as 21 days, before causing symptoms. Diphtheria incubates for
1-10 days. The incubation period of Epstein-Barr virus (EBV) is 4-6 weeks.
Most symptoms of URIsincluding local swelling, erythema, edema,
secretions, and feverresult from the inflammatory response of the immune
system to invading pathogens and from toxins produced by pathogens.
An initial nasopharyngeal infection may spread to adjacent structures,
resulting in the following:
Sinusitis
Otitis media
Epiglottitis
Laryngitis
Tracheobronchitis
Pneumonia
Inflammatory narrowing at the level of the epiglottis and larynx may result in a
dangerous compromise of airflow, especially in children, in whom a small
reduction in the luminal diameter of the subglottic larynx and trachea may be
critical. Beyond childhood, laryngotracheal inflammation may also pose
serious threats to individuals with congenital or acquired subglottic stenosis.
Susceptibility
Genetic susceptibility is involved in determining which patients have more
severe disease courses than others. There are some recognized candidate
gene polymorphisms with known functional changes in genes that may lead to
immunosuppression. [8] It has also been shown that host immunogenetic
variation plays a role in the immune response to H1N1 and H5N1 viruses,
thereby influencing disease severity and outcome in influenza caused by
these viruses. [9, 10]
Etiology
Most URIs are viral in origin. Typical viral agents that cause URIs include the
following:
Rhinoviruses
Coronaviruses
Adenoviruses
Coxsackieviruses
For the most part, similar agents cause URI in adults and children;
however,Moraxella catarrhalis and bocavirus cause URIs more commonly in
children than in adults.
Nasopharyngitis
Of the more than 200 viruses known to cause the symptoms of the common
cold, the principal ones are as follows:
Rhinoviruses: These cause approximately 30-50% of colds in adults;
they grow optimally at temperatures near 32.8C (91F), which is the
temperature inside the human nares
Coronaviruses: While they are a significant cause of colds, exact case
numbers are difficult to determine because, unlike rhinoviruses,
coronaviruses are difficult to culture in the laboratory
Enteroviruses, including coxsackieviruses, echoviruses, and others
Other viruses that account for many URIs include the following:
Adenoviruses
Orthomyxoviruses (including influenza A and B viruses)
Paramyxoviruses (eg, parainfluenza virus [PIV])
RSV
EBV
Human metapneumovirus (hMPV)
 Bocavirus: Commonly associated with nasopharyngeal symptoms in
children [11]
Unidentified, but presumably viral, pathogens account for more than 30% of
common colds in adults. In addition, varicella, rubella, and rubeola infections
may manifest as nasopharyngitis before other classic signs and symptoms
develop.
Pharyngitis
This is most often viral in origin. Recognition of group A streptococcal
pharyngitis is vital because serious complications may follow untreated
disease.
Viral causes of pharyngitis include the following:
Adenovirus: May also cause laryngitis and conjunctivitis
Influenza viruses
Coxsackievirus
Herpes simplex virus (HSV)
EBV (infectious mononucleosis)
Cytomegalovirus (CMV)
Bacterial causes of pharyngitis include the following:
Group A streptococci (approximately 5-15% of all cases of pharyngitis in
adults; 20-30% in children) [2]
Group C and G streptococci
Neisseria gonorrhoeae
Arcanobacterium ( Corynebacterium) hemolyticum
Corynebacterium diphtheriae
Atypical bacteria (eg, Mycoplasma pneumoniae and Chlamydia
pneumoniae; absent lower respiratory tract disease, the clinical
significance of these pathogens is uncertain)
Anaerobic bacteria
Rhinosinusitis
Rhinosinusitis in an immunocompetent person is typically related to an
uncomplicated viral URI. Viral causes are similar to those of viral
nasopharyngitis and include the following:
Rhinovirus
Enterovirus
Coronavirus
Influenza A and B virus
PIV
 RSV
Adenovirus
Bacterial causes are similar to those seen in otitis media. Bacterial pathogens
isolated from maxillary sinus aspirates of patients with acute bacterial
rhinosinusitis include the following [7] :
Streptococcus pneumoniae: 38% in adults, 21-33% in children
Haemophilus influenzae: 36% in adults, 31-32% in children
Moraxella catarrhalis: 16% in adults; 8-11% in children
Staphylococcus aureus: 13% in adults, 1% in children
Other pathogens include group A streptococci and other streptococcal
species. Uncommon causes include C pneumoniae, Neisseria species,
anaerobes, and gram-negative rods.
Nosocomial sinusitis often involves pathogens that colonize the upper
respiratory tract and migrate into the sinuses. Prolonged endotracheal
intubation places patients at increased risk for nosocomial sinusitis.
Methicillin-resistant S aureus(MRSA) is less common than sensitive
staphylococci. [7] Gram-negative bacilli (eg,Escherichia coli,Pseudomonas
aeruginosa) are other causes.
Aspergillus species are the leading causes of noninvasive fungal sinusitis.
Although fungi are part of the normal flora of the upper airways, they may
cause acute sinusitis in patients with immunocompromise or diabetes mellitus.
Epiglottitis
This is a bacterial infection. In the vast majority of children, H influenzae type
b (Hib) is isolated from blood or epiglottal cultures. Since the routine use of
the Hib conjugate vaccine began in 1990, case rates in children younger than
5 years have declined by more than 95%. The prevalence of invasive Hib
disease is approximately 1.3 cases per 100,000 children. [12] Rates in adults
have remained low and stable; Alaskan Natives have the highest rates of
disease.
Other bacteria, found more commonly in adults than in children, include group
A streptococci, S pneumoniae, and M catarrhalis. In adults, cultures are most
likely to be negative.
Laryngotracheitis
Croup, or laryngotracheobronchitis, is typically caused by PIV type 1, 2, or 3.
PIVs account for up to 80% of croup cases. PIV type 1 is the leading cause of
croup in children. [13] Other viruses include influenza viruses and RSV.
Uncommon causes include hMPV, adenovirus, rhinovirus, enterovirus
(including coxsackievirus and enteric cytopathic human orphan [ECHO]
viruses), and measles virus.
Approximately 95% of all cases of whooping cough are caused by the gram-
negative rod Bordetella pertussis. The remaining cases result from B
parapertussis.
Other forms of laryngitis and laryngotracheitis are typically caused by viruses
similar to those that cause nasopharyngitis, including rhinovirus, coronavirus,
adenovirus, influenza virus, parainfluenza virus, and RSV. Candida species
may cause laryngitis in immunocompromised hosts.
Bacterial laryngitis is far less common than viral laryngitis. [14] Bacterial causes
include the following:Group A streptococci
Corynebacterium diphtheriae, an aerobic gram-positive rod that may
infect only the larynx or may represent an extension of nasopharyngeal
infection
Chlamydia pneumoniae
Mycoplasma pneumoniae
Moraxella catarrhalis
H influenzae
S aureus
Mycobacterium tuberculosis: Tuberculosis has been reported in renal
transplant recipients and human immunodeficiency virus (HIV) infected
patients
Risk factors for URIs
Risk factors for contracting a URI include the following:
Contact: Close contact with small children who frequent group settings,
such as school or daycare, increases the risk of URI, as does the
presence of URI in the household or family
Inflammation: Inflammation and obstruction from allergic rhinitis or
asthma can predispose to infections
Travel: The incidence of contracting a URI is increased because of
exposure to large numbers of individuals in closed settings
Smoking and exposure to second-hand smoke: These may alter
mucosal resistance to URI
Immunocompromise that affects cellular or humoral immunity:
Weakened immune function may result from splenectomy, HIV infection,
use of corticosteroids, immunosuppressive treatment after stem cell or
organ transplantation, multiple medical problems, or common stress; cilia
dyskinesia syndrome and cystic fibrosis also predispose individuals to
URIs
 Anatomic changes due to facial dysmorphisms, previous upper airway
trauma, and nasal polyposis
Carrier state: Although some people are chronic carriers of group A
streptococci, repeated URIs in such patients may be viral in origin [2]
Epidemiology
URIs are the most common infectious illness in the general population and are
the leading cause of missed days at work or school. They represent the most
frequent acute diagnosis in the office setting. [15]
Nasopharyngitis
The incidence of the common cold varies by age. Rates are highest in
children younger than 5 years. Children who attend school or day care are a
large reservoir for URIs, and they transfer infection to the adults who care for
them. In the first year after starting at a new school or day care, children
experience more infections, as do their family members. Children have about
3-8 viral respiratory illnesses per year, adolescents and adults have
approximately 2-4 colds annually, and people older than 60 years have fewer
than 1 cold per year.
Pharyngitis
Acute pharyngitis accounts for 1% of all ambulatory office visits. [15] The
incidence of viral and bacterial pharyngitis peaks in children aged 4-7 years.
Rhinosinusitis
Sinusitis is common in persons with viral URIs. Transient changes in the
paranasal sinuses are noted on computed tomography (CT) scans in more
than 80% of patients with uncomplicated viral URIs. [16] However, bacterial
rhinosinusitis occurs as a complication in only about 2% of persons with viral
URIs. [17]
Epiglottitis
The occurrence of epiglottitis has decreased dramatically in the United States
and other developed nations since the introduction of Hib vaccine. A Swedish
study documented that the Hib vaccination program was associated with a
decrease in the overall annual incidence of acute epiglottitis from 4.5 cases to
0.98 cases per 100,000 population; the incidence decreased in children and
adults. However, the annual incidence of pneumococcal epiglottitis in adults
increased from 0.1 to 0.28 cases per 100,000 population over the same
period. [18]
Laryngitis and laryngotracheitis
Croup, or laryngotracheobronchitis, may affect people of any age but usually
occurs in children aged 6 months to 6 years. The peak incidence is in the
second year of life. Thereafter, the enlarging caliber of the airway reduces the
severity of the manifestations of subglottic inflammation.
Vaccination has dramatically reduced rates of pertussis. However, the
incidence of whooping cough in the United States has increased steadily
since 2007, reaching approximately 9 cases per 100,000 population in 2010.
Rates of pertussis are highest in infants below age 1 year; adolescents and
adults accounted for approximately 44% of the 27,550 cases of pertussis
reported in the United States in 2010. [19]
Worldwide, pertussis has an estimated incidence of 48.5 million cases and
causes nearly 295,000 deaths per year. In low-income countries, the case-
fatality rate among infants may be as high as 4%. [20]
Although pertussis is a nationally notifiable disease in the United States, many
cases likely go undiagnosed and unreported. On the other hand, challenges in
laboratory diagnosis and overreliance on polymerase chain reaction (PCR)
assays have resulted in reports of respiratory illness outbreaks mistakenly
attributed to pertussis. [21]
Occurrence rate of selected pathogens
Group A streptococcal bacteria cause approximately 5-15% of all pharyngitis
infections, [2] accounting for several million cases of streptococcal pharyngitis
each year. This infection is rarely diagnosed in children younger than 2 years.
Influenza affects approximately 5-20% of the US population during each flu
season.[22] Early presentations include symptoms of URI.
EBV infection affects as many as 95% of American adults by age 35-40 years.
Childhood EBV infection is indistinguishable from other transient childhood
infections. Approximately 35-50% of adolescents and young adults who
contract EBV infection have mononucleosis. [23]
Diphtheria rates fell dramatically in the United States after the advent of
diphtheria vaccine. Since 1980, the prevalence of diphtheria has been
approximately 0.001 case per 100,000 population. A confirmed case of the
disease has not been reported in the United States since 2003. [24] However,
diphtheria remains endemic in developing countries.
Seasonality
Although URIs may occur year round, in the United States most colds occur
during fall and winter. Beginning in late August or early September, rates of
colds increase over several weeks and remain elevated until March or
April. [25] Epidemics and mini-epidemics are most common during cold months,
with a peak incidence from late winter to early spring.
Cold weather results in more time spent indoors (eg, at work, home, school)
and close exposure to others who may be infected. Humidity may also affect
the prevalence of colds, because most viral URI agents thrive in the low
humidity that is characteristic of winter months. Low indoor air moisture may
increase friability of the nasal mucosa, increasing a person's susceptibility to
infection.
Laryngotracheobronchitis, or croup, occurs in fall and winter. Seasonality does
not affect rates of epiglottitis.
The figure below illustrates the peak incidences of various agents by season.
Rhinoviruses, which account for a substantial percentage of URIs, are most
active in spring, summer, and early autumn. Coronaviral URIs manifest
primarily in the winter and early spring. Enteroviral URIs are most noticeable
in summer and early fall, when other URI pathogens are at a nadir. Adenoviral
respiratory infections can occur throughout the year but are most common in
the late winter, spring, and early summer.

Seasonal variation of selected

upper respiratory tract infection pathogens. PIV is parainfluenza virus, RSV is
respiratory syncytial virus, MPV is metapneumovirus, and Group A Strept is
group A streptococcal disease.
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Seasonal influenza typically lasts from November until March. Some PIVs
have a biennial pattern. The patterns for human PIV types 1-3 are as follows:
Human PIV type 1: Currently produces autumnal outbreaks in the
United States during odd-numbered years; the leading cause of croup in
children
Human PIV type 2: May cause annual or biennial fall outbreaks
Human PIV type 3: Peak activity is during the spring and early summer
months; however, the virus may be isolated throughout the year. [13]
Human metapneumovirus (hMPV) infection may also occur year round,
although the infection rates peak between December and February.
Race- and sex-related demographics
No notable racial difference is observed with URIs. However, Alaskan Natives
have rates of Hib disease higher than those of other groups. [12]
Sexual disparities among URIs are as follows:
Rhinitis: Hormonal changes during the middle of the menstrual cycle
and during pregnancy may produce hyperemia of the nasal and sinus
mucosa and increase nasal secretions; URI may be superimposed over
these baseline changes and may increase the intensity of symptoms in
some women
Nasopharyngitis: The common cold occurs frequently in women,
especially those aged 20-30 years [25] ; this frequency may represent
increased exposure to small children, who represent a large reservoir for
URIs, but hormonal effects on the nasal mucosa may also play a role
Epiglottitis: A male predominance is reported, with a male-to-female
ratio of approximately 3:2
Laryngotracheobronchitis, or croup: More common in boys than in girls,
with a male-to-female ratio of approximately 3:2
Age-related demographics
The incidence of the common cold varies by age. Rates are highest in
children younger than 5 years. Children have approximately 3-8 viral
respiratory illnesses per year, while adolescents and adults have
approximately 2-4 colds a year, and people older than 60 years have fewer
than 1 cold per year.
The age-related occurrence of other infections is as follows:
Viral and bacterial pharyngitis: Peaks in children aged 4-7 years.
Epiglottitis: Typically occurs in children aged 2-7 years and has a peak
incidence in those aged 3 years
Laryngotracheobronchitis (croup): As previously stated, it may affect
people of any age but usually occurs in children aged 6 months to 6
years; the peak incidence is in the second year of life
Prognosis
URIs cause people to spend time away from their usual daily activities, but
alone, these infections rarely cause permanent sequelae or death. URIs may,
however, serve as a gateway to infection of adjacent structures, resulting in
the following infections (and others, as well):
Otitis media
 Bronchitis
Bronchiolitis
Pneumonia
Sepsis
Meningitis
Intracranial abscess
Serious complications may result in clinically significant morbidity and rare
deaths.
Nasopharyngitis
A common cold may last up to 14 days, with symptoms averaging 7-11 days in
duration. [17]
Fever, sneezing, and sore throat typically resolve early, whereas cough and
nasal discharge are among the symptoms that last longest.
Attendance at day care may affect the duration of symptoms in young
children. In one study, the duration of viral URIs ranged from 6.6 days for
children aged 1-2 years in home care to 8.9 days for children younger than 1
year who were in day care. Young children in day care were also more likely
to have protracted respiratory symptoms lasting more than 15 days. [26]
Most patients with influenza recover within a week, although cough, fatigue,
and malaise may persist for up to 2 weeks. For newborns, elderly persons,
and patients with chronic medical conditions, the flu may be life threatening.
More than 200,000 people per year are hospitalized because of complications
of the flu, with 0.36 deaths per 100,000 patients occurring
annually. [27] Influenza may be followed by bacterial superinfection.
Pharyngitis
Viral pharyngitis typically resolves in 1-2 weeks, but immunocompromised
persons may have a more severe course.
Untreated group A streptococcal pharyngitis can result in the following:
Acute rheumatic fever
Acute glomerulonephritis
Peritonsillar abscess
Toxic shock syndrome
Impetigo
Cellulitis or abscess
Otitis
Sinusitis
Conjunctivitis
 Bronchitis
Mortality from group A streptococcal pharyngitis is rare, but serious morbidity
or death may result from one of its complications.
Streptococcal pharyngitis without complications rarely poses significant risk
for morbidity. However, retropharyngeal, intraorbital, or intracranial abscesses
may cause serious sequelae. The risk of mortality is significant in patients who
progress to streptococcal toxic shock syndrome, which is characterized by
multiorgan failure and hypotension.
In patients with penicillin-sensitive streptococcal pharyngitis, symptomatic
improvement is expected within 24-72 hours if antibiotic treatment is started in
the first 24 hours after onset. Treatment failures are common and are mainly
attributed to poor adherence, antibiotic resistance, and untreated close
contacts, usually within the household or family.
A chronic carrier state may develop with group A streptococcal infection.
Eradicating the pathogen is difficult in these cases; however, carriers without
active symptoms are unlikely to spread group A streptococci, and they are at
low risk for developing rheumatic fever.
Mononucleosis
With infectious mononucleosis from EBV, complete resolution of symptoms
may take up to 2 months. Acute symptoms rarely last more than 4 months.
EBV typically remains dormant throughout the patient's life. Reactivation of
the virus is not usually symptomatic.
Rhinosinusitis
The prognosis is generally favorable for acute rhinosinusitis, and many cases
appear to resolve even without antibiotic therapy. As many as 70% of
immunocompetent adults with rhinosinusitis begin to improve within 2 weeks
of presentation without antibiotics. With antibiotics, up to 85% have
improvement at 2 weeks. Complete resolution may take weeks to months.
Sinusitis itself is rarely life threatening, but it can lead to serious complications
if the infection extends into surrounding deep tissue, including the following:
Orbital cellulitis
Subperiosteal abscess
Orbital abscess
Frontal and maxillary osteomyelitis
Subdural abscess
Meningitis
Brain abscess
Epiglottitis
Epiglottitis poses a risk of death due to sudden airway obstruction and other
complications, including septic arthritis, meningitis, empyema, and
mediastinitis. In adults, epiglottitis has a fatality rate of approximately 1%.
The prognosis is favorable with appropriate airway management, and most
patients noticeably improve within 24-48 hours after antibiotics are started.
Rarely, cases of epiglottitis may recur. Recurrent symptoms raise concern
about potential underlying disorders, such as rheumatic conditions,
sarcoidosis, and occult malignancy.
Laryngitis and laryngotracheitis
With croup, laryngotracheobronchitis typically begins to improve within 3-4
days. Recovery is usually complete. However, patients may have a
recurrence, including during the same season.
Pertussis (whooping cough) leads to hospitalization in more than half of
infants younger than 12 months and particularly in infants younger than 6
months. Infants and young children are most susceptible to severe courses
that include respiratory compromise.
Of infants who are hospitalized with pertussis, approximately 50% have
apnea, 20% develop pneumonia, 1% have seizures, 1% die, and 0.3% have
encephalopathy. [28]Recovery from whooping cough is typically complete.
However, paroxysms of coughing may last for several weeks.
Complications
Most URIs are self-limited and resolve completely. However, a variety of
conditions may complicate a URI. Fluid loss may occur in patients unable to
tolerate adequate oral intake because of upper airway inflammation or may
result from fever. Otitis media may complicate 5% of colds in children and up
to 2% of colds in adults [29]
Airway hyperreactivity may increase after a URI, resulting in new or
exacerbated asthma. Cough asthma, wherein a cough is the predominant
manifestation of reactive airways disease, may mimic ongoing infection. This
may be diagnosed with pulmonary function testing.
A postinfectious cough is defined as coughing that persists 3-8 weeks after
the onset of a URI in the absence of other clearly defined causes.
Exacerbations of chronic obstructive pulmonary disease, including
emphysema and chronic bronchitis, may occur during and after a URI. Upper
airways cough syndrome (post-nasal drip) may result from upper airway
secretions dripping onto the pharynx. Epistaxis may also occur.
Lower respiratory tract disease and sepsis represent serious complications,
especially in patients with immunocompromise. Lower respiratory tract
disease should be considered when symptoms such as fever, cough, sputum,
and malaise worsen progressively or after initial transient improvement.
Tachypnea and dyspnea are also signs of lower respiratory involvement.
Viral infection and resulting inflammation may make an individual susceptible
to concomitant or sequential infection with a bacterial agent. Streptococcus
pneumoniae, Staphylococcus aureus, H influenzae, and Streptococcus
pyogenesare common superinfecting agents. Meningococci may cause
superinfection with influenzal infections.
Inflammation of the larynx and trachea area may lead to airway compromise,
especially in children and in patients with narrowed airways due to congenital
or acquired subglottic stenosis. The work of breathing during epiglottitis or
laryngotracheitis may lead to respiratory failure. Sleep apnea may occur from
hypertrophied tonsils.
Deep tissue infection may occur by extension of the infection into the orbit,
middle ear, cranium, or other areas. Peritonsillar abscess (quinsy) may
complicate bacterial pharyngitis, leading to difficulty swallowing and pain
radiating to the ear. Retropharyngeal abscess may also complicate
pharyngitis. Lemierre syndrome is an extension of pharyngitis that leads to a
suppurative thrombophlebitis of the internal jugular vein; septic thromboemboli
may then spread throughout the body.
Complications of sinusitis include the following:
Orbital cellulitis
Subperiosteal abscess
Orbital abscess
Mastoiditis
Frontal or maxillary osteomyelitis
Subdural abscess
Cavernous sinus thrombosis
Brain abscess
Suspect a deep tissue infection when a patient has orbital or periorbital
swelling, proptosis, impaired extraocular movements, or impaired vision.
Signs of increased intracranial pressure (eg, papilledema, altered mental
status, neurologic findings) may suggest intracranial involvement.
Encephalitis, meningitis, or subarachnoid hemorrhage may follow a URI.
Osteomyelitis may complicate persistent or recurrent sinusitis. Osteomyelitis
may affect the orbital plate, frontal bone, or sphenoid bone. Mucoceles are
expanding cystic defects of the paranasal sinuses that may result from
prolonged sinusitis. Epiglottic abscess may result from epiglottitis.
Lymphadenitis may follow or accompany URI. Guillain-Barr syndrome may
manifest as an ascending polyneuropathy a few days or weeks after a URI. In
children or adolescents, the use of aspirin during a viral infection may rarely
cause Reye syndrome. Aspirin is contraindicated for the management of
fevers in children or adolescents.
URI, especially with fever, may increase the work of the heart, adding strain to
persons with suboptimal cardiovascular status, and can lead to cardiovascular
decompensation. Myositis or pericarditis may result from viral infection.
Hyperglycemia may occur during a URI in patients with diabetes. Rib fracture
may be seen following an episode of severe coughing, such as that
associated with whooping cough. Hernia may develop following an episode of
severe coughing.
Cutaneous complications such as rash, cellulitis, and toxic shock syndrome
may occur with group A streptococcus. This pathogen can also be associated
with glomerulonephritis, acute rheumatic fever, and PANDAS syndrome
(Pediatric Autoimmune Neuropsychiatric Disorders Associated with
Streptococcal infections).
Hemoptysis suggests the possibility of tuberculosis. A tuberculin skin test,
chest radiography, or both are appropriate in these patients.
Complications of specific conditions
Complications of group A streptococcal disease
Group A streptococcal pharyngitis is of special concern because its
complications include streptococcal toxic shock syndrome, acute rheumatic
fever (ARF), acute glomerulonephritis, and scarlet fever, as well as cutaneous
infections. In addition, this pathogen is readily transmissible, especially in
households, families, and other intimate groups.
ARF affects approximately 3% of patients with strep throat, primarily occurring
in persons aged 6-20 years. The condition develops approximately 2-4 weeks
after streptococcal pharyngitis occurs, and it may last several months. Signs
of rheumatic fever include arthritis, fever, and valvular disease. Uncommon
features include an expanding truncal exanthem (erythema marginata),
subcutaneous nodules, and chorea.
Poststreptococcal glomerulonephritis can affect persons of any age group, but
it is most common in children aged 3-7 years. Boys are affected slightly more
often than girls. Patients with glomerulonephritis may have loss of appetite,
lethargy, dull back pain, and dark urine. Blood pressure may be elevated, and
edema may occur.
Scarlet fever is a self-limited exanthem that spreads from the chest and
abdomen to the entire body. Tiny red papules create a rough skin texture
similar to that of sandpaper. The rash is typically blanching. Although it
commonly affects the face, circumoral pallor is present. During recovery, the
skin on the fingers and toes peels. Streptococcal toxic shock syndrome may
also occur, affecting skin and mucosa.
PANDAS is a rare syndrome in children and adolescents, who experience
sudden onset or worsening of obsessive-compulsive disorder following
streptococcal infection. Associated manifestations include tics and a variety of
neuropsychiatric symptoms. [30]
Complications of mononucleosis
Complications can include the following:
Splenic rupture
Hepatitis
Guillain-Barr syndrome
Encephalitis
Hemolytic anemia
Agranulocytosis
Myocarditis
Burkitt lymphoma
Nasopharyngeal carcinoma
Rash (with concomitant use of ampicillin)
Complications of diphtheria
Complications may include airway obstruction, myocarditis, polyneuritis,
thrombocytopenia, and proteinuria. Among patients who survive diphtheria, as
many as 20% have permanent hearing loss or other long-term sequelae. [13]
Complications from pertussis
More than half of infants younger than 12 months who contract pertussis
require hospitalization, especially those who are younger than 6 months.
Complications of pertussis in hospitalized infants include the following [28] :
Apnea (50%)
Pneumonia (20%)
Seizures (1%)
Encephalopathy (0.3%)
Death (1%)
In addition, severe cough may result in rib fractures, hernia, incontinence, or
subconjunctival hemorrhages.
Complications of influenza
These include the following:
Bacterial superinfection
Pneumonia
Volume depletion
Myositis
Pericarditis
 Rhabdomyolysis
Encephalitis
Meningitis
Myelitis
Renal failure
Disseminated intravascular coagulation
As with any systemic infection, the flu poses a risk of worsening underlying
medical conditions, such as heart failure, asthma, or diabetes. After influenzal
infection, children may experience sinus problems or otitis media.
Patient Education
Address the patient's expectations about antibiotic therapy. Validate the
patient's symptoms and their severity, listen to the concerns expressed, and
educate the patient about possible consequences of inappropriate antibiotic
use, including consequences affecting him/her and the community.
Many people hold misperceptions about the duration and intensity of
symptoms associated with URI and about the benefits and risks of antibiotic
therapy. Some are unaware that cold symptoms may last as long as 14 days.
Some believe that antibiotics will help them to avoid serious disease and
recover more quickly than without treatment.
Patients may expect to receive antibiotics solely based on the severity of their
symptoms, and they may not appreciate the negative consequences of using
antibiotics in viral disease. Negative results on a rapid strep test may provide
reassurance about the appropriateness of supportive care.
Actively promote self-care, and outline a realistic time course for the resolution
of symptoms. Reassure the patient about access to clinical care and follow-up
in the event that symptoms progress. Briefly explore factors that may have
contributed to the current infection, and address prevention for the future.
Patient satisfaction is less linked to antibiotic prescriptions and more linked to
the quality of the physician-patient interaction. Reflecting understanding of the
details of the patient's situation, expressing concern for the patient's well-
being, explaining how recommendations are appropriately tailored to the
individual's current condition, and providing reassurance are important to
patient satisfaction.
Patients should be counseled on handwashing and proper methods of
covering coughs and sneezes. Patients who smoke should receive smoking
cessation encouragement and materials. When antibiotics are prescribed,
patients should be instructed to complete the full course of antibiotic therapy.
Patients should be instructed to follow up when indicated or if symptoms
worsen. Finally, patients with infectious mononucleosis should be instructed to
avoid contact sports for 6 weeks because of the possibility of splenic rupture.
For patient education information, see the Headache and Migraine Center, as
well as Sinus Infection and Sore Throat.

Practice Essentials
Hypertension affects approximately 86 million adults (20 years) in the United
States; it is a major risk factor for stroke, myocardial infarction, vascular
disease, and chronic kidney disease. See the image below.

Anteroposterior x-ray from a 28-year old

woman who presented with congestive heart failure secondary to her chronic
hypertension, or high blood pressure. The enlarged cardiac silhouette on this
image is due to congestive heart failure due to the effects of chronic high
blood pressure on the left ventricle. The heart then becomes enlarged, and
fluid accumulates in the lungs, known as pulmonary congestion.
View Media Gallery
Signs and symptoms
Hypertension is defined as a systolic blood pressure (SBP) of 140 mm Hg or
more, or a diastolic blood pressure (DBP) of 90 mm Hg or more, or taking
antihypertensive medication. [1]
Based on recommendations of the Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC 7), the classification of BP for adults aged 18 years or older
has been as follows [2] :
 Normal: Systolic lower than 120 mm Hg, diastolic lower than 80 mm Hg
Prehypertension: Systolic 120-139 mm Hg, diastolic 80-89 mm Hg
Stage 1: Systolic 140-159 mm Hg, diastolic 90-99 mm Hg
Stage 2: Systolic 160 mm Hg or greater, diastolic 100 mm Hg or greater
Hypertension may be primary, which may develop as a result of environmental
or genetic causes, or secondary, which has multiple etiologies, including renal,
vascular, and endocrine causes. Primary or essential hypertension accounts
for 90-95% of adult cases, and secondary hypertension accounts for 2-10% of
cases.
See Clinical Presentation for more detail.
Diagnosis
The evaluation of hypertension involves accurately measuring the patients
blood pressure, performing a focused medical history and physical
examination, and obtaining results of routine laboratory studies. [2, 3] A 12-lead
electrocardiogram should also be obtained. These steps can help determine
the following [2, 3, 4] :
Presence of end-organ disease
Possible causes of hypertension
Cardiovascular risk factors
Baseline values for judging biochemical effects of therapy
Other studies may be obtained on the basis of clinical findings or in individuals
with suspected secondary hypertension and/or evidence of target-organ
disease, such as CBC, chest radiograph, uric acid, and urine microalbumin. [2]
See Workup for more detail.
Management
Many guidelines exist for the management of hypertension. Most groups,
including the JNC, the American Diabetes Associate (ADA), and the American
Heart Association/American Stroke Association (AHA/ASA) recommend
lifestyle modification as the first step in managing hypertension.
Lifestyle modifications
JNC 7 recommendations to lower BP and decrease cardiovascular disease
risk include the following, with greater results achieved when 2 or more
lifestyle modifications are combined [2] :
Weight loss (range of approximate systolic BP reduction [SBP], 5-20
mm Hg per 10 kg)
Limit alcohol intake to no more than 1 oz (30 mL) of ethanol per day for
men or 0.5 oz (15 mL) of ethanol per day for women and people of lighter
weight (range of approximate SBP reduction, 2-4 mm Hg)
 Reduce sodium intake to no more than 100 mmol/day (2.4 g sodium or
6 g sodium chloride; range of approximate SBP reduction, 2-8 mm Hg) [5]
Maintain adequate intake of dietary potassium (approximately 90
mmol/day)
Maintain adequate intake of dietary calcium and magnesium for general
health
Stop smoking and reduce intake of dietary saturated fat and cholesterol
for overall cardiovascular health
Engage in aerobic exercise at least 30 minutes daily for most days
(range of approximate SBP reduction, 4-9 mm Hg)
The AHA/ASA recommends a diet that is low in sodium, is high in potassium,
and promotes the consumption of fruits, vegetables, and low-fat dairy
products for reducing BP and lowering the risk of stroke. Other
recommendations include increasing physical activity (30 minutes or more of
moderate intensity activity on a daily basis) and losing weight (for overweight
and obese persons).
The 2013 European Society of Hypertension (ESH) and the European Society
of Cardiology (ESC) guidelines recommend a low-sodium diet (limited to 5 to
6 g per day) as well as reducing body-mass index (BMI) to 25 kg/m2 and waist
circumference (to < 102 cm in men and < 88 cm in women). [6, 7]
Pharmacologic therapy
If lifestyle modifications are insufficient to achieve the goal BP, there are
several drug options for treating and managing hypertension. Thiazide
diuretics, an angiotensin-converting enzyme (ACE) inhibitor/angiotension
receptor blocker (ARB), or calcium channel blocker (CCB) are the preferred
agents in nonblack populations, whereas CCBs or thiazide diuretics are
favored in black hypertensive populations. [8] These recommendations do not
exclude the use of ACE inhibitors or ARBs in treatment of black patients, or
CCBs or diuretics in non-black persons. Often, patients require several
antihypertensive agents to achieve adequate BP control.
Compelling indications for specific agents include comorbidities such as heart
failure, ischemic heart disease, chronic kidney disease, and diabetes. Drug
intolerability or contraindications may also be factors. [2]
The following are drug class recommendations for compelling indications
based on various clinical trials [2] :
Heart failure: Diuretic, beta-blocker, ACE inhibitor/ARB, aldosterone
antagonist
Following myocardial infarction: Beta-blocker, ACE inhibitor
Diabetes: ACE inhibitor/ARB
Chronic kidney disease: ACE inhibitor/ARB
See Treatment and Medication for more detail.
Hypertensionor high blood pressurecan happen steadily over long time
periods. The cause may not be clear (ie, primary hypertension) or
hypertension may be caused by an underlying condition (ie, secondary
hypertension).
View Media Gallery
Background
Hypertension is one of the most common worldwide diseases afflicting
humans and is a major risk factor for stroke, myocardial infarction, vascular
disease, and chronic kidney disease. Despite extensive research over the
past several decades, the etiology of most cases of adult hypertension is still
unknown, and control of blood pressure is suboptimal in the general
population. Due to the associated morbidity and mortality and cost to society,
preventing and treating hypertension is an important public health challenge.
Fortunately, recent advances and trials in hypertension research are leading
to an increased understanding of the pathophysiology of hypertension and the
promise for novel pharmacologic and interventional treatments for this
widespread disease.
According to the American Heart Association (AHA), approximately 86 million
adults (34%) in the United States are affected by hypertension, which is
defined as a systolic blood pressure (SBP) of 140 mm Hg or more or a
diastolic blood pressure (DBP) of 90 mm Hg or more, taking antihypertensive
medication, or having been told by clinicians on at least 2 occasions as having
hypertension. [1] Substantial improvements have been made with regard to
enhancing awareness and treatment of hypertension. However, a National
Health Examination Survey (NHANES) spanning 2011-2014 revealed that
34% of US adults aged 20 years and older are hypertensive and NHANES
2013-2014 data showed that 15.9% of these hypertensive adults are unaware
they are hypertensive; these data have increased from NHANES 2005-2006
data that showed 29% of US adults aged 18 years and older were
hypertensive and that 7% of these hypertensive adults had never been told
that they had hypertension. [1]
Furthermore, of those with high blood pressure (BP), 78% were aware they
were hypertensive, 68% were being treated with antihypertensive agents, and
only 64% of treated individuals had controlled hypertension. [1] In addition,
previous data from NHANES estimated that 52.6% (NHANES 2009-2010) to
55.8% (NHANES 1999-2000) of adults aged 20 years and older have
prehypertension, defined as an untreated SBP of 120-139 mm Hg or
untreated DBP of 80-89 mmHg. [1] (See Epidemiology.)
Data from the Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), which
was released in 2003, were relatively similar to the NHANES data. The JNC 7
noted that approximately 30% of adults were unaware of their hypertension;
up to 40% of people with hypertension were not receiving treatment; and, of
those treated, up to 67% did not have their BP controlled to less than 140/90
mm Hg. [2]
Hypertension is the most important modifiable risk factor for coronary heart
disease (the leading cause of death in North America), stroke (the third
leading cause), congestive heart failure, end-stage renal disease, and
peripheral vascular disease. Therefore, health care professionals must not
only identify and treat patients with hypertension but also promote a healthy
lifestyle and preventive strategies to decrease the prevalence of hypertension
in the general population. (See Treatment.)
Definition and classification
Defining abnormally high blood pressure (BP) is extremely difficult and
arbitrary. Furthermore, the relationship between systemic arterial pressure and
morbidity appears to be quantitative rather than qualitative. A level for high BP
must be agreed upon in clinical practice for screening patients with
hypertension and for instituting diagnostic evaluation and initiating therapy.
Because the risk to an individual patient may correlate with the severity of
hypertension, a classification system is essential for making decisions about
aggressiveness of treatment or therapeutic interventions. (See Presentation.)
Based on recommendations of the JNC 7, the classification of BP (expressed
in mm Hg) for adults aged 18 years or older is as follows [2] :
Normal: systolic lower than 120 mm Hg, diastolic lower than 80 mm Hg
Prehypertension: systolic 120-139 mm Hg, diastolic 80-89 mm Hg
Stage 1: systolic 140-159 mm Hg, diastolic 90-99 mm Hg
Stage 2: systolic 160 mm Hg or greater, diastolic 100 mm Hg or greater
The classification above is based on the average of 2 or more readings taken
at each of 2 or more visits after initial screening. [2, 4] Normal BP with respect to
cardiovascular risk is less than 120/80 mm Hg. However, unusually low
readings should be evaluated for clinical significance.
Prehypertension, a new category designated in the JNC 7 report, emphasizes
that patients with prehypertension are at risk for progression to hypertension
and that lifestyle modifications are important preventive strategies.
From another perspective, hypertension may be categorized as either
essential or secondary. Primary (essential) hypertension is diagnosed in the
absence of an identifiable secondary cause. Approximately 90-95% of adults
with hypertension have primary hypertension, whereas secondary
hypertension accounts for around 5-10% of the cases. [9] However, secondary
forms of hypertension, such as primary hyperaldosteronism, account for 20%
of resistant hypertension (hypertension in which BP is >140/90 mm Hg despite
the use of medications from 3 or more drug classes, 1 of which is a thiazide
diuretic).
Especially severe cases of hypertension, or hypertensive crises, are defined
as a BP of more than 180/120 mm Hg and may be further categorized as
hypertensive emergencies or urgencies. Hypertensive emergencies are
characterized by evidence of impending or progressive target organ
dysfunction, whereas hypertensive urgencies are those situations without
progressive target organ dysfunction. [2]
In hypertensive emergencies, the BP should be aggressively lowered within
minutes to an hour by no more than 25%, and then lowered to 160/100-110
mm Hg within the next 2-6 hours. [2] Acute end-organ damage in the setting of
a hypertensive emergency may include the following [10] :
Neurologic: hypertensive encephalopathy, cerebral vascular
accident/cerebral infarction, subarachnoid hemorrhage, intracranial
hemorrhage
Cardiovascular: myocardial ischemia/infarction, acute left ventricular
dysfunction, acute pulmonary edema, aortic dissection, unstable angina
pectoris
Other: acute renal failure/insufficiency, retinopathy, eclampsia,
microangiopathic hemolytic anemia
With the advent of antihypertensives, the incidence of hypertensive
emergencies has declined from 7% to approximately 1%. [11] In addition, the 1-
year survival rate associated with this condition has increased from only 20%
(prior to 1950) to more than 90% with appropriate medical treatment. [12] (See
Medication.)
Pathophysiology
The pathogenesis of essential hypertension is multifactorial and
complex. [13]Multiple factors modulate the blood pressure (BP) including
humoral mediators, vascular reactivity, circulating blood volume, vascular
caliber, blood viscosity, cardiac output, blood vessel elasticity, and neural
stimulation. A possible pathogenesis of essential hypertension has been
proposed in which multiple factors, including genetic predisposition, excess
dietary salt intake, and adrenergic tone, may interact to produce hypertension.
Although genetics appears to contribute, the exact mechanisms underlying
essential hypertension have not been established.
Investigations into the pathophysiology of hypertension, both in animals and
humans, have revealed that hypertension may have an immunological basis.
Studies have revealed that hypertension is associated with renal infiltration of
immune cells and that pharmacologic immunosuppression (such as with the
drug mycophenolate mofetil) or pathologic immunosuppression (such as
occurs with HIV) results in reduced blood pressure in animals and humans.
Evidence suggests that T lymphocytes and T-cell derived cytokines (eg,
interleukin 17, tumor necrosis factor alpha) play an important role in
hypertension. [14, 15]
One hypothesis is that prehypertension results in oxidation of lipids such as
arichidonic acid that leads to the formation of isoketals or isolevuglandins,
which function as neoantigens, which are then presented to T cells, leading to
T-cell activation and infiltration of critical organs (eg, kidney,
vasculature). [16] This results in persistent or severe hypertension and end
organ damage. Sympathetic nervous system activation and noradrenergic
stimuli have also been shown to promote T-lymphocyte activation and
infiltration and contribute to the pathophysiology of hypertension. [17, 18, 19]
The natural history of essential hypertension evolves from occasional to
established hypertension. After a long invariable asymptomatic period,
persistent hypertension develops into complicated hypertension, in which end-
organ damage to the aorta and small arteries, heart, kidneys, retina, and
central nervous system is evident.
The progression of essential hypertension is as follows:
1. Prehypertension in persons aged 10-30 years (by increased cardiac
output)
2. Early hypertension in persons aged 20-40 years (in which increased
peripheral resistance is prominent)
3. Established hypertension in persons aged 30-50 years
4. Complicated hypertension in persons aged 40-60 years
As evident from the above, younger individuals may present with hypertension
associated with an elevated cardiac output (high-output hypertension). High-
output hypertension results from volume and sodlum retention by the kidney,
leading to increased stroke volume and, often, with cardiac stimulation by
adrenergic hyperactivity. Systemic vascular resistance is generally not
increased at such earlier stages of hypertension. As hypertension is
sustained, however, vascular adaptations including remodeling,
vasoconstriction, and vascular rarefaction occur, leading to increased
systemic vascular resistance. In this situation, cardiac output is generally
normal or slightly reduced, and circulating blood volume is normal.
Cortisol reactivity, an index of hypothalamic-pituitary-adrenal function, may be
another mechanism by which psychosocial stress is associated with future
hypertension. [20] In a prospective substudy of the Whitehall II cohort, with 3
years follow-up of an occupational cohort in previously healthy patients,
investigators reported 15.9% of the patient sample developed hypertension in
response to laboratory-induced mental stressors and found an association
between cortisol stress reactivity and incident hypertension. [20]
Etiology
Hypertension may be primary, which may develop as a result of environmental
or genetic causes, or secondary, which has multiple etiologies, including renal,
vascular, and endocrine causes. Primary or essential hypertension accounts
for 90-95% of adult cases, and a small percentage of patients (2-10%) have a
secondary cause. Hypertensive emergencies are most often precipitated by
inadequate medication or poor compliance.
Environmental and genetic/epigenetic causes
Hypertension develops secondary to environmental factors, as well as
multiple genes, whose inheritance appears to be complex. [12, 21] Furthermore,
obesity, diabetes, and heart disease also have genetic components and
contribute to hypertension. Epidemiological studies using twin data and data
from Framingham Heart Study families reveal that BP has a substantial
heritable component, ranging from 33-57%. [22, 23, 24]
In an attempt to elucidate the genetic components of hypertension, multiple
genome wide association studies (GWAS) have been conducted, revealing
multiple gene loci in known pathways of hypertension as well as some novel
genes with no known link to hypertension as of yet. [25] Further research into
these novel genes, some of which are immune-related, will likely increase the
understanding of hypertension's pathophysiology, allowing for increased risk
stratification and individualized treatment.
Epigenetic phenomena, such as DNA methylation and histone modification,
have also been implicated in the pathogenesis of hypertension. For example,
a high-salt diet appears to unmask nephron development caused by
methylation. Maternal water deprivation and protein restriction during
pregnancy increase renin-angiotensin expression in the fetus. Mental stress
induces a DNA methylase, which enhances autonomic responsiveness. The
pattern of serine protease inhibitor gene methylation predicts preeclampsia in
pregnant women. [26]
Despite these genetic findings, targeted genetic therapy seems to have little
impact on hypertension. In the general population, not only does it appear that
individual and joint genetic mutations have very small effects on BP levels, but
it has not been shown that any of these genetic abnormalities are responsible
for any applicable percentage of cases of hypertension in the general
population. [27]
Secondary causes of hypertension related to single genes are very rare. They
include Liddle syndrome, glucocorticoid-remediable hyperaldosteronism, 11
beta-hydroxylase and 17 alpha-hydroxylase deficiencies, the syndrome of
apparent mineralocorticoid excess, and pseudohypoaldosteronism type II. [2]
Causes of secondary hypertension
Renal causes (2.5-6%) of hypertension include the renal parenchymal
diseases and renal vascular diseases, as follows:
Polycystic kidney disease
Chronic kidney disease
Urinary tract obstruction
Renin-producing tumor
Liddle syndrome
Renovascular hypertension (RVHT) causes 0.2-4% of cases. Since the
seminal experiment in 1934 by Goldblatt et al, [28] RVHT has become
increasingly recognized as an important cause of clinically atypical
hypertension and chronic kidney diseasethe latter by virtue of renal
ischemia. The coexistence of renal arterial vascular (ie, renovascular) disease
and hypertension roughly defines this type of nonessential hypertension. More
specific diagnoses are made retrospectively when hypertension is improved
after intravascular intervention.
Vascular causes include the following:
Coarctation of aorta
Vasculitis
Collagen vascular disease
Endocrine causes account for 1-2% and include exogenous or endogenous
hormonal imbalances. Exogenous causes include administration of steroids.
The most common form of secondary hypertension is a renal cause (although
the true prevalence of hyperaldosteronism is not clear).
Another common endocrine cause is oral contraceptive use. Activation of the
renin-angiotensin-aldosterone system (RAAS) is the likely mechanism,
because hepatic synthesis of angiotensinogen is induced by the estrogen
component of oral contraceptives. Approximately 5% of women taking oral
contraceptives may develop hypertension, which abates within 6 months after
discontinuation. The risk factors for oral contraceptiveassociated
hypertension include mild renal disease, familial history of essential
hypertension, age older than 35 years, and obesity. It would be better to group
oral contraceptives and steroids with drug-induced hypertension (see Table 1,
below).
Exogenous administration of the other steroids used for therapeutic purposes
also increases blood pressure (BP), especially in susceptible individuals,
mainly by volume expansion. Nonsteroidal anti-inflammatory drugs (NSAIDs)
may also have adverse effects on BP. NSAIDs block both cyclooxygenase-1
(COX-1) and COX-2 enzymes. The inhibition of COX-2 can inhibit its
natriuretic effect, which, in turn, increases sodium retention. NSAIDs also
inhibit the vasodilating effects of prostaglandins and the production of
vasoconstricting factorsnamely, endothelin-1. These effects can contribute
to the induction of hypertension in a normotensive or controlled hypertensive
patient.
Endogenous hormonal causes include the following:
Primary hyperaldosteronism
Cushing syndrome
Pheochromocytoma
Congenital adrenal hyperplasia
Neurogenic causes include the following:
Brain tumor
Autonomic dysfunction
Sleep apnea
Intracranial hypertension
Drugs and toxins that cause hypertension include the following:
Alcohol
Cocaine
Cyclosporine, tacrolimus
NSAIDs
Erythropoietin
Adrenergic medications
Decongestants containing ephedrine
Herbal remedies containing licorice (including licorice root) or ephedrine
(and ephedra)
Nicotine
Other causes include the following:
Hyperthyroidism and hypothyroidism
Hypercalcemia
Hyperparathyroidism
Acromegaly
Obstructive sleep apnea
Pregnancy-induced hypertension
Obstructive sleep apnea (OSA) is a common but frequently undiagnosed
sleep-related breathing disorder defined as an average of at least 10 apneic
and hypopenic episodes per sleep hour, which leads to excessive daytime
sleepiness. Multiple studies have shown OSA to be an independent risk factor
for the development of essential hypertension, even after adjusting for age,
gender, and degree of obesity.
Approximately half of individuals with hypertension have OSA, and
approximately half with OSA have hypertension. Ambulatory BP monitoring
normally reveals a "dip" in BP of at least 10% during sleep. However, if a
patient is a "nondipper," the chances that the patient has OSA is increased.
Nondipping is thought to be caused by frequent apneic/hypopneic episodes
that end with arousals associated with marked spikes in BP that last for
several seconds. Apneic episodes are associated with striking increases in
sympathetic nerve activity and enormous elevations of BP. Individuals with
sleep apnea have increased cardiovascular mortality, in part likely related to
the high incidence of hypertension.
Although treatment of sleep apnea with continuous airway positive pressure
(CPAP) would logically seem to improve CV outcomes and hypertension,
studies evaluating this mode of therapy have been disappointing. A 2016
review of several studies indicated that CPAP either had no effect or a modest
BP-lowering effect. [29]Findings from the SAVE study showed no effect of CPAP
therapy on BP above usual care. [30] It is likely that patients with sleep apnea
have other etiologies of hypertension, including obesity, hyperaldosteronism,
increased sympathetic drive, and activation of the renin/angiotensin system
that contribute to their hypertension. Although CPAP remains an effective
therapy for other aspects of sleep apnea, it should not be expected to
normalize BP in the majority of patients.
Causes of hypertensive emergencies
The most common hypertensive emergency is a rapid unexplained rise in BP
in patients with chronic essential hypertension. Most patients who develop
hypertensive emergencies have a history of inadequate hypertensive
treatment or an abrupt discontinuation of their medications. [31, 32]
Other causes of hypertensive emergencies include the use of recreational
drugs, abrupt clonidine withdrawal, post pheochromocytoma removal, and
systemic sclerosis, as well as the following:
Renal parenchymal disease: chronic pyelonephritis, primary
glomerulonephritis, tubulointerstitial nephritis (accounts for 80% of all
secondary causes)
Systemic disorders with renal involvement: systemic lupus
erythematosus, systemic sclerosis, vasculitides
Renovascular disease: atherosclerotic disease, fibromuscular dysplasia,
polyarteritis nodosa
 Endocrine disease: pheochromocytoma, Cushing syndrome, primary
hyperaldosteronism
Drugs: cocaine, [33] amphetamines, cyclosporine, clonidine (withdrawal),
phencyclidine, diet pills, oral contraceptive pills
Drug interactions: monoamine oxidase inhibitors with tricyclic
antidepressants, antihistamines, or tyramine-containing food
Central nervous system factors: CNS trauma or spinal cord disorders,
such as Guillain-Barr syndrome
Coarctation of the aorta
Preeclampsia/eclampsia
Postoperative hypertension
Epidemiology
Hypertension is a worldwide epidemic; accordingly, its epidemiology has been
well studied. Data from National Health and Nutrition Examination Survey
(NHANES) spanning 2011-2014 in the United States found that in the
population aged 20 years or older, an estimated 86 million adults had
hypertension, with a prevalence of 34%.[1] Hypertension affects US men and
women nearly equally, affecting an estimated 40.8 million men and 44.9
million women. [1]
Globally, an estimated 26% of the worlds population (972 million people) has
hypertension, and the prevalence is expected to increase to 29% by 2025,
driven largely by increases in economically developing nations. [34] The high
prevelance of hypertension exacts a tremendous public health burden. As a
primary contributor to heart disease and stroke, the first and third leading
causes of death worldwide, respectively, high blood pressure was the top
modifiable risk factor for disability adjusted life-years lost worldwide in
2013. [35, 36]
Between 2006 and 2011, there was a 25% increase in the number of people
visiting US emergency rooms for essential hypertension, according to an
analysis of data from the Nationwide Emergency Department Sample in
2014. [37] The reason for the increase, however, remained uncertain. The rate
of emergency department visits also increased significantly, according to the
study, rising from 190.1 visits per 100,000 population in 2006 to 238.5 visits
per 100,000 population in 2011. Over the same period, however, admission
rates decreased, from 10.47% in 2006 to 8.85% in 2011. [37]
Emergency department visits for hypertension with complications and
secondary hypertension also rose, from 71.2 per 100,000 population in 2006
to 84.7 per 100,000 population in 2011, while again, admission rates fell,
dropping from 77.79% in 2006 to 68.75% in 2011. The in-hospital mortality
rate for admitted patients dropped as well, from 1.95% in 2006 to 1.25% in
2011. [37]
Hypertension and sex- and age-related statistics
Until age 45 years, a higher percentage of men than women have
hypertension; from age 45 to 64 years, the percentages are nearly equal
between men and women. Beyond age 64 years, a higher percentage of
women have hypertension than men. [38]
Hypertension in black adults
Globally, black adults have among the highest rates of hypertension, with an
increasing prevalence. Although white adults also have an increasing
incidence of high BP, they develop this condition later in life than black adults
and have much lower average BPs. In fact, compared to hypertensive white
persons, hypertensive black individuals have a 1.3-fold higher rate of nonfatal
stroke, a 1.8-fold higher rate of fatal stroke, a 1.5-fold higher mortality rate due
to heart disease, and a 4.2-fold higher rate of end-stage renal disease
(ESRD). [38]
Table 1, below, summarizes age-adjusted prevalence estimates from the
National Health Interview Survey (NHIS) and the National Center for Health
Statistics (NCHS) according to racial/ethnic groups and diagnosed conditions
in individuals 18 years of age and older.
Table 1. NHIS/NCHS Age-Adjusted Prevalence Estimates in Individuals Aged
18 Years and Older in 2015. (Open Table in a new window)
Have Have
Have
Heart Coronary Have Had a
Race/Ethnic Group Hypertension,
Disease, Heart Stroke, %
%
% Disease, %

White only 23.8 11.3 5.6 2.4

Black/African American 34.4 9.5 5.4 3.7

Hispanic/Latino 23.0 8.2 5.1 2.4

Asian 20.6 7.1 3.7 1.4

2.2 (this
number is
American Indian/Alaska Native 28.4 13.7 9.3
considered
unreliable)

Source: Summary health statistics: National Health Interview Survey, 2015. Available
at:https://ftp.cdc.gov/pub/Health_Statistics/NCHS/NHIS/SHS/2015_SHS_Table_A-1.pdf. Accessed:
November 14, 2016.
NCHS = National Center for Health Statistics; NHIS = National Health Interview Survey.

Prognosis
Most individuals diagnosed with hypertension will have increasing blood
pressure (BP) as they age. Untreated hypertension is notorious for increasing
the risk of mortality and is often described as a silent killer. Mild to moderate
hypertension, if left untreated, may be associated with a risk of atherosclerotic
disease in 30% of people and organ damage in 50% of people within 8-10
years after onset.
Death from ischemic heart disease or stroke increases progressively as BP
increases. For every 20 mm Hg systolic or 10 mm Hg diastolic increase in BP
above 115/75 mm Hg, the mortality rate for both ischemic heart disease and
stroke doubles. [2]
Hypertensive retinopathy was associated with an increased long-term risk of
stroke, even in patients with well-controlled BP, in a report of 2907 adults with
hypertension participating in the Atherosclerosis Risk in Communities (ARIC)
study.[39, 40] Increasing severity of hypertensive retinopathy was associated with
an increased risk of stroke; the stroke risk was 1.35 in the mild retinopathy
group and 2.37 in the moderate/severe group.
In a meta-analysis of pooled data from 19 prospective cohort studies involving
762,393 patients, Huang et al reported that, after adjustment for multiple
cardiovascular risk factors, prehypertension was associated with a 66%
increased risk for stroke, compared with an optimal blood pressure (<120/80
mm Hg). [41, 42]Patients in the high range of prehypertension (130-139/85-89
mm Hg) had a 95% increased risk of stroke, compared with a 44% increased
risk for those in the low range of prehypertension (120-129/80-84 mm
Hg). [41, 42]
The morbidity and mortality of hypertensive emergencies depend on the
extent of end-organ dysfunction on presentation and the degree to which BP
is controlled subsequently. With BP control and medication compliance, the
10-year survival rate of patients with hypertensive crises approaches 70%. [43]
In the Framingham Heart Study, the age-adjusted risk of congestive heart
failure was 2.3 times higher in men and 3 times higher in women when the
highest BP was compared to the lowest BP. [44] Multiple Risk Factor
Intervention Trial (MRFIT) data showed that the relative risk for coronary
artery disease mortality was 2.3 to 6.9 times higher for persons with mild to
severe hypertension than it was for persons with normal BP. [45] The relative
risk for stroke ranged from 3.6 to 19.2. The population-attributable risk
percentage for coronary artery disease varied from 2.3 to 25.6%, whereas the
population-attributable risk for stroke ranged from 6.8-40%.
The Framingham Heart Study found a 72% increase in the risk of all-cause
death and a 57% increase in the risk of any cardiovascular event in patients
with hypertension who were also diagnosed with diabetes mellitus. [46]
Nephrosclerosis is one of the possible complications of long-standing
hypertension. The risk of hypertension-induced end-stage renal disease is
higher in black patients, even when blood pressure is under good control.
Furthermore, patients with diabetic nephropathy who are hypertensive are
also at high risk for developing end-stage renal disease.
Comparative data from the NHANES I and III showed a decrease in mortality
over time in hypertensive adults, but the mortality gap between hypertensive
and normotensive adults remained high. [47]
Clinical trials have demonstrated the following benefits with antihypertensive
therapy [2] :
Average 35-40% reduction in stroke incidence
Average 20-25% reduction in myocardial infarction
Average >50% reduction in heart failure
Moreover, it is estimated that 1 death is prevented per 11 patients treated for
stage 1 hypertension and other cardiovascular risk factors when a sustained
reduction of 12 mm Hg in systolic BP over 10 years is achieved. [2] However,
for the same reduction is systolic BP reduction, it is estimated that 1 death is
prevented per 9 patients treated when cardiovascular disease or end-organ
damage is present. [2]
Patient Education
Hypertension is a lifelong disorder. For optimal control, a long-term
commitment to lifestyle modifications and pharmacologic therapy is required.
Therefore, repeated in-depth patient education and counseling not only
improve compliance with medical therapy but also reduce cardiovascular risk
factors.
Various strategies to decrease cardiovascular disease risk include the
following:
Prevention and treatment of obesity: an increase in body mass index
(BMI) and waist circumference is associated with an increased risk of
developing conditions with high cardiovascular risk, such as
hypertension, diabetes mellitus, impaired fasting glucose, and left
ventricular hypertrophy [LVH] [48]
Appropriate amounts of aerobic physical activity
Diets low in salt, total fat, and cholesterol
Adequate dietary intake of potassium, calcium, and magnesium
 Limited alcohol consumption
Avoidance of cigarette smoking
Avoidance of the use of illicit drugs, such as cocaine
Clinicians may also wish to refer patients to the following short video, which
provides a simplified but clear and concise overview about what hypertension
is, as well as its different stages, causes, and types.

Practice Essentials
Type 2 diabetes mellitus consists of an array of dysfunctions characterized by
hyperglycemia and resulting from the combination of resistance to insulin
action, inadequate insulin secretion, and excessive or inappropriate glucagon
secretion. See the image below.

Simplified scheme for the

pathophysiology of type 2 diabetes mellitus.
View Media Gallery
See Clinical Findings in Diabetes Mellitus, a Critical Images slideshow, to help
identify various cutaneous, ophthalmologic, vascular, and neurologic
manifestations of DM.
Signs and symptoms
Many patients with type 2 diabetes are asymptomatic. Clinical manifestations
include the following:
Classic symptoms: Polyuria, polydipsia, polyphagia, and weight loss
 Blurred vision
Lower-extremity paresthesias
Yeast infections (eg, balanitis in men)
See Presentation for more detail.
Diagnosis
Diagnostic criteria by the American Diabetes Association (ADA) include the
following [1] :
A fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or
higher, or
A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher
during a 75-g oral glucose tolerance test (OGTT), or
A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a
patient with classic symptoms of hyperglycemia or hyperglycemic crisis
Whether a hemoglobin A1c (HbA1c) level of 6.5% or higher should be a
primary diagnostic criterion or an optional criterion remains a point of
controversy.
Indications for diabetes screening in asymptomatic adults includes the
following [2,3] :
Sustained blood pressure >135/80 mm Hg
Overweight and 1 or more other risk factors for diabetes (eg, first-
degree relative with diabetes, BP >140/90 mm Hg, and HDL < 35 mg/dL
and/or triglyceride level >250 mg/dL)
ADA recommends screening at age 45 years in the absence of the
above criteria
See Workup for more detail.
Management
Goals of treatment are as follows:
Microvascular (ie, eye and kidney disease) risk reduction through
control of glycemia and blood pressure
Macrovascular (ie, coronary, cerebrovascular, peripheral vascular) risk
reduction through control of lipids and hypertension, smoking cessation
Metabolic and neurologic risk reduction through control of glycemia
Recommendations for the treatment of type 2 diabetes mellitus from the
European Association for the Study of Diabetes (EASD) and the American
Diabetes Association (ADA) place the patient's condition, desires, abilities,
and tolerances at the center of the decision-making process. [4, 5, 6]
The EASD/ADA position statement contains 7 key points:
1. Individualized glycemic targets and glucose-lowering therapies
 2. Diet, exercise, and education as the foundation of the treatment
program
3. Use of metformin as the optimal first-line drug unless contraindicated
4. After metformin, the use of 1 or 2 additional oral or injectable agents,
with a goal of minimizing adverse effects if possible
5. Ultimately, insulin therapy alone or with other agents if needed to
maintain blood glucose control
6. Where possible, all treatment decisions should involve the patient, with
a focus on patient preferences, needs, and values
7. A major focus on comprehensive cardiovascular risk reduction
The 2013 ADA guidelines for SMBG frequency focus on an individual's
specific situation rather than quantifying the number of tests that should be
done. The recommendations include the following [7, 8] :
Patients on intensive insulin regimens Perform SMBG at least before
meals and snacks, as well as occasionally after meals; at bedtime; before
exercise and before critical tasks (eg, driving); when hypoglycemia is
suspected; and after treating hypoglycemia until normoglycemia is
achieved.
Patients using less frequent insulin injections or noninsulin therapies
Use SMBG results to adjust to food intake, activity, or medications to
reach specific treatment goals; clinicians must not only educate these
individuals on how to interpret their SMBG data, but they should also
reevaluate the ongoing need for and frequency of SMBG at each routine
visit.
Approaches to prevention of diabetic complications include the following:
HbA1c every 3-6 months
Yearly dilated eye examinations
Annual microalbumin checks
Foot examinations at each visit
Blood pressure < 130/80 mm Hg, lower in diabetic nephropathy
Statin therapy to reduce low-density lipoprotein cholesterol
See Treatment and Medication for more detail.
Background
Type 2 diabetes mellitus consists of an array of dysfunctions characterized by
hyperglycemia and resulting from the combination of resistance to insulin
action, inadequate insulin secretion, and excessive or inappropriate glucagon
secretion. Poorly controlled type 2 diabetes is associated with an array of
microvascular, macrovascular, and neuropathic complications.
Microvascular complications of diabetes include retinal, renal, and possibly
neuropathic disease. Macrovascular complications include coronary artery
and peripheral vascular disease. Diabetic neuropathy affects autonomic and
peripheral nerves. (See Pathophysiology and Presentation.)
Unlike patients with type 1 diabetes mellitus, patients with type 2 are not
absolutely dependent on insulin for life. This distinction was the basis for the
older terms for types 1 and 2, insulin dependent and noninsulin dependent
diabetes.
However, many patients with type 2 diabetes are ultimately treated with
insulin. Because they retain the ability to secrete some endogenous insulin,
they are considered to require insulin but not to depend on insulin.
Nevertheless, given the potential for confusion due to classification based on
treatment rather than etiology, the older terms have been
abandoned. [9] Another older term for type 2 diabetes mellitus was adult-onset
diabetes. Currently, because of the epidemic of obesity and inactivity in
children, type 2 diabetes mellitus is occurring at younger and younger ages.
Although type 2 diabetes mellitus typically affects individuals older than 40
years, it has been diagnosed in children as young as 2 years of age who have
a family history of diabetes. In many communities, type 2 diabetes now
outnumbers type 1 among children with newly diagnosed diabetes. (See
Epidemiology.)
Diabetes mellitus is a chronic disease that requires long-term medical
attention to limit the development of its devastating complications and to
manage them when they do occur. It is a disproportionately expensive
disease; in the United States in 2007, the direct medical costs of diabetes
were $116 billion, and the total costs were $174 billion; people with diabetes
had average medical expenditures 2.3 times those of people without diabetes.
The emergency department utilization rate by people with diabetes is twice
that of the unaffected population. [10, 11]
This article focuses on the diagnosis and treatment of type 2 diabetes and its
acute and chronic complications, other than those directly associated with
hypoglycemia and severe metabolic disturbances, such as hyperosmolar
hyperglycemic state (HHS) and diabetic ketoacidosis (DKA). For more
information on those topics, seeHyperosmolar Hyperglycemic
State and Diabetic Ketoacidosis.
Pathophysiology
Type 2 diabetes is characterized by a combination of peripheral insulin
resistance and inadequate insulin secretion by pancreatic beta cells. Insulin
resistance, which has been attributed to elevated levels of free fatty acids and
proinflammatory cytokines in plasma, leads to decreased glucose transport
into muscle cells, elevated hepatic glucose production, and increased
breakdown of fat.
A role for excess glucagon cannot be underestimated; indeed, type 2 diabetes
is an islet paracrinopathy in which the reciprocal relationship between the
glucagon-secreting alpha cell and the insulin-secreting beta cell is lost,
leading to hyperglucagonemia and hence the consequent hyperglycemia. [10]
For type 2 diabetes mellitus to occur, both insulin resistance and inadequate
insulin secretion must exist. For example, all overweight individuals have
insulin resistance, but diabetes develops only in those who cannot increase
insulin secretion sufficiently to compensate for their insulin resistance. Their
insulin concentrations may be high, yet inappropriately low for the level of
glycemia.
A simplified scheme for the pathophysiology of abnormal glucose metabolism
in type 2 diabetes mellitus is depicted in the image below.

Simplified scheme for the

pathophysiology of type 2 diabetes mellitus.
View Media Gallery
With prolonged diabetes, atrophy of the pancreas may occur. A study by
Philippe et al used computed tomography (CT) scan findings, glucagon
stimulation test results, and fecal elastase-1 measurements to confirm
reduced pancreatic volume in individuals with a median 15-year history of
diabetes mellitus (range, 5-26 years). [12]This may also explain the associated
exocrine deficiency seen in prolonged diabetes.
Beta-cell dysfunction
Beta-cell dysfunction is a major factor across the spectrum of prediabetes to
diabetes. A study of obese adolescents by Bacha et al confirms what is
increasingly being stressed in adults as well: Beta-cell dysfunction develops
early in the pathologic process and does not necessarily follow the stage of
insulin resistance.[13] Singular focus on insulin resistance as the "be all and end
all" is gradually shifting, and hopefully better treatment options that address
the beta-cell pathology will emerge for early therapy.
Insulin resistance
In the progression from normal to abnormal glucose tolerance, postprandial
blood glucose levels increase first. Eventually, fasting hyperglycemia develops
as suppression of hepatic gluconeogenesis fails.
During the induction of insulin resistance (such as occurs with a high-calorie
diet, steroid administration, or physical inactivity), increased glucagon levels
and increased glucose-dependent insulinotropic polypeptide (GIP) levels
accompanyglucose intolerance. However, the postprandial glucagonlike
peptide-1 (GLP-1) response is unaltered. [14]
Genomic factors
Genome-wide association studies of single-nucleotide polymorphisms (SNPs)
have identified a number of genetic variants that are associated with beta-cell
function and insulin resistance. Some of these SNPs appear to increase the
risk for type 2 diabetes. Over 40 independent loci demonstrating an
association with an increased risk for type 2 diabetes have been shown. [15] A
subset of the most potent are shared below [16] :
Decreased beta-cell responsiveness, leading to impaired insulin
processing and decreased insulin secretion ( TCF7L2)
Lowered early glucose-stimulated insulin release ( MTNR1B, FADS1,
DGKB,GCK)
Altered metabolism of unsaturated fatty acids ( FSADS1)
Dysregulation of fat metabolism ( PPARG)
Inhibition of serum glucose release ( KCNJ11) [17]
Increased adiposity and insulin resistance ( FTO and IGF2BP2) [18, 19]
Control of the development of pancreatic structures, including beta-islet
cells (HHEX) [20]
Transport of zinc into the beta-islet cells, which influences the
production and secretion of insulin ( SLC30A8) [20]
Survival and function of beta-islet cells ( WFS1) [21]
Susceptibility to type 2 diabetes may also be affected by genetic variants
involving incretin hormones, which are released from endocrine cells in the
gut and stimulate insulin secretion in response to digestion of food. For
example, reduced beta-cell function has been associated with a variant in the
gene that codes for the receptor of gastric inhibitory polypeptide (GIPR). [22]
The high mobility group A1 (HMGA1) protein is a key regulator of the insulin
receptor gene (INSR). [23] Functional variants of the HMGA1 gene are
associated with an increased risk of diabetes.
Amino acid metabolism
Amino acid metabolism may play a key role early in the development of type 2
diabetes. Wang et al reported that the risk of future diabetes was at least 4-
fold higher in normoglycemic individuals with high fasting plasma
concentrations of 3 amino acids (isoleucine, phenylalanine, and tyrosine).
Concentrations of these amino acids were elevated up to 12 years prior to the
onset of diabetes. [24] In this study, amino acids, amines, and other polar
metabolites were profiled using liquid chromatography tandem mass
spectrometry.
Diabetes complications
Although the pathophysiology of the disease differs between the types of
diabetes, most of the complications, including microvascular, macrovascular,
and neuropathic, are similar regardless of the type of diabetes. Hyperglycemia
appears to be the determinant of microvascular and metabolic complications.
Macrovascular disease may be less related to glycemia.
Telomere attrition may be a marker associated with presence and the number
of diabetic complications. Whether it is a cause or a consequence of diabetes
remains to be seen. [25]
Cardiovascular risk
Cardiovascular risk in people with diabetes is related in part to insulin
resistance, with the following concomitant lipid abnormalities:
Elevated levels of small, dense low-density lipoprotein (LDL) cholesterol
particles
Low levels of high-density lipoprotein (HDL) cholesterol
Elevated levels of triglyceride-rich remnant lipoproteins
Thrombotic abnormalities (ie, elevated type-1 plasminogen activator inhibitor
[PAI-1], elevated fibrinogen) and hypertension are also involved. Other
conventional atherosclerotic risk factors (eg, family history, smoking, elevated
LDL cholesterol) also affect cardiovascular risk.
Insulin resistance is associated with increased lipid accumulation in liver and
smooth muscle, but not with increased myocardial lipid
accumulation. [26] Persistent lipid abnormalities remain in patients with diabetes
despite the use of lipid-modifying drugs, although evidence supports the
benefits of these drugs. Statin dose up-titration and the addition of other lipid-
modifying agents are needed. [27]
Increased cardiovascular risk appears to begin prior to the development of
frank hyperglycemia, presumably because of the effects of insulin resistance.
Stern in 1996 [28] and Haffner and D'Agostino in 1999 [29] developed the "ticking
clock" hypothesis of complications, asserting that the clock starts ticking for
microvascular risk at the onset of hyperglycemia, while the clock starts ticking
for macrovascular risk at some antecedent point, presumably with the onset of
insulin resistance.
The question of when diabetes becomes a cardiovascular risk equivalent has
not yet been settled. Debate has moved beyond automatically considering
diabetes a cardiovascular risk equivalent. Perhaps it would be prudent to
assume the equivalency with diabetes that is more than 5-10 years in
duration.
Cognitive decline
In a cross-sectional study of 350 patients aged 55 years and older with type 2
diabetes and 363 control participants aged 60 years and older without
diabetes, diabetic individuals were more likely to have brain atrophy than
cerebrovascular lesions, with patterns resembling those of preclinical
Alzheimer disease. [30, 31] Type 2 diabetes was associated with hippocampal
atrophy; temporal, frontal, and limbic gray-matter atrophy; and, to a lesser
extent, frontal and temporal white-matter atrophy.
Type 2 diabetes was also linked with poorer performance on certain cognitive
tests. The strength of these associations dropped by almost 50% when
adjusted for hippocampal and total gray-matter volumes but was unchanged
when adjusted for cerebrovascular lesions or white-matter
volume. [30, 31] Patients with type 2 diabetes were more likely to have gray-
matter atrophy in several bilateral regions of the cortices, especially in the left
hemisphere, similar to the distribution of cortical atrophy described in early
Alzheimer disease. [30]
In a 40-month study of 2977 middle-aged and older adults with long-standing
type 2 diabetes, depression at baseline was associated with accelerated
cognitive decline. [32, 33] The 531 subjects with scores of 10 or higher on the
Patient Health Questionnaire Depression Scale at baseline had significantly
lower scores on the Digit Symbol Substitution Test (DSST), the Rey Auditory
Verbal Learning Test (RAVLT), and the modified Stroop test. Adjustment for
other risk factors did not affect the association.
Secondary diabetes
Various other types of diabetes, previously called secondary diabetes, are
caused by other illnesses or medications. Depending on the primary process
involved (eg, destruction of pancreatic beta cells or development of peripheral
insulin resistance), these types of diabetes behave similarly to type 1 or type 2
diabetes.
The most common causes of secondary diabetes are as follows:
Diseases of the pancreas that destroy the pancreatic beta cells (eg,
hemochromatosis, pancreatitis, cystic fibrosis, pancreatic cancer)
Hormonal syndromes that interfere with insulin secretion (eg,
pheochromocytoma)
Hormonal syndromes that cause peripheral insulin resistance (eg,
acromegaly, Cushing syndrome, pheochromocytoma)
Drugs (eg, phenytoin, glucocorticoids, estrogens)
Gestational diabetes
Gestational diabetes mellitus is defined as any degree of glucose intolerance
with onset or first recognition during pregnancy (see Diabetes Mellitus and
Pregnancy). Gestational diabetes mellitus is a complication of approximately
4% of all pregnancies in the United States. A steady decline in insulin
sensitivity as gestation progresses is a normal feature of pregnancy;
gestational diabetes mellitus results when maternal insulin secretion cannot
increase sufficiently to counteract the decrease in insulin sensitivity.
Etiology
The etiology of type 2 diabetes mellitus appears to involve complex
interactions between environmental and genetic factors. Presumably, the
disease develops when a diabetogenic lifestyle (ie, excessive caloric intake,
inadequate caloric expenditure, obesity) is superimposed on a susceptible
genotype.
The body mass index (BMI) at which excess weight increases risk for diabetes
varies with different racial groups. For example, compared with persons of
European ancestry, persons of Asian ancestry are at increased risk for
diabetes at lower levels of overweight. [34] Hypertension and prehypertension
are associated with a greater risk of developing diabetes in whites than in
African Americans. [35]
In addition, an in utero environment resulting in low birth weight may
predispose some individuals to develop type 2 diabetes mellitus. [36, 37, 38] Infant
weight velocity has a small, indirect effect on adult insulin resistance, and this
is primarily mediated through its effect on BMI and waist circumference. [39]
About 90% of patients who develop type 2 diabetes mellitus are obese.
However, a large, population-based, prospective study has shown that an
energy-dense diet may be a risk factor for the development of diabetes that is
independent of baseline obesity. [40]
Some studies suggest that environmental pollutants may play a role in the
development and progression of type 2 diabetes mellitus. [41] A structured and
planned platform is needed to fully explore the diabetes-inducing potential of
environmental pollutants.
Secondary diabetes may occur in patients taking glucocorticoids or when
patients have conditions that antagonize the actions of insulin (eg, Cushing
syndrome, acromegaly, pheochromocytoma).
Major risk factors
The major risk factors for type 2 diabetes mellitus are the following:
Age greater than 45 years (though, as noted above, type 2 diabetes
mellitus is occurring with increasing frequency in young individuals)
Weight greater than 120% of desirable body weight
Family history of type 2 diabetes in a first-degree relative (eg, parent or
sibling)
Hispanic, Native American, African American, Asian American, or Pacific
Islander descent
History of previous impaired glucose tolerance (IGT) or impaired fasting
glucose (IFG)
Hypertension (>140/90 mm Hg) or dyslipidemia (HDL cholesterol level <
40 mg/dL or triglyceride level >150 mg/dL)
History of gestational diabetes mellitus or of delivering a baby with a
birth weight of over 9 lb
Polycystic ovarian syndrome (which results in insulin resistance)
Genetic influences
The genetics of type 2 diabetes are complex and not completely understood.
Evidence supports the involvement of multiple genes in pancreatic beta-cell
failure and insulin resistance.
Genome-wide association studies have identified dozens of common genetic
variants associated with increased risk for type 2 diabetes. [16] Of the variants
thus far discovered, the one with the strongest effect on susceptibility is the
transcription factor 7like 2 (TCF7L2) gene. (For more information, see Type 2
Diabetes and TCF7L2.)
Identified genetic variants account for only about 10% of the heritable
component of most type 2 diabetes. [16] An international research consortium
found that use of a 40-SNP genetic risk score improves the ability to make an
approximate 8-year risk prediction for diabetes beyond that which is
achievable when only common clinical diabetes risk factors are used.
Moreover, the predictive ability is better in younger persons (in whom early
preventive strategies could delay diabetes onset) than in those older than 50
years. [42]
Some forms of diabetes have a clear association with genetic defects. The
syndrome historically known as maturity onset diabetes of youth (MODY),
which is now understood to be a variety of defects in beta-cell function,
accounts for 2-5% of individuals with type 2 diabetes who present at a young
age and have mild disease. The trait is autosomal dominant and can be
screened for through commercial laboratories.
To date, 11 MODY subtypes have been identified, involving mutations in the
following genes [43, 44] :
HNF-4-alpha
Glucokinase gene
HNF-1-alpha
IPF-1
HNF-1-beta
NEUROD1
KLF11 [45]
CEL [46]
PAX4 [47]
INS
BLK [48]
Most of the MODY subtypes are associated with diabetes only; however,
MODY type 5 is known to be associated with renal cysts, [49] and MODY type 8
is associated with exocrine pancreatic dysfunction. [46]
A number of variants in mitochondrial deoxyribonucleic acid (DNA) have been
proposed as an etiologic factor for a small percentage of patients with type 2
diabetes. Two specific point mutations and some deletions and duplications in
the mitochondrial genome can cause type 2 diabetes and sensorineural
hearing loss.[50]
Diabetes can also be a finding in more severe mitochondrial disorders such as
Kearns-Sayre syndrome and mitochondrial encephalomyopathy, lactic
acidosis, and strokelike episode (MELAS). Mitochondrial forms of diabetes
mellitus should be considered when diabetes occurs in conjunction with
hearing loss, myopathy, seizure disorder, strokelike episodes, retinitis
pigmentosa, external ophthalmoplegia, or cataracts. These findings are of
particular significance if there is evidence of maternal inheritance.
A meta-analysis of two studies indicated that a genetically associated low birth
weight increases an individuals risk for developing type 2 diabetes. The report
found that for each one-point increase in an individuals genetic risk score for
low birth weight, the type 2 diabetes risk rose by 6%. [51, 52]
Depression
Accumulating evidence suggests that depression is a significant risk factor for
developing type 2 diabetes. Pan et al found that the relative risk was 1.17 in
women with depressed mood and 1.25 in women using
antidepressants. [53] Antidepressant use may be a marker of more severe,
chronic, or recurrent depression, or antidepressant use itself may increase
diabetes risk, possibly by altering glucose homeostasis or promoting weight
gain.
In turn, type 2 diabetes has been identified as a risk factor for the
development of depression. Depressive symptoms and major depressive
disorder are twice as prevalent in patients with type 2 diabetes as in the
general population. [54]
Schizophrenia
Schizophrenia has been linked to the risk for type 2 diabetes. Dysfunctional
signaling involving protein kinase B (Akt) is a possible mechanism for
schizophrenia; moreover, acquired Akt defects are associated with impaired
regulation of blood glucose and diabetes, which is overrepresented in first-
episode, medication-naive patients with schizophrenia. [55] In addition, second-
generation antipsychotics are associated with greater risk for type-2 diabetes.
Preeclampsia and gestational hypertension
A population-based, retrospective cohort study of 1,010,068 pregnant women
examined the association between preeclampsia and gestational hypertension
during pregnancy and the risk of developing diabetes post partum. Results
showed the incidence rate of diabetes per 1000 person-years was 6.47 for
women with preeclampsia and 5.26 for those with gestational hypertension,
compared with 2.81 in women with neither condition. Risk was further
elevated in women with preeclampsia or gesntational hypertension comorbid
with gestational diabetes. [56]
Epidemiology
Occurrence in the United States
A 2011 Centers for Disease Control and Prevention (CDC) report estimated
that nearly 26 million Americans have diabetes. [11] Additionally, an estimated
79 million Americans have prediabetes.
Diabetes affects 8.3% of Americans of all ages, 11.3% of adults aged 20 years
and older, and 25% of persons age 65 and older, according to the National
Diabetes Fact Sheet for 2011. [11] About 27% of those with diabetes7 million
Americansdo not know that they have the disease. About 215,000 people
younger than 20 years had diabetes (type 1 or type 2) in the United States in
2010. [11]
In 2014, the CDC reported that about 40% of US adults will develop diabetes,
primarily type 2, in their lifetime, and more than 50% of ethnic minorities will
be affected. This is substantially higher than previous estimates. The central
reason for the increase is obesity. [57, 58]
Prediabetes affects 35% of adults aged 20 years and older. Prediabetes, as
defined by the American Diabetes Association, is that state in which blood
glucose levels are higher than normal but not high enough to be diagnosed as
diabetes. It is presumed that most persons with prediabetes will subsequently
progress to diabetes. The CDC estimated that in 2010, 79 million Americans
aged 20 years or older had prediabetes35% of US adults aged 20 years or
older and 50% of those aged 65 years or older.
A study by Ludwig et al found that neighborhoods with high levels of poverty
are associated with increases in the incidence of extreme obesity and
diabetes. Although the mechanisms behind this association is unclear, further
investigation is warranted. [59]
International occurrence
Type 2 diabetes mellitus is less common in non-Western countries where the
diet contains fewer calories and daily caloric expenditure is higher. However,
as people in these countries adopt Western lifestyles, weight gain and type 2
diabetes mellitus are becoming virtually epidemic.
Rates of diabetes are increasing worldwide. The International Diabetes
Federation predicts that the number of people living with diabetes will to rise
from 366 million in 2011 to 552 million by 2030. [60] In the United States, the
prevalence of diagnosed diabetes has more than doubled in the last 3
decades, largely because of the increase in obesity.
The top 10 countries in number of people with diabetes are currently India,
China, the United States, Indonesia, Japan, Pakistan, Russia, Brazil, Italy, and
Bangladesh. The greatest percentage increase in rates of diabetes will occur
in Africa over the next 20 years. Unfortunately, at least 80% of people in Africa
with diabetes are undiagnosed, and many in their 30s to 60s will die from
diabetes there.
Race-related demographics
The prevalence of type 2 diabetes mellitus varies widely among various racial
and ethnic groups. The image below shows data for various populations. Type
2 diabetes mellitus is more prevalent among Hispanics, Native Americans,
African Americans, and Asians/Pacific Islanders than in non-Hispanic whites.
Indeed, the disease is becoming virtually pandemic in some groups of Native
Americans and Hispanic people. The risk of retinopathy and nephropathy
appears to be greater in blacks, Native Americans, and Hispanics.

Prevalence of type 2 diabetes

mellitus in various racial and ethnic groups in the United States (2007-2009
data).
View Media Gallery
In a study by Selvin et al, differences between blacks and whites were noted
in many glycemic markers and not just the hemoglobin A1c (HbA1c)
level. [61] This suggests real differences in glycemia, rather than in the
hemoglobin glycation process or erythrocyte turnover, between blacks and
whites.
Age-related demographics
Type 2 diabetes mellitus occurs most commonly in adults aged 40 years or
older, and the prevalence of the disease increases with advancing age.
Indeed, the aging of the population is one reason that type 2 diabetes mellitus
is becoming increasingly common. Virtually all cases of diabetes mellitus in
older individuals are type 2.
In addition, however, the incidence of type 2 diabetes is increasing more
rapidly in adolescents and young adults than in other age groups. The disease
is being recognized increasingly in younger persons, particularly in highly
susceptible racial and ethnic groups and the obese. In some areas, more type
2 than type 1 diabetes mellitus is being diagnosed in prepubertal children,
teenagers, and young adults. The prevalence of diabetes mellitus by age is
shown in the image below.
 Prevalence of diabetes
mellitus type 2 by age in the United States (2007 estimates).
View Media Gallery
Prognosis
The prognosis in patients with diabetes mellitus is strongly influenced by the
degree of control of their disease. Chronic hyperglycemia is associated with
an increased risk of microvascular complications, as shown in the Diabetes
Control and Complications Trial (DCCT) in individuals with type 1
diabetes [62, 63] and the United Kingdom Prospective Diabetes Study (UKPDS)
in people with type 2 diabetes. [64]
Reversion to normal glucose regulation during attempts to prevent
progression of pre-diabetes to frank diabetes is a good indicator of slowing
disease progression, and it is associated with a better prognosis. [65]
Prognosis in intensive therapy
In the UKPDS, more than 5000 patients with type 2 diabetes were followed up
for up to 15 years. Those in the intensely treated group had a significantly
lower rate of progression of microvascular complications than did patients
receiving standard care. Rates of macrovascular disease were not altered
except in the metformin-monotherapy arm in obese individuals, in which the
risk of myocardial infarction was significantly decreased.
In the 10-year follow-up to the UKPDS, patients in the previously intensively
treated group demonstrated a continued reduction in microvascular and all-
cause mortality, as well as in cardiovascular events, despite early loss of
differences in glycated hemoglobin levels between the intensive-therapy and
conventional-therapy groups.[66] The total follow-up was 20 years, half while in
the study and half after the study ended.
Other, shorter studies, such as Action in Diabetes and Vascular Disease:
Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE)
and the Veterans Affairs Diabetes Trial (VADT), showed no improvement in
cardiovascular disease and death with tight control (lower targets than in the
UKPDS). [67, 68, 69]
In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study,
increased mortality was noted among the poorly-controlled patients in the
intensive glycemic arm; indeed there was a 66% increase in mortality for each
1% increase in HbA1c; the best outcome occurred among patients who
achieved the target of an HbA1c of less than 6%. The excess mortality
between the intensive and conventional glycemic arms occurred for A1c
above 7%.
Differences between the patient populations in these studies and the UKPDS
may account for some of the differences in outcome. The patients in these 3
studies had established diabetes and had a prior cardiovascular disease
event or were at high risk for a cardiovascular disease event, whereas
patients in the UKPDS study were younger, with new-onset diabetes and low
rates of cardiovascular disease.
Early, intensive, multifactorial (blood pressure, cholesterol) management in
patients with type 2 diabetes mellitus was associated with a small,
nonsignificant reduction in the incidence of cardiovascular disease events and
death in a multinational European study. [70] The 3057 patients in this study had
diabetes detected by screening and were randomized to receive either
standard diabetes care or intensive management of hyperglycemia (target
HbA1c < 7.0%), blood pressure, and cholesterol levels.
The benefits of intensive intervention were demonstrated in the Steno-2 study
in Denmark, which included 160 patients with type 2 diabetes and persistent
microalbuminuria; the mean treatment period was 7.8 years, followed by an
observational period for a mean of 5.5 years. Intensive therapy was
associated with a lower risk of cardiovascular events, death from
cardiovascular causes, progression to end-stage renal disease, and need for
retinal photocoagulation. [71]
A British study indicated that the HbA1c level achieved 3 months after the
initial diagnosis of type 2 diabetes mellitus predicts subsequent mortality. In
other words, according to the report, aggressive lowering of glucose after
diagnosis bodes well for long-term survival. (Intensified diabetes control must
be introduced gradually in newly diagnosed patients.) [72]
Another study, a review of randomized clinical trials, showed that intensive
glycemic control reduces the risk of microvascular complications, but at the
expense of increased risk of hypoglycemia. All-cause mortality and
cardiovascular mortality in the study did not differ significantly with intensive
versus conventional glycemic control; however, trials conducted in usual-care
settings showed a reduction in the risk of nonfatal myocardial infarction. [73]
Overall, these studies suggest that tight glycemic control (HbA1c < 7% or
lower) is valuable for microvascular and macrovascular disease risk reduction
in patients with recent-onset disease, no known cardiovascular diseases, and
a longer life expectancy. In patients with known cardiovascular disease, a
longer duration of diabetes (15 or more years), and a shorter life expectancy,
however, tighter glycemic control is not as beneficial, particularly with regard
to cardiovascular disease risk. Episodes of severe hypoglycemia may be
particularly harmful in older individuals with poorer glycemic control and
existing cardiovascular disease.
Vascular disease considerations
One prospective study with a long follow-up challenges the concept of
coronary disease risk equivalency between nondiabetic patients with a first
myocardial infarction and patients with type 2 diabetes but without any
cardiovascular disease. The study found that patients with type 2 diabetes
had lower long-term cardiovascular risk compared with patients with first
myocardial infarction. Other studies have similarly questioned this risk
equivalency. [74]
Patients with diabetes have a lifelong challenge to achieve and maintain blood
glucose levels as close to the reference range as possible. With appropriate
glycemic control, the risk of microvascular and neuropathic complications is
decreased markedly. In addition, if hypertension and hyperlipidemia are
treated aggressively, the risk of macrovascular complications decreases as
well.
These benefits are weighed against the risk of hypoglycemia and the short-
term costs of providing high-quality preventive care. Studies have shown cost
savings due to a reduction in acute diabetes-related complications within 1-3
years after starting effective preventive care. Some studies suggest that
broad-based focus on treatment (eg, glycemia, nutrition, exercise, lipids,
hypertension, smoking cessation) is much more likely to reduce the burden of
excess microvascular and macrovascular events.
Yamasaki et al found that abnormal results on single-photon CT myocardial
perfusion imaging in asymptomatic patients with type 2 diabetes indicated a
higher risk for cardiovascular events (13%), including cardiac death. Smoking
and low glomerular filtration rate were significant contributing
factors. [75] However, an earlier study questioned the merit of routine screening
with adenosine-stress radionuclide myocardial perfusion imaging (MPI) in
otherwise asymptomatic type 2 diabetic patients (the Detection of Ischemia in
Asymptomatic Diabetics [DIAD] study). [76]
In both diabetic and nondiabetic patients, coronary vasodilator dysfunction is a
strong independent predictor of cardiac mortality. In diabetic patients without
coronary artery disease, those with impaired coronary flow reserve have event
rates similar to those with prior coronary artery disease, while patients with
preserved coronary flow reserve have event rates similar to nondiabetic
patients.[77]
Diabetes-associated mortality and morbidity
In 2009, diabetes mellitus was the seventh leading cause of death in the
United States. [78] In addition, diabetes is a contributing cause of death in many
cases, and it is probably underreported as a cause of death. Overall, the
death rate among people with diabetes is about twice that of people of similar
age but without diabetes. [11]
Diabetes mellitus causes morbidity and mortality because of its role in the
development of cardiovascular, renal, neuropathic, and retinal disease. These
complications, particularly cardiovascular disease (approximately 50-75% of
medical expenditures), are the major sources of expenses for patients with
diabetes mellitus.
The American Diabetes Association estimated that in 2007, direct medical
costs due to diabetes in the United States were $116 billion, with another $58
billion in indirect costs (eg, disability, work loss, premature mortality).
Approximately 1 in 5 health care dollars in the United States was spent caring
for someone with diagnosed diabetes, while 1 in 10 health care dollars was
attributed to diabetes. [79]
Diabetic retinopathy
Diabetes mellitus is the major cause of blindness in adults aged 20-74 years
in the United States; diabetic retinopathy accounts for 12,000-24,000 newly
blind persons every year. [80] The National Eye Institute estimates that laser
surgery and appropriate follow-up care can reduce the risk of blindness from
diabetic retinopathy by 90%. [80]
End-stage renal disease
Diabetes mellitus, and particularly type 2 diabetes mellitus, is the leading
contributor to end-stage renal disease (ESRD) in the United
States. [80] According to the Centers for Disease Control and Prevention,
diabetes accounts for 44% of new cases of ESRD. [11] In 2008, 48,374 people
with diabetes in the United States and Puerto Rico began renal replacement
therapy, and 202,290 people with diabetes were on dialysis or had received a
kidney transplant. [80]
Neuropathy and vasculopathy
Diabetes mellitus is the leading cause of nontraumatic lower limb amputations
in the United States, with a 15- to 40-fold increase in risk over that of the
nondiabetic population. In 2006, about 65,700 nontraumatic lower limb
amputations were performed related to neuropathy and vasculopathy. [80]
Cardiovascular disease
The risk for coronary heart disease (CHD) is 2-4 times greater in patients with
diabetes than in individuals without diabetes. Cardiovascular disease is the
major source of mortality in patients with type 2 diabetes mellitus.
Approximately two thirds of people with diabetes die of heart disease or
stroke. Men with diabetes face a 2-fold increased risk for CHD, and women
have a 3- to 4-fold increased risk.
Although type 2 diabetes mellitus, both early onset (< 60 y) and late onset
(>60 y), is associated with an increased risk of major CHD and mortality, only
the early onset type (duration >10 y) appears to be a CHD risk equivalent. [81]
In patients with type 2 diabetes mellitus, a fasting glucose level of more than
100 mg/dL significantly contributes to the risk of cardiovascular disease and
death, independent of other known risk factors. [82] This is based on a review of
97 prospective studies involving 820,900 patients.
Data from a large population-based study affirms that worsening glycemic
control appears to increase the risk of heart failure. [83]
Adolescents with obesity and obesity-related type 2 diabetes mellitus
demonstrate a decrease in diastolic dysfunction. [84] This suggests that they
may be at increased risk of progressing to early heart failure compared with
adolescents who are either lean or obese but do not have type 2 diabetes
mellitus.
Cancer
A 2010 Consensus Report from a panel of experts chosen jointly by the
American Diabetes Association and the American Cancer Society suggested
that people with type 2 diabetes are at an increased risk for many types of
cancer. [85] Patients with diabetes have a higher risk for bladder cancer,
particularly those patients who use pioglitazone. [86, 87] Age, male gender,
neuropathy, and urinary tract infections were associated with this risk.
In a meta-analysis of 20 publications comprising 13,008 cancer patients with
concurrent type 2 diabetes, researchers found that patients treated with
metformin had better overall and cancer-specific survival than those treated
with other types of glucose-lowering agents. [88, 89] These improvements were
observed across cancer subtypes and geographic locations. Risk reduction
was significant among patients with prostate, pancreatic, breast, colorectal
and other cancers, but not for those with lung cancer. However, it remains
unclear whether metformin can modulate clinical outcomes in cancer patients
with diabetes.
Pregnancy outcome
Untreated gestational diabetes mellitus can lead to fetal macrosomia,
hypoglycemia, hypocalcemia, and hyperbilirubinemia. In addition, mothers
with gestational diabetes mellitus have increased rates of cesarean delivery
and chronic hypertension.
Despite advanced age, multiparity, obesity, and social disadvantage, patients
with type 2 diabetes were found to have better glycemic control, fewer large-
for-gestational-age infants, fewer preterm deliveries, and fewer neonatal care
admissions compared with patients with type 1 diabetes. This suggests that
better tools are needed to improve glycemic control in patients with type 1
diabetes. [90](For more information, see Diabetes Mellitus and Pregnancy.)
Patient Education
No longer is it satisfactory to provide patients who have diabetes with brief
instructions and a few pamphlets and expect them to manage their disease
adequately. Instead, education of these patients should be an active and
concerted effort involving the physician, nutritionist, diabetes educator, and
other health professionals. Moreover, diabetes education needs to be a
lifetime exercise; believing that it can be accomplished in 1 or 2 encounters is
misguided.
A randomized, controlled trial found that for patients with poorly controlled
diabetes, individual attention and education is superior to group
education. [91]Similarly, a diabetes education and self-management group
program in the UK for newly diagnosed patients failed to yield significant
benefits. [92] Nonphysician health professionals are usually much more
proficient at diabetes education and have much more time for this very
important activity.
A systematic review suggested that patients with type 2 diabetes who have a
baseline HbA1c of greater than 8% may achieve better glycemic control when
given individual education rather than usual care. Outside that subgroup,
however, the report found no significant difference between usual care and
individual education. In addition, comparison of individual education with
group education showed equal impact on HbA1c at 12-18 months. [93]
Patient education is an immensely complex topic, however. The clinical
impression of most experts in the field is that there is merit in the provision of
careful diabetes education at all stages of the disease.

Background

According to the 2011 US Renal Data System (USRDS) data, in the year
2009, hypertensive nephrosclerosis (HN) accounted for 28% of patients
reaching end-stage renal disease (ESRD). The rate of ESRD attributed to
hypertension has grown 8.7% since the year 2000. [1] Hypertensive
nephrosclerosis is reportedly the second most common cause of ESRD in
white people (23%) and is the leading cause of ESRD in black people (46%).
The histologic effects of nephrosclerosis are demonstrated in the images
below.

Nephrosclerosis. The
glomerular tuft is shrunken, with wrinkling of the capillary walls (asterisk),
global glomerular sclerosis (arrow), and complete obliteration of the capillary
loops and glomerular ischemia (periodic acid-Schiff stain at 250X
magnification).

View Media Gallery

Nephrosclerosis. Glomerulus
with wrinkling of glomerular basement membranes accompanied by reduction
of capillary lumen diameter (silver stain at 400X magnification).

View Media Gallery

 Nephrosclerosis. Hyaline
arteriosclerosis with hyaline deposits (arrows) (trichrome stain at 250X
magnification).

View Media Gallery

Nephrosclerosis. Fibrointimal
proliferation of the arcuate artery (periodic acid-Schiff stain at 150X
magnification).

View Media Gallery

The term hypertensive nephrosclerosis has traditionally been used to describe

a clinical syndrome characterized by long-term essential hypertension,
hypertensiveretinopathy, left ventricular hypertrophy, minimal proteinuria, and
progressive renal insufficiency. Most cases are diagnosed based solely on
clinical findings. In fact, most of the literature dedicated to hypertensive
nephrosclerosis is based on the assumption that progressive renal failure in a
patient with long-standing hypertension, moderate proteinuria, and no
evidence suggesting an alternative diagnosis characterizes hypertensive
nephrosclerosis.

The lack of firm criteria on which to base a histologic diagnosis and the lack of
a clear demonstration that hypertension initiates the development of renal
failure likely indicate that the true prevalence of hypertensive nephrosclerosis
has been overestimated. The paradoxical results of increasing incidence of
renal failure despite wider antihypertensive drug therapy and reduction in
hypertensive target events, such as stroke and cardiovascular disease, raises
questions about the causal role of hypertension in this disorder.

As reported by Zuccal and Zucchelli (1996), part of the confusion in the

classification of hypertensive nephrosclerosis stems from the use of the word
nephrosclerosis. [2] Coined almost a century ago by Theodor Fahr,
nephrosclerosis literally means "hardening of the kidney." In the United States
and Europe, the terms hypertensive nephrosclerosis, benign nephrosclerosis,
and nephroangiosclerosis are commonly used to describe the same clinical
condition. These terms refer more to the renal pathologic changes attributed
to the effects ofhypertension than to the clinical disorder in
question. [3] Unfortunately, the pathologic changes are not specific to
hypertensive renal injury; they are also observed in kidney biopsy specimens
of patients who are normotensive, particularly those of advanced age or with
diabetes.

Unlike morbidity and mortality of stroke and coronary disease, incident cases
of ESRD attributed to hypertension continue to increase. Some authors
suggest that many of these cases are more likely related to other factors,
including small vessel injury related to aging, diabetes, or obesity -related
kidney injury.

A couple of important points have been made in different studies. First, among
an unselected sample of community-based participants in the Framingham
Heart Study, the combination of hypertension and a mild reduction in the
glomerular filtration rate (GFR) was found to be an important risk factor for the
development of new-onset kidney disease. Other factors noted were diabetes,
obesity, smoking, and a low high-density lipoprotein cholesterol level. Second,
systolic blood pressure (BP) is a strong, independent predictor of a decline in
kidney function among older persons with isolated systolic hypertension. This
is a significant finding because most cases of uncontrolled hypertension in the
United States are due to systolic hypertension among older adults.

Most patients reaching ESRD from any cause are hypertensive, with
nephrosclerosis being the classic finding in end-stage kidneys. Regardless of
the etiology, once hypertension develops, a cycle of renal injury,
nephrosclerosis, worsening of hypertension, and further renal injury is
established. As a result, in a patient presenting with ESRD, determining
whether nephrosclerosis is the cause or the consequence of chronic renal
injury may be difficult.

Pathophysiology

Two pathophysiologic mechanisms have been proposed for the development

of hypertensive nephrosclerosis. One mechanism suggests that glomerular
ischemia causes hypertensive nephrosclerosis. This occurs as a consequence
of chronic hypertension resulting in narrowing of preglomerular arteries and
arterioles, with a consequent reduction in glomerular blood flow. Alternatively,
glomerulosclerosis occurs because of glomerular hypertension and glomerular
hyperfiltration. According to this theory, hypertension causes some glomeruli
to become sclerotic. As an attempt to compensate for the loss of renal
function, the remaining nephrons undergo vasodilation of the preglomerular
arterioles and experience an increase in renal blood flow and glomerular
filtration. The result is glomerular hypertension, glomerular hyperfiltration, and
progressive glomerular sclerosis. These mechanisms are not mutually
exclusive, and they may operate simultaneously in the kidney.

Furthermore, Tracy and Ishii (2000) postulate that nephrosclerosis may not be
a single disease entity in the sense of responding to a single etiology, such as
hypertension or aging. [4] Rather, nephrosclerosis appears to be multifactorial.
It may be, in part, a consequence of fibroplasias in microscopic arteries
causing ischemic damage to some nephrons; however, it also may be the end
product of a mixture of converging separate pathologic conditions, ie, "second
hits," of which only some are known.
Genetically mediated animal models of hypertension, including the Dahl rat
and the spontaneous hypertensive rat (SHR), have been used to investigate
the role of hypertension in the development of nephrosclerosis. Fundamental
differences exist among the strains and between rat and human hypertension.
The SHR most closely resembles human essential hypertension. The SHR
becomes hypertensive without exposure to salt. Micropuncture studies in
hypertensive rats demonstrate an increased preglomerular vasoconstriction
that is effective in preventing the development of intraglomerular
hypertension. In fact, the SHR develops little renal damage, unless
uninephrectomized. In these animals, rigorous BP control does not prevent
the development of proteinuria and the pathologic changes of hypertensive
nephrosclerosis. The Dahl salt-sensitive rat develops proteinuria before
hypertension and before a high-sodium diet is administered.

In patients with primary hypertension, hemodynamic studies frequently show a

reduction in renal blood flow. The increased preglomerular vasoconstriction of
the afferent arteriole and interlobular artery is thought, at least initially, to exert
a protective effect in the glomerulus. With time, sclerosis of the preglomerular
vessels causes further reduction in renal blood flow. The GFR is maintained
because of increased intraglomerular pressure secondary to efferent arteriolar
vasoconstriction and systemic hypertension. Eventually, glomerular ischemia
and tubular ischemia develop. Considered together, these data suggest that
hypertension precedes and accelerates arteriolar changes in the renal
vessels.

Wang et al investigated whether podocyte injury is an important factor in the

pathogenesis of hypertensive nephrosclerosis. In a study involving 41 patients
with biopsy-proven hypertensive nephrosclerosis, 10 cadaveric kidney donors,
and 9 healthy subjects, the authors found that compared with controls,
intrarenal messenger ribonucleic acid (mRNA) expression was lower, and
urinary mRNA expression was higher, for the podocyte-associated molecules
nephrin, podocin, and synaptopodin in patients with hypertensive
nephrosclerosis. Moreover, patients with nephrosclerosis had a significantly
lower density of glomerular podocytes than did kidney donors (545 +/- 237 vs
773 +/- 296 per glomeruli, respectively; P < .02).[5, 6]

Genetics
A genetic link for hypertension and related renal failure is supported by studies
demonstrating familial clustering of hypertensive nephrosclerosis in black
people and, to some extent, in white people.

In the Multiple Risk Factor Intervention Trial (MRFIT), no changes in the

reciprocal creatinine slope were observed in white people, but a significant
loss in kidney function was observed in black people despite similar levels of
BP control. Similarly, secondary analyses from the Modification of Diet in
Renal Diseases (MDRD) study demonstrated that at equivalent mean arterial
pressures greater than 98 mm Hg, black patients had a reduction in their GFR
at a rate of approximately 1 mL/min/y more than white patients. These
observations have led to investigations into genetic factors predisposing to
renal damage.

In 2008, 2 separate groups showed strong association between genomic

variants within MYH9 (nonmuscle myosin heavy chain 9) on 22q and
nondiabetic ESRD in African Americans. [7, 8] The 2 other disease entities
associated with MYH9 included HIV nephropathy and focal segmental
glomerulosclerosis (FSGS) in African Americans.

In 2010, 2 other groups showed an even stronger association between

the APOL1gene and risk of ESRD in African Americans. [9, 10] APOL1, which
encodes apolipoprotein L1, is also on 22q and is separated from
the MYH9 gene by only 14000 nucleotides. Two variants of APOL1 that have
been associated with increased risk of nephropathy include nonsynonymous
coding variants termed G1 (glycine-342 to methionine-384) and in-frame 6bp
deletion termed G2. The ApoL1 protein protects
against Trypanosoma infection. However, the wild-type ApoL1 protein can be
neutralized by Trypanosoma brucei rhodesiense. These 2 gene variants
restore immunity to Trypanosoma brucei rhodesiense. As a result, genomic
evolution has led to positive selection for APOL1 risk variant.

More recent studies have further shown that nondiabetic carriers of

2 APOL1variants have a 3-times higher rate of proteinuria and reduced renal
function and carriers of 1 or 2 variants are significantly younger at the time of
initiation of dialysis.
The African American Study of Kidney disease (AASK) trial evaluated the role
of intensive versus standard BP control on progression of kidney disease in
1094 black patients with chronic kidney disease (GFR 20-65
mL/min/SA). [11] The study was done in a trial phase followed by a cohort
phase. Overall, no difference was noted in the rate of disease progression in
the 2 groups. In the subanalysis, in which patients were stratified based on the
degree of proteinuria, patients who had initial urinary protein-to-creatinine
ratios of less than 0.22 did not benefit from the intensive BP control, whereas
those with urinary protein-to-creatinine ratio of greater than 0.22 benefited
from the intensive therapy at the end of the cohort
phase. APOL1 and MYH9 nephropathy risk variants have been associated
with kidney disease in the AASK participants. [12]

This genetic predisposition may be the reason why tighter control of BP in this
black population does not slow the progression of kidney disease. Some
authors argue that hypertension in this setting is secondary to underlying renal
injury. [13]

In different populations studied regarding polymorphism in the angiotensin-

converting enzyme (ACE) gene, the DD genotype is associated with a higher
prevalence of progressive renal disease. This genotype is more common in
the black population than the white population. Black people with hypertension
also have increased angiotensinogen mutations compared with white people
with hypertension. Homozygous D polymorphism is associated with an
enhanced pressor response to angiotensin I. In patients with immunoglobulin
A nephropathy, homozygous D polymorphism appears to influence the rate of
progression of renal diseases and the response to ACE inhibitors; thus, ACE
polymorphism could be a modulator for the renal response to injury and the
response to treatment in persons with hypertensive nephrosclerosis. Whether
these data are also applicable to the black population remains to be
determined.

Noting that hypertension-associated ESRD displays familial aggregation in the

black population, Fung et al investigated possible links between genetic
variations and GFR declines. In a study of 554 black patients, the
investigators found evidence that such declines can be predicted by variations
in the adrenergic beta-1 (ADRB1) receptor at the Ser49Gly position. The
authors also found that GFR decline was significantly smaller in patients who
were Gly(49)/Gly(49) (minor allele) homozygotes than in those who were
Ser(49) carriers. [14]

Epidemiology

Frequency

United States

Over the last 2 decades, ESRD attributed to hypertensive nephrosclerosis has

contributed significantly to the increase in new patients starting dialysis in the
United States. According to the 2011 USRDS data, the rate of ESRD due to
hypertension has grown 8.7% since the year 2000, whereas the rate of ESRD
due to glomerulonephritis has fallen 23% and rate of ESRD secondary to
diabetes has remained relatively stable. When patients are separated
according to race, hypertension is the leading cause of ESRD in black people,
accounting for 34% of patients initiating dialysis during this period.

International

In Europe, according to the European Dialysis and Transplant

Association registry, hypertensive nephrosclerosis is a less common cause of
ESRD, accounting for 12% of new patients starting renal replacement therapy.
However, the reported incidence varies among different countries, with France
and Italy reporting hypertensive nephrosclerosis as being responsible for
ESRD in 25% and 17% of patients starting dialysis, respectively. Whereas in
United Kingdom (all countries included), it accounts for 6.1% of patients
starting new on dialysis. In Asia, hypertension appears to be a relatively
infrequent cause of ESRD, with both Japanese and Chinese registries
reporting 6% and 7%, respectively. Establishing whether these differences are
real or reflect differences in accuracy of diagnosis or criteria for diagnosis in
different countries is difficult.

Mortality/Morbidity
According to the 2011 USRDS, the annual mortality rate for patients on
hemodialysis in the United States is 23.3%. Hypertensive nephrosclerosis
accounts for more than one third of patients on hemodialysis.

Race

Marked differences exist in the stated prevalence of hypertensive

nephrosclerosis among patients of different ethnic backgrounds. Although
black people make up 12% of the US population, they account for 28.3% of
the patients on renal replacement therapy. With perhaps the exception of
atherosclerotic renal disease, black people are at an increased risk of renal
diseases from any cause, especially hypertensive nephrosclerosis. In black
people, hypertensive nephrosclerosis occurs earlier, is more severe, and more
often causes ESRD (36.8% in black patients vs 26% in white patients).

In persons of all age groups, ESRD is more common in black people; the rate
of developing ESRD is 3.5 times higher than the rate found among whites.
The increased susceptibility of black patients with hypertension to develop
progressive renal failure cannot be explained solely by the higher prevalence
of hypertension, severity of hypertension, or socioeconomic factors because
the rate of new ESRD cases has remained stable in African Americans,
whereas it has grown 7.2% among white, and, in addition, the rates of stroke
and cardiovascular mortality have decreased equally in both white and African
American populations.

Results from the MRFIT trial indicated that effective BP control was
associated with stable renal function in white people but not in black people.
In the AASK trial, which specifically evaluated black populations, intensive
control of BP in nonproteinuric patients did not decrease progression of kidney
disease.

Several renal, hormonal, physiologic, and genetic factors have been proposed
as explanations for the increased rate of hypertension and progression of
chronic kidney disease in African Americans. These include increased BP
sensitivity to high-salt diet, increased renal vascular resistance, decreased
renal blood flow, increased tortuosity and occlusion in the interlobular and
arcuate arteries based on renal angiograms in African Americans, and
decreased nephron mass secondary to low birth weight (more common in
African Americans). Lastly, the increased variant in APOL1 gene has been
proposed as the cause of the increased rate of ESRD in African Americans.

Age

The diagnosis of hypertensive nephrosclerosis increases with advancing age.

The peak age for the development of ESRD in white patients is 65 years and
older, while the peak age is 45-65 years in black people. In most cases, the
diagnosis of hypertensive nephrosclerosis in older patients is made clinically
because of the reluctance to perform a renal biopsy in this elderly
population. [15] Even when a renal biopsy specimen is available, distinguishing
vascular lesions due to aging from those due to hypertension may be difficult.
In this respect, atheromatous renal vascular disease has been increasingly
recognized as a common finding in patients older than 50 years.

Rimmer and Gennari (1993) estimate that atheromatous renal vascular

disease accounts for 5-15% of all patients who develop ESRD each year. [16] In
addition, cholesterol embolism resulting from atheromatous plaque disruption
with subsequent shedding of cholesterol crystals into the renal circulation is
frequently diagnosed in this patient population. Both renal artery stenosis and
cholesterol embolism are associated with renal microvascular lesions and with
glomerular sclerosis. Neither of these findings should be underestimated
because patients older than 65 years represent at least 45% of the total
population of patients on dialysis in the United States.

Similarly, Appel et al (1995) found bilateral renal artery stenoses in 11% of

patients on hemodialysis who are older than 50 years. [17] After extrapolating
their results to the total number of cases of ESRD, multiplying by the number
of patients aged 50 years or older, and multiplying by the number of patients
with ischemic renal disease, Appel et al concluded that more than 3500 cases
of ischemic renal disease remain undiagnosed each year in the United
States. [17] If these predictions are correct, ischemic renal disease is likely the
fourth most common cause of ESRD in patients older than 50 years.

Hansen et al (2002) provided the first population-based estimate of the

prevalence of renovascular disease among free-living elderly American
participants of the Cardiovascular Health Study (CHS). [18] This is a multicenter,
longitudinal cohort study of cardiovascular disease risk factors, morbidity, and
mortality among free-living adults older than 65 years. CHS participants
numbered 870, and each underwent renal duplex sonography to assess for
the presence or absence of renovascular disease, defined as greater than or
equal to 60% diameter-reducing renal artery stenosis or occlusion. The results
of this study show that renovascular disease is present in 6.8% of all
individuals, regardless of race (6.9% of white participants and 6.7% of black
participants).

Background

Pott disease, also known as tuberculous spondylitis, is one of the oldest

demonstrated diseases of humankind, having been documented in spinal
remains from the Iron Age in Europe and in ancient mummies from Egypt and
the Pacific coast of South America. [1, 2] In 1779, Percivall Pott, for whom the
disease is named, presented the classic description of spinal tuberculosis.
(See the image below.) [3]

MRI of a 31-year-old man with

tuberculosis of the spine. Images show the thoracic spine before and after an
infusion of intravenous gadolinium contrast. The abscess and subsequent
destruction of the T11-T12 disc interspace is marked with arrowheads.
Vertebral body alignment is normal. Courtesy of Mark C. Diamond, MD, and J.
Antonio Bouffard, MD, Detroit, Mich.

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Since the advent of antituberculous drugs and improved public health

measures, spinal tuberculosis has become rare in industrialized countries,
although it is still a significant cause of disease in developing nations.
Tuberculous involvement of the spine has the potential to cause serious
morbidity, including permanent neurologic deficits and severe deformities.
Medical treatment or combined medical and surgical strategies can control the
disease in most patients. [4, 5]

Patient education

Patients with Pott disease should be instructed on the importance of therapy

compliance. For patient education information, see the Infections Center, as
well asTuberculosis.

Pathophysiology

Pott disease is usually secondary to an extraspinal source of infection. Pott

disease manifests as a combination of osteomyelitis and arthritis that usually
involves more than 1 vertebra. The anterior aspect of the vertebral body
adjacent to the subchondral plate is usually affected. Tuberculosis may spread
from that area to adjacent intervertebral disks. In adults, disk disease is
secondary to the spread of infection from the vertebral body. In children, the
disk, because it is vascularized, can be the primary site. [6]

Progressive bone destruction leads to vertebral collapse and kyphosis. The

spinal canal can be narrowed by abscesses, granulation tissue, or direct dural
invasion, leading to spinal cord compression and neurologic deficits.

The kyphotic deformity is caused by collapse in the anterior spine. Lesions in

the thoracic spine are more likely to lead to kyphosis than those in the lumbar
spine. A cold abscess can occur if the infection extends to adjacent ligaments
and soft tissues. Abscesses in the lumbar region may descend down the
sheath of the psoas to the femoral trigone region and eventually erode into the
skin.

Epidemiology

Occurrence in the United States

Although the incidence of tuberculosis increased in the late 1980s to early

1990s, the total number of cases has decreased in recent years. The
frequency of extrapulmonary tuberculosis has remained stable.

Bone and soft-tissue tuberculosis accounts for approximately 10-15% of

extrapulmonary tuberculosis cases and between 1% and 2% of total cases.
Tuberculous spondylitis is the most common manifestation of musculoskeletal
tuberculosis, accounting for approximately 40-50% of cases. These figures
are roughly similar for North American and international series. [7, 8]

International occurrence

Approximately 1-2% of total tuberculosis cases are attributable to Pott

disease. In the Netherlands, between 1993 and 2001, tuberculosis of the bone
and joints accounted for 3.5% of all tuberculosis cases (0.2-1.1% in patients of
European origin, and 2.3-6.3% in patients of non-European origin). [9]

Race-, sex-, and age-related demographics

Data from Los Angeles and New York show that musculoskeletal tuberculosis
affects primarily African Americans, Hispanic Americans, Asian Americans,
and foreign-born individuals.

As with other forms of tuberculosis, the frequency of Pott Disease is related to

socioeconomic factors and historical exposure to the infection.

Although some series have found that Pott disease does not have a sexual
predilection, the disease is more common in males (male-to-female ratio of
1.5-2:1).
In the United States and other developed countries, Pott disease occurs
primarily in adults. In countries with higher rates of Pott disease, involvement
in young adults and older children predominates. [10, 11]

Prognosis

Current treatment modalities are highly effective against Pott disease if the
disorder is not complicated by severe deformity or established neurologic
deficit.

Deformity and motor deficit are the most serious consequences of Pott
disease and continue to be a serious problem when diagnosis is delayed or
presentation of the patient is in advanced stages of the disease. [12]

Therapy compliance and drug resistance are additional factors that

significantly affect individual outcomes.

Paraplegia resulting from cord compression caused by the active disease

usually responds well to chemotherapy. However, paraplegia can manifest or
persist during healing because of permanent spinal cord damage.

Operative decompression can greatly increase the recovery rate, offering a

means of treatment when medical therapy does not bring rapid improvement.

Careful long-term follow up is also recommended, since late-onset

complications can still occur (disease reactivation, late instability or
deformity). [13]

Morbidity

Pott disease is the most dangerous form of musculoskeletal tuberculosis

because it can cause bone destruction, deformity, and paraplegia.

Pott disease most commonly involves the thoracic and lumbosacral spine.
However, published series have shown some variation. [14, 15, 16, 17] The lower
thoracic vertebrae make up the most common area of involvement (40-50%),
followed closely by the lumbar spine (35-45%). In other series, proportions are
similar but favor lumbar spine involvement. [18] Approximately 10% of Pott
disease cases involve the cervical spine.

Internal Fixation for Fractures

A broken bone must be carefully stabilized and supported until it is strong enough to handle the body's weight and
movement. Until the last century, physicians relied on casts and splints to support and stabilize the bone from outside
the body. The advent of sterile surgical procedures reduced the risk of infection, allowing doctors to internally set and
stabilize fractured bones.

During a surgical procedure to set a fracture, the bone fragments are first repositioned (reduced) into their normal
alignment. They are held together with special implants, such as plates, screws, nails and wires.

Internal fixation allows shorter hospital stays, enables patients to return to function earlier, and reduces the incidence
of nonunion (improper healing) and malunion (healing in improper position) of broken bones.

The implants used for internal fixation are made from stainless steel and titanium, which are durable and strong. If a
joint is to be replaced, rather than fixed, these implants can also be made of cobalt and chrome. Implants are
compatible with the body and rarely cause an allergic reaction.

Plates
Plates are like internal splints that hold the broken pieces of bone together. They are attached to the bone with
screws. Plates may be left in place after healing is complete, or they may be removed (in select cases).

Top of page
Screws
Screws are used for internal fixation more often than any other type of implant. Although the screw is a simple device,
there are different designs based on the type of fracture and how the screw will be used. Screws come in different
sizes for use with bones of different sizes. Screws can be used alone to hold a fracture, as well as with plates, rods,
or nails. After the bone heals, screws may be either left in place or removed.

Top of page
Nails or Rods
In some fractures of the long bones the best way to hold the bone pieces together is by inserting a rod or nail through
the hollow center of the bone that normally contains some marrow. Screws at each end of the rod are used to keep
the fracture from shortening or rotating, and also hold the rod in place until the fracture has healed. Rods and screws
may be left in the bone after healing is complete. This is the method used to treat the majority of fractures in the
femur (thighbone) and tibia (shinbone).
(Left) This x-ray shows a healed thighbone fracture treated with intramedullary nailing. (Right) In this x-ray, the thighbone
fracture has been treated with plates and screws.
Top of page
Wires/Pins
Wires are often used to pin the bones back together. They are often used to hold together pieces of bone that are too
small to be fixed with screws. In many cases, they are used in conjunction with other forms of internal fixation, but
they can be used alone to treat fractures of small bones, such as those found in the hand or foot. Wires are usually
removed after a certain amount of time, but may be left in permanently for some fractures.

Top of page
External Fixators
An external fixator acts as a stabilizing frame to hold the broken bones in proper position. In an external fixator, metal
pins or screws are placed into the bone through small incisions into the skin and muscle. The pins and screws are
attached to a bar outside the skin. Because pins are inserted into bone, external fixators differ from casts and splints
which rely solely on external support.

In many cases, external fixation is used as a temporary treatment for fractures. Because they are easily applied,
external fixators are often put on when a patient has multiple injuries and is not yet ready for a longer surgery to fix
the fracture. An external fixator provides good, temporary stability until the patient is healthy enough for the final
surgery.

Other times, an external fixator can be used as the device to stabilize the bone until healing is complete.

There may be some inflammation or, less commonly, infection associated with the use of external fixators. This is
typically managed with wound care and/or oral antibiotics.
External fixation is often used to hold the bones together temporarily when the skin and muscles have been injured.
Top of page
Other Considerations
Sterile conditions and advances in surgical techniques reduce, but do not remove, the risk of infection when internal
fixation is used. The severity of the fracture, its location, and the medical status of the patient must all be considered.

In addition, no technique is foolproof. The fracture may not heal properly or the plate or rod may break or deform.
Although some media attention has focused on the possibility that cancer could develop near a long-term implant,
there is little evidence documenting an actual cancer risk and much evidence against that possibility. Orthopaedic
surgeons are continuing their research to develop improved methods for treating fractures.

Top of page

External Fixation
External Fixation of Lower Leg

External fixationof the lower leg is a surgical procedure to externally immobilise and fix a
bone following a fracture allowing the bone to heal effectively. Physiotherapy after external
fixation surgery is essential to mobilise and return function in the lower leg.

The bones in the lower leg include the tibia (shin bone) and the fibula (smaller long bone). A
fracture of the lower leg can affect the shaft of one or both of the bones in the lower leg.
Fractures of the tibia / fibula are mainly caused by either a direct blow to the lower leg or by
a twisting force when the foot is fixed. There are many different types and severity of
fractures. The various severities of fractures to the lower leg include:

Non-displaced (bones are still in position)

Displaced (out of position)

Closed fractures (where the skin is not broken by the fracture fragments)

Open fractures (where the fracture fragments have broken through the skin)

The skin and tissues that cover the front of the tibia and fibula are very thin and as a result
of this, a significant number of fractures to the lower leg are displaced, open fractures.

The main symptoms that follow a fracture to the lower leg include severe pain and reduced
mobility as the leg will be extremely painful and difficult to move. With fractures of the lower
leg there will be deformity at the site of the fracture, especially with open fractures. As a
result of the large amount of tissue damage and loss of blood at the fracture site, there will
also be a considerable amount of swelling and discolouration.

Treatment of lower leg fractures can vary depending on the severity of the fracture. If the
bone is still in its correct alignment (non-displaced) then immobilisation with use of a splint
or cast followed by physiotherapy is recommended. If the fracture is out of position
(displaced) but the skin is still intact (closed fracture) then ORIF of the lower leg (open
reduction internal fixation) is required.

In severe cases, external fixation surgery is necessary. External fixation surgery is a method
of holding together the fragments of a fractured bone by using transfixing metal pins through
the fragments and a compression device attached to the pins outside the skin surface. The
main indications for the use of external fixation surgery are in cases where there has been a
displaced, open fracture (the bone is out of position and has broken through the skin). Also
external fixation is indicated when there is high risk of infection, considerable bone loss at
the fracture site, and when other methods such as ORIF of the lower leg are inappropriate.
Common types of external fixation used in the treatment of a lower leg fracture include X-
Fix and Llizarov.

External fixation is a procedure that sets and immobilises the fractured bone in its correct
alignment so as to enable and facilitate adequate healing of the lower leg. The method
provides rigid fixation of the bones outside the body (external) in cases where other forms of
immobilizationare inappropriate. External fixation is performed in an operating room,
normally under general anaesthesia. During external fixation small holes are drilled into
uninjured areas of bones around the fracture and special bolts or wires are screwed into the
holes. Outside the body, a rod or a curved piece of metal with special ball-and-socket joints
joins the bolts to make a rigid support. The fracture can be set in the proper anatomical
configuration by adjusting the ball-and-socket joints. After the rods are fixed, regular
cleaning where the pins have been insertedmust be performed to prevent infection at the
site of surgery.In most cases it may be necessary for the external fixator to be in place for
many weeks or even months. Most fractures of the lower leg heal from between 6 and 12
weeks. After this time the external fixators are removed using specialised wrenches and can
be removed without any anaesthesia.

Once the external fixator has been removed, it is imperative to undergo a comprehensive
and prolonged course of physiotherapy to maximise the success of the procedure and to
help ensure the return of full or near to full function in the lower leg post fracture.

Symptoms after External Fixation of the Lower Leg

During the months you have external fixators inserted into your lower leg you will be given
elbow crutches to provide protection, support and independence. You will experience pain in
the area of insertion along with abnormal sensations. You will be given medication to control
for pain, reduce swelling and prevent infection. The pin sites can be a source of infection
therefore you will be shown by hospital staff how to carry out effective wound care and you
may have to return to the hospital for regular check ups during s period.

After you have had the external fixators removed, you will experience pain, swelling and
stiffness in and around the fracture site. You will have decreased range of movement,
strength and muscle control in your lower leg as a result of the surgery and prolonged
immobilisation. You will be non-weight bearing initially with progression to full weight bearing
being encouraged as soon as possible. A comprehensive physiotherapy programme with
Physio.co.uk should be initiated as soon as possible after the external fixators have been
removed to regain mobility as well as full or near to full function in your lower leg. You will
not be able to drive until you have full and painless function in your affected leg.
Physiotherapy after External Fixation of the Lower Leg

Physiotherapy can begin immediately after you have had external fixation of your lower leg
to help reduce pain, swelling and stiffness. It is encouraged to begin physiotherapy as soon
as possible as this will help you regain mobility and improve range of movement and
strength in your affected leg. Physio.co.uk offers a comprehensive physiotherapy course
that will maximise the success of the surgery, prevent any problems occurring and ensure
the return of full or near to full function in your lower leg. Rehabilitation can take up to 6
months after you have had ORIF surgery to your lower leg. The main goals of your
rehabilitation with Physio.co.uk include:

To restore a pain free lower leg

To restore full range of motion (ROM)

To restore full muscle strength

To restore full muscle length and flexibility

To improve cardiovascular fitness and muscle endurance

To re-establish independence

0-4 weeks

The main goals of your physiotherapy programme in the first month after undergoing
external fixation will be to reduce pain and swelling in your lower leg. Your physiotherapy
programme with Physio.co.uk will aim to gradually introduce you back to gentle activity.
Physio.co.uk will focus on maintaining the range of movement and strength in your affected
and unaffected leg. Additionally, your physiotherapy will include activities that aim to
progress your ability to weight bear as soon as possible. Your rehabilitation will include:

Pain killers (to control pain)

 Elevation (to control swelling)

Crutch training

Non weight bearing activities progressed to partial weight bearing activities

Passive (assisted) range of movement exercises for affected leg (knee, ankle etc)

Strengthening and range of movement exercises for unaffected leg

Upper limb activities

5-8 weeks

During the second month of your rehabilitation with Physio.co.uk your physiotherapy will
focus on the continuation and progression of activities from previous weeks. Your
physiotherapy programme with Physio.co.uk will continue to focus on controlling pain and
swelling. Physio.co.uk will also continue to focus on improving range of movement nd
flexibility along with increasing muscle strength and control. Your physiotherapy will include:

Continuation of modalities for pain and swelling

Passive (assisted) and active (independent) range of movement exercises

Strengthening exercises for muscles of affected leg (calf, hamstring, quadriceps etc)

Stretching exercises for muscles of affected leg (calf, hamstring, quadricep etc)

Range of movement, strengthening and stretching exercises for unaffected leg

Progression of weight bearing full weight bearing activities if possible

Gait re-education training

Proprioception and balance training

Hip and ankle exercises

 Hydrotherapy

Static bicycle

9-12 weeks

After 2 months of physiotherapy, your rehabilitation your physiotherapy programme will

continue to focus on the progression from previous weeks. The main goals of your
physiotherapy programme with Physio.co.uk will aim to minimise pain, improve range of
movement and increase strength. Once your ability to weight bear has improved, your
physiotherapy programme will now focus on gait re-training (walking) and improving
proprioception (balance) in your lower leg. At this stage, your physiotherapy will also begin
to include activities that will improve your cardiovascular fitness and muscle endurance.
Your physiotherapy will include:

Pain control

Gait training (walking)

Proprioception training (balance)

Range of movement exercises

Flexibility exercises

Strengthening exercises for muscles in affected and unaffected leg (calf, hamstring,
quadriceps, tibialis anterior etc)

Hydrotherapy

Static bicycle

3-6 months
Following three months of successful rehabilitation with Physio.co.uk you will have seen
marked improvements in the function of your lower leg and you will be experiencing minimal
if no pain and swelling. After 12 weeks, the external pins will have been surgically removed
and you will now be fully weight bearing. The main goals of your physiotherapy will continue
to focus on the progression of exercises from previous weeks. Your physiotherapy will
concentrate on activities that help improve the strength in the muscles of your lower leg by
consistently building up resistance in the strengthening exercises. You should have full
range of movement and your physiotherapy will aim to maintain and improve flexibility of
both your lower limbs. Your rehabilitation will continue with proprioception and gait training.
Cardiovascular activities such as hydrotherapy, cycling and gentle jogging can be included
in your programme. Functional activities that focus on specific tasks related to your lifestyle,
hobbies or job will also be included in your physiotherapy programme.

The success of your recovery after external fixation surgery will highly depend on you
commitment to your physiotherapy programme as well as the condition of your leg prior to
the surgery. Recovery will take up to 6 months.

Summary

External fixation of the lower leg is a surgical procedure that uses rods or plates to
immobilise and fix a bone following a fracture to allow the bone to heal in its correct
position. Fractures in the lower leg can occur along the shaft of the tibia (shin bone), along
the shaft of the fibula (smaller long bone) or both. Treatment of a fracture to lower leg can
vary depending on the severity of the injury. In severe cases where the bone is displaced
and the fracture fragments have broken the skin (open fracture) external fixation is the most
commonly utilised procedure. External fixation is required to enable correct alignment as
well as facilitating adequate healing of the lower leg. External fixation allows the return of
function as well as preventing future complications and deformation of the lower leg.
Physiotherapy with Physio.co.uk after external fixation is crucial to ensure the success of
the surgery, prevent the likelihood of any future problems and to help you achieve the return
of full or near to full function within your lower leg. Commitment to a personal physiotherapy
programme with Physio.co.uk will allow a more rapid return to everyday activities, work,
hobbies, and sport. Call Physio.co.uk now on 0330 088 7800 for more
information or to book an appointment please contact us.
Add:

External Fixation Devices Concept and Use

PUBLISHED - BY DR ARUN PAL SINGH LAST EDITED AUG 29, 2016 @ 4:01 PM

External fixation is a useful tool in the management of fractures and certain difficult orthopedic
problems such as limb length discrepancy. External fixation a useful tool in fracture management and
in the case of pelvic fracture it may be a primary life saving device

With external fixation, pins and/or wires are percutaneously inserted into the bone and held in place
by an external frame.

[Know more about other types of fixations]

External fixation is most successful in superficial bones like tibia than deeper bones like femur or
humerus here the chance of pin tract sepsis is greater.

External fixators consist of modular components which are assembled to form a stable construct
between bone fragments and an adjustable beam system. The beam system is joined to the bone by
means of a number of pins screwed into the bone.

Technique of external fixation was popularized in the mid-20th century by Hoffman.

Indications of external Fixation

Limb length discrepancy surgeries

Arthrodesis

Correction of angulatory or rotator deformity

Bone segment transportation to fill the bone gap

Temporary fixation of open fractures

o Maintains stability

o Eases dressing

o When definitive surgery is delayed for some reason

 Rapid Stabilization

o Pelvic fixation to stop bleeding

o Rapid fixation of polytrauma patients

Definitive external fixation of fractures especially intraarticular fractures

Ligamentotaxis

To position limb in desired position as in nerve or tendon repair

Infected fractures

Burns

Advantages of External Fixation

Provides rigid fixation when other forms of immobilization are not feasible. For example,
severe open fractures cannot be managed by plaster casts or internal fixation due to risk
involved.

Allows compression, neutralization, or fixed distraction of the fracture fragments.

Allows surveillance of the limb and wound status.

Allows other treatments like dressing changes, skin grafting, bone grafting, and irrigation, is
possible without disturbing the fracture alignment or fixation.

Allows immediate motion of the proximal and distal joints This aids in reduction of edema and
nutrition of articular surfaces and retards capsular fibrosis, joint stiffening, muscle atrophy,
and osteoporosis.

Allows limb elevation by suspending frame from overhead frames

Allows early patient ambulation

Can be done with the patient under local anesthesia, if necessary.

External fixators cause less disruption of the soft tissues, osseus blood supply, and
periosteum. This makes externa fixation excellent choice in

o Acute trauma with skin contusions and open wounds

o In chronic trauma where the extremity is covered in thin skin grafts and muscle flaps,
 o Patients with poor skin healing

Ability to fix the bone avoid fixation at the site of fracture or lesion, and still obtained
the rigid fixation

Disadvantages of external fixation

Pins inserted in the bones are exposed to internal environment and risk of pin tract infection is
always there

Fracture may occur through pin tracts after frame removal. Extended protection may be
required.

Assembly of the fixator lies outside the limb, is cumbersome and needs meticulous care. High
degree of compliance and motivation is required

Not suitable for non-cooperative patients

In fixators with pins near the joint or fixators that span joint, joint stiffness can occur.

Types of External Fixators

In strictest sense there are two types of fixators unilateral and circular. A combination of two is
called hybrid fixators.

Unilateral Fixator [Modular AO Type]

External Fixator TIbia
 Xray of External Fixator In Tibia With Kwires In Heel

They are called so because they are generally are distinguished from circular frames in that they are
positioned on one side of the limb. Unilateral frames allow the limb to remain functional, avoid
complications, and provide bony stability

Two most common designs are the bulkier

Monobody designs
The monobody frames have considerable intrinsic stability owing to their heavy and rigid design.
Pin-to-bar fixators.
These are kind of fixators use combination of schanz screws, rods and clamps which are assembled to
form a construct.

Circular Fixators

Ilizarov External Fixation Device in Tibia. Note the circular rings and thin wires
Image Credit: Wikipedia
These kind of external fixators use construct formed by circular rings, wires, connecting rods, and
struts. This is quite versatile type of external fixator. A partial ring is commonly used around
the proximal and around the shoulder and proximalfemur where a full ring would not fit comfortably.

Unilateral or Modular AO External Fixation

Components of this fixator are given below.

Schanz Screws

Connecting rods

Clamps

Each of the components can come in different dimensions to suit the scale of the bone to which they
are to be applied and to permit variation in the shape and configuration of the final bone-external
fixator construct.

Schanz screws

Schanz screws are partially threaded pins. These are available in different diameters and lengths of
shaft and threaded part and with different tips.

Standard screws have trocar-shaped tips. They require predrilling. Self-drilling and self-cutting screws
are available.

Schanz screws are available in steel and titanium. Shanz pins with hydroxyapatite coating are aso
available. This makes bone purchase better and allows easier osseointegration, preventing loosening.
Pins with hydroxyapatite coating may be preferred for long-term application of external fixators, eg,
bone transport or deformity correction.

Rods/tubes

The AO fixators consist of systems in four sizes, depending on the size of the rod:

Large: 11 mm tubes/rods with Schanz screws from 4 to 6 mm;

Medium: 8 mm tubes/rods with Schanz screws from 3 to 6 mm;

Small: 4 mm tubes/rods with Schanz screws from 1.8 to 4 mm;

Mini: 2 mm system for fingers. Includes multipin clamps for K-wires and 2 mm longitudinal
rods.

All systems are compatible with each other.

The large 11 mm system contains both steel tubes and carbon fiber rods.

Precurved contoured and T shaped rods are also available.

Currently the 4.7mm short threaded Schanz screw is used in cortical bone and the 5.0mm long
threaded screw in cancellous bone. For hand and wrist application smaller sizes are used.

Connecting rods are made of stainless steel of carbon fibre. The latter are very strong and are also
radiolucent which is helpful when assessing bone alignment on x-ray.

Clamps

The clamps provide the connection between the tubes or rods and the pins. Likewise, rods or tubes
can be connected to each other using the appropriate clamps (tube-to-tube). If one clamp allows the
connection of both tubes and rods, they are called combination clamps.

Both single-pin and multipin clamps are available.

Clamps are available in three sizes with identical clamp design and application technique.

A larger tube to tube clamp permits two fracture components to be held together in relatively stable
alignment irrespective of the position the Schanz pins take up in the bone.

Stability of Unilateral or Modular AO External Fixator

The bending stiffness of unilateral fixators is dependent on the plane of the half pins and the plane of
loading with anteriorly mounted frames providing greater bending stiffness. When these frames were
loaded out of plane, with varusvalgus and torsional forces, they had poor control of the bone
fragments with significant motion at the fracture site.

More stability would be obtained from a multiplanar system.

The stiffness of the frame depends upon the following factors:

Closer the Schanz screws to the fracture, stiffer the construct

Farther the last Schanz screw placed on the fragment on each side of fracture, stiffer the
construct

Closer the he longitudinal connecting tube/bar to the bone. Stiffer the construct

Two bars/tubes are stiffer than one;

Frame configuration The stiffness of construct depends on the assembly. Different

constructions of tubular external fixator which will produce increasing levels of stability are
 o Unilateral uniplanar single-tube fixator.

o Unilateral uniplanar single-tube modular fixator.

o Unilateral uniplanar double tube fixator.

o Unilateral biplanar frame (delta-frame or triangular frame).

o Bilateral frame with transfixing pins [Hardly used now].

Circular Fixator

Ilizarov fixator is a typical circular fixator. Circular fixators consist of series of rings or arches which are
connected to each other by connecting rods and rings are fixed to the bones by means of tensioned
wires.

Many modifications can be added and accordingly the implant used in particular fracture is used
according to the indication for use and goals of the surgery.

Ilizarov fixtor is very versatile fixator and most people know it because it is used for lengthening the
bones.

Ilizarov external fixator is discussed in detail separately.

In circular external fixators, frame stability is greatly impacted by ring properties. Smaller diameter
rings are more stable than larger rings of the same thickness but a ring should not put pressure on
the tissues and the final size is dictated by limb girth.

Different diameter rings may be used in the same frame to adjust to contours of the limb. Centralizing
the bone is preferred but eccentric positioning has been found to have no adverse effect.

The closer the rings are , better is the frame stability.

The stability of construct is increased by

Use of greater number of rings

Shorter distances between rings

Increasing the span of the rings across the bone controlling both near and far ends of each
segment

Increasing the number of connections between the rings

Increasing number of points of fixation to the bone.

Best Practice Tips for External Fixator

1. Placing pins with aseptic technique

2. Protecting soft tissues so that no necrotic tissue is left to encourage infection

3. Drilling a pilot hole to remove bone debris and to reduce frictional resistance and so heat
production during pin insertion.

4. Achieving a firm pin fit with radial distribution of forces the pin is 0.2mm larger than the
pilot hole and this induces compression on the bone termed radial pre-load.

Complications of External Fixation

Complications may arise in the fixator itself or most commonly at the bone pin interface. As with any
fracture especially in severe injury complications may occur at the fracture as a direct result of the
injury.

Pin Tract infection

This this may be the most common complication, occurring in about 30% of patients. The infection
varies from minor skin inflammation to osteomyelitis requiring sequestrectomy.

Pin site infection occurs more when

Pin is inserted at place with greater soft tissue

Skin tethering over the pin

Inadequate pin care

Neurovascular Injury

The radial nerve in the distal half of the arm and proximal half of the forearm, thedorsal sensory radial
nerve just above the wrist, and the anterior tibial artery and deep peroneal nerve at the junction of
the third and fourth quarters of the leg are the structures most often involved.

The pins are known to penetrate vessels, cause thrombosis when they are adjoining the vessel, cause
late erosion of the vessel, arteriovenous fistulas, and the formation of aneurysms.

Muscle Fibrosis and Tendon Rupture

Pins inserted through tendons may restrain normal excursion and can lead to tendon rupture, or
muscle fibrosis
Fracture Complications

Non union and delayed union can be seen with any mode of fixation and can occur with external
fixator also.

Refracture can occur after fixator removal and the fracture needs protection for extended period after
fixator is removed.

Internal fixation is an operation in orthopedics that involves the surgical implementation

of implants for the purpose of repairing a bone, a concept that dates to the mid-nineteenth century
and was made applicable for routine treatment in the mid-twentieth century.[1] An internal fixator may
be made of stainless steel or titanium.[2]

Types of internal fixators include:

Plate and screws

Kirschner wires

Intramedullary nails

Open Reduction Internal Fixation (ORIF)[edit]

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Open Reduction Internal Fixation (ORIF) involves the implementation of implants to guide the
healing process of a bone, as well as the open reduction, or setting, of the
bone. Open reduction refers to open surgery to set bones, as is necessary for
some fractures. Internal fixation refers to fixation of screws and/or plates, intramedullary bone nails
(femur, tibia, humerus) to enable or facilitate healing. Rigid fixation prevents micro-motion across
lines of fracture to enable healing and prevent infection, which happens when implants such as
plates (e.g. dynamic compression plate) are used. Open Reduction Internal Fixation techniques
often are used in cases involving serious fractures such as comminuted or displaced fractures or, in
cases where the bone otherwise would not heal correctly with casting or splinting alone.

Risks and complications may include bacterial colonization of the bone, infection, stiffness and loss
of range of motion, non-union, mal-union, damage to the muscles, nerve damage and
palsy, arthritis, tendonitis, chronic pain associated with plates, screws, and pins, compartment
syndrome, deformity, audible popping and snapping, and possible future surgeries to remove the
hardware.

Closed Reduction Internal Fixation[edit]

Closed Reduction Internal Fixation (CRIF) is reduction without any open surgery, followed by
internal fixation. It appears to be an acceptable alternative in unstable distressed or hyperfalotated
[need reference, no results on the web for "falotated"] lateral condylar fractures of the humerus in
children, but if fracture displacement after closed reduction exceeds 2 mm, open reduction and
internal fixation is recommended.[3] Various techniques of minimally invasive surgery for internal
fixation of bones have been reported. The treatment of fractures of the distal third of the tibia has
evolved with the development of improved imaging and surgical techniques. [4]

Background
Rabies is a viral disease that affects the central nervous system (CNS). The
genusLyssavirus contains more than 80 viruses. Classic rabies, the focus of
this article, is the prototypical human Lyssavirus pathogen. (See Etiology.)
There are 10 viruses in the rabies serogroup, most of which only rarely cause
human disease. The genus Lyssavirus, rabies serogroup, includes the classic
rabies virus, Mokola virus, Duvenhage virus, Obodhiang virus, Kotonkan virus,
Rochambeau virus, European bat Lyssavirus types 1 and 2, and Australian
batLyssavirus. (See Etiology.) Five antigenic variants of rabies strains are
recognized in the United States (see the image below).
 Distribution of the 5 strains of
rabies virus and the associated wildlife in the United States.
View Media Gallery
The rabies virus is a bullet-shaped virion with a single-stranded ribonucleic
acid (RNA) nucleocapsid core and lipoprotein envelope. Its nucleocapsid
material consists of Negri bodies, which are observed in the cytoplasm of
infected neurons (see the image below). The virus is transmitted in saliva or in
aerosolized secretions from infected animals, typically via a bite. The virus is
not hardy and is quickly inactivated by drying, ultraviolet rays, x-rays, trypsin,
detergents, and ether. (See Etiology.)
 Hematoxylin and eosin stain
of Negri body in a rabies-infected neuron. Courtesy of the US Centers for
Disease Control and Prevention.
View Media Gallery
The fatal madness of rabies has been described throughout recorded history,
and its association with rabid canines is well known. For centuries, dog bites
were treated prophylactically with cautery, with predictable and unfortunate
results. In the 19th century, Pasteur developed a vaccine that successfully
prevented rabies after inoculation and launched a new era of hope in the
management of this uniformly fatal disease. (See Treatment and Medications.)
Etiology
Rabies is a highly neurotropic virus that evades immune surveillance by its
sequestration in the nervous system. Upon inoculation, it enters the peripheral
nerves. A prolonged incubation follows, the length of which depends on the
size of the inoculum and its proximity to the CNS. Amplification occurs until
bare nucleocapsids spill into the myoneural junction and enter motor and
sensory axons. At this point, prophylactic therapy becomes futile, and rabies
can be expected to follow its fatal course, with a mortality rate of 100%.
The rabies virus travels along these axons at a rate of 12-24 mm/d to enter
the spinal ganglion. Its multiplication in the ganglion is heralded by the onset
of pain or paresthesia at the site of the inoculum, which is the first clinical
symptom and a hallmark finding. From here, the rabies virus spreads quickly,
at a rate of 200-400 mm/d, into the CNS, and spread is marked by rapidly
progressive encephalitis. Thereafter, the virus spreads to the periphery and
salivary glands.
From the standpoint of diagnosis and therapeutic opportunities, it is important
to understand that rabies does not cause cytotoxicity. Neuronal morphology
and lifespan is normal throughout the course of the disease. Death occurs
from global neurologic and organ dysfunction. The virion acts in the synaptic
space, where homology in amino acid sequences between neurotransmitter
receptors for acetylcholine, GABA, and glycine may afford a mechanism for
viral binding of these receptors. Thus, its action is neurotoxic, rather than
direct damage.
Further, as disease progresses, virus may no longer be viable or replicating in
tissue, although Negri bodies are present. If the virus could be contained or
the binding action reversed, a cure might indeed be possible.
Epidemiology
United States
Rabies is recognized as global zoonosis yet remains remarkably neglected,
despite unmatched lethality. It remains a threat underappreciated by
healthcare practitioners in many endemic areas, often owing to lack of rapid
diagnostic tools, postmortem evaluation, and public health reporting. Further,
few resources have been devoted to its mechanisms of disease and potential
therapeutic targets; the therapeutic approach remains a crude guess at best,
based on anecdotal experiences shared across the globe. Most attention has
focused on preventive strategies, which are fortunately highly effective where
implemented.
The prevalence of rabies varies by location depending on animal-control
effectiveness and immunization programs. The largest number of human
deaths annually was recorded during the first half of the 20th century, with an
average of 50 documented cases per year. Most were related to rabid-dog
exposure. After 1940, when canine rabies vaccination programs began, the
average number of documented cases declined to 2 per year. From 2001-
2005, 15 cases of human rabies were reported in the United States.
Human rabies reflects the prevalence of animal infection and the extent of
contact this population has with humans. Less than 5% of cases in developed
nations occur in domesticated dogs; however, unvaccinated dogs serve as the
main reservoir worldwide. Undomesticated canines, such as coyotes, wolves,
jackals, and foxes, are most prone to rabies and serve as reservoirs. These
reservoirs allow rabies to remain an indefinite public health concern, and
ongoing public health measures are critical to its control.Animal-control and
vaccination strategies currently supersede postexposure prophylaxis in
preventing the spread of rabies. Through such programs, rabies has been
eliminated in some parts of the United States, as well as several nations.
Terrestrial rabies in the United States is most common in raccoons on the
eastern coast and in skunks, foxes, coyotes, and dogs on the Texas-Mexico
border. Canine rabies, and to a lesser extent, bat rabies are significant
problems in Mexico and around the world. (Opossums are rarely infected and
are not considered a likely risk for exposure.)
The only rodent in the United States that can carry rabies long enough to
transmit it to humans is the groundhog. Other small rodents (eg, squirrels,
chipmunks, rats, mice) and lagomorphs (eg, rabbits, hares) usually die before
being able to transmit rabies virus to humans, and human disease has not
been documented from these mammals.
Domestic animals usually succumb to the virus strain predominant in their
geographic region. Other cases have been associated with dog or animal
bites in travelers returning from abroad, especially in countries where wild
canine rabies is endemic. In other countries, canines are the most common
source of rabies. Other animals, such as mongooses, jackals, ferrets, and
domestic farm animals, may be common sources. Human-to-human
transmission has only occurred with corneal and other organ
transplants. [1, 2] Transmission of virus in saliva through mucous membranes,
open wounds, or scratches is possible but rarely documented.
Rabies continues to adapt to new hosts and evolve transmissibility in
previously dead-end hosts. In Arizona 2001, a mutated bat strain was
confirmed to have developed both pathogenicity and transmissibility in both
foxes and skunks, which previously were not seriously affected or contagious
upon infection. Human encroachments into natural areas, as in suburban
development, have been associated with the spread of rabies strains in the
past. [3]
In addition, changes in epidemiology are expected to follow global climate
change and are most likely to be detected in areas of climate extremes. This
is being illustrated in Alaska, as increased viral transmission shifts from red
fox to arctic fox populations following warming trends. Increased surveillance
is needed to improve predictive models of epidemiology and human risk. [4]
Bats
Bat (avian) rabies appears to be widespread in the 49 continental states, and
since 1980, most endemic rabies cases in humans in the United States have
been associated with bat strains. [5]
Bat bites, if noticed by the patient, are generally thought to be trivial injuries
because of the small size of most temperate-zone species (eg, silver-haired
bats, eastern pipistrelles). In addition, bat bites can go completely
unrecognized by the patient; consequently, appropriate postexposure
prophylaxis is not administered.
One third of rabies cases occur in children, and most have no known
exposure to a rabid animal. Because children may not be able to recall
contact with a bat, if a bat is found in a room where a child has been sleeping,
the bat should be captured and submitted for examination to the county or
state health authorities. In 60% of cases, testing of the bat can avoid the need
for rabies immunization. [6]
At least 30 of the more than 39 species of bats in the United States have been
reported as rabid at some time.
Raccoons
Raccoons have been recognized a reservoir for rabies in the southeastern
United States since the 1950s. [7] Currently, the risk of raccoon transmission
exists in all of the eastern coastal states and Alabama, Pennsylvania,
Vermont, West Virginia, and Ohio.
Skunks
Three areas are associated with skunk-borne rabies: the north-central United
States, the south-central United States, and California. As recently as 2001, a
new skunk-borne variant arose from a bat strain and has since been quickly
spreading.
Dogs and cats
Cats are the most common domestic animals reported by US health
departments as being rabid, owing to the high number of unvaccinated strays
with possible contacts with bats and other mammals. [8, 9]
Dogs and cats along the Mexican border
Limited resources and minimal public health infrastructure in the bordering
communities have hindered efforts to maintain animal control through dog-
vaccination programs. Viral studies of human cases reported from US border
states implicate an urban canine rabies strain and a link to coyote rabies in
southern Texas. [10]
Lower-risk animal species in the United States
Any mammal is potentially at risk for rabies, some more than others. Lower-
risk animal species in the United States include dogs, cats, and ferrets in
areas not near a border. No person in the United States has ever contracted
rabies from a dog, cat, or ferret held in quarantine for 10 days. American
opossums are especially at low risk, because the species low body
temperature hinders replication.
Animal rabies vaccine
The vaccinia-rabies glycoprotein virus used in rabies vaccineladen baits for
wild animals is a self-replicating agent. This oral animal vaccine may cause
adverse effects in some humans exposed to it through animal bits, particularly
in hosts with altered immunocompetence and persons in whom smallpox
vaccination is contraindicated (eg, pregnant women, patients with an
exfoliative skin condition). [11]
Transplantation patients
The innate state of immunosuppression in this population often provides a
favorable environment for viral replication. Recipients of neurally derived
tissues are at highest risk; however, any tissue poses a risk. In 2004, kidneys
and liver were inadvertently transplanted from a donor from Texas with rabies
that had gone undiagnosed; the recipients developed clinical rabies within 30
days, resulting in 100% mortality. [12]
International
Rabies is more prevalent in the developing world than in industrialized
countries. The World Health Organization (WHO) estimates that rabies is
responsible for 35,000-50,000 deaths annually worldwide and that gross
underreporting is likely. An estimated 10 million people receive postexposure
prophylaxis each year after being exposed to animals with suspected rabies.
Unvaccinated dogs are the major reservoir for rabies.
Global reservoirs of rabies virus are as follows [13, 14] :
Europe - Foxes, bats
Middle East - Wolves, dogs
Asia - Dogs
Africa - Dogs, mongooses, antelopes
North America - Foxes, skunks, raccoons, insectivorous bats
South America - Dogs, vampire bats
Sex-related demographics
Encounters with rabid animal vectors may be increased in males, who may
have greater contact in certain geographic areas. Evidence to support this is
found in data on dog bites, which are observed more frequently in males than
in females.