Esophageal Motility Disorders

1. Embryology
Muscular epithelial-lined tube
Derived from primitive foregut
Second week of embryologic development
Mesoderm forms and separates ectoderm from endoderm--providesmaterial necessary for connective tissue, muscular coats, serous coverings
2. Histology and Final Development
Adventitia: outer loose connective tissue containing nerves, lymphatics, blood vessels
Muscularis: two layers of muscle--outer longitudinal and an inner circular
Submucosa: connects muscularis with the mucosa--strongest layer--elastic tissue; collagenous fibers; network of vessels & nerves
Mucosa: squamous, columnar; Z-line
3. Vascularity
Arterial: 3 sources
1. Inferior and superior thyroid arteries: cervical esophagus
2. Tracheobronchial, aortic arch and esophageal branches: body of esophagus
3. Left gastric and splenic arteries: GEJ
Veins: drainage pattern similar to lymphatics
Submucosal plexus--communicating veins--perforating veins that pierce the muscularis
Eventually drain into inferior thyroid, azygous, hemiazygous,left gastric, splenic, left gastroepiploic systems
4. Lymphatics:
Submucosal lymphatics form long channels that run parallel to esophageal axis
May travel long distances before draining into regional nodes
5. Innervation
Nerves: extraesophageal
Sympathetic: cervical, thoracic chains; celiac plexus and ganglia
Parasympathetic: vagus nerve muscular plexus around the circular layer of the muscularis (Auerbach's plexus)
Submucosal plexus (Meissner's plexus)
Auerbach's and Meissner's plexus are interconnected and are responsible for the fine- control mechanism of esophageal function
6. Nerves: central
Nucleus ambiguous
Dorsal motor nucleus of Vagus through the myenteric plexus
Both work together on the longitudinal and circular muscles to propel a bolus--peristalsis
7. Peristalsis
Primary: normal propulsive wave in response to the stimulation of normal voluntary deglutition
Secondary: normal wave without voluntary deglutition: best defense
Tertiary: abnormal; may occur spontaneously or following deglutition
8. Normal function
Upper Esophageal Sphincter (UES)
Level of cricoid cartilage C 5-6
Composed of cricopharyngeus and inferior pharyngeal constrictors
Remains contracted between swallows due to continuous stimulation by IX and XI
Resting tone: 45 - 65 mmHg (range 32 -101 mmHg)
Swallow: inhibition of all motor nerve stimulation; UES opens; closes; rebound; baseline pressures
9. Esophageal Body
Proximal striated muscle: direct innervation to its motor end plate from nucleus ambiguous
Smooth muscle: indirect neural input from dorsal motor nucleus (X) via myenteric plexus
Innervation: longitudinal muscle shortens; circular muscle contracts; peristalsis
Duration and amplitude: weaker in proximal esophagus; stronger, longer in distal esophagus
10. Lower esophageal sphincter (LES)
Specialized muscle arrangement 3 - 4 cm above gastroesophageal junction (GEJ)
High pressure zone with resting tone 15 - 25 mmHg (24.8 mmHg)
Influenced by neural and hormonal factors; drugs
Relaxes at time of swallowing; closes with passage of contraction through sphincterManometry
11. Diagnostic Techniques
Radiology
Endoscopy
Reflux Disease
Esophageal Malignancies
Esophageal Biopsies
Motility Studies
24 Hour pH Monitoring
Acid Perfusion Tests (Bernstein's Test)
Radionuclide Emptying Studies
12. Oropharyngeal Dysphagia
Neurologic: central vs peripheral
Myogenic
Cricopharyngeal Muscle Dysfunction
Iatrogenic
Lower esophageal disease
13. Idiopathic Motor Disorders
Hypomotility Disorders
Achalasia
Hypermotility Disorders
Diffuse Esophageal Spasm
Hyperperistalsis (Nutcracker; Supersqueeze)
Hypertensive LES
Nonspecific Esophageal Motility Disorders
14. Achalasia
Young adults -- 1 in 100,000 -- Cause unknown
Loss of control at the postganglionic, nonadrenergic and noncholinergic inhibitory nerves -- LES dysfunction and esophageal body changes
? denervation; Chagas' Disease
Compounded by physical & psychologic stress
LES: normal or increased resting pressure
Incomplete or absent relaxation
15. Symptoms: dysphagia; odynophagia; regurgitation; aspiration and its complications; made worse by cold liquids and stressful situations
Squamous cell carcinoma 1-10%
Peristalsis absent in esophageal body; high resting pressure
Contractions weak at all recording levels
Esophageal dilatation; megaesophagus
Barium swallow: "bird's beak" esophagus
16. CXR: widened mediastinum; air-fluid level in posterior mediastinum; absence of gastric bubble
Endoscopy: changes vary with stage
Normal
Food/fluid retention in fasting state
Thickened mucosa with wide folds
Hyperemia: stasis esophagitisAchalasia Upper GIAchalasia Manometry
17. Treatment
Medication: calcium channel blockers--decrease LES resting pressures--improves symptoms, not emptying
Early disease with minimal symptoms
Dilatation: stretches/ruptures fibers of the LES
Lowers LES resting pressure; improves emptying
Good to excellent short term results in 65% of patients
Esophageal rupture seen in 4%
Reflux seen in 7 - 17%
18. Esophageal myotomy: improves obstructive symptoms more effectively than dilatation
Can be done via left thoracotomy, laparotomy, or scope
5 - 7 cm myotomy on distal esophagus
Extends 1 cm onto gastric wall
Mucosa dissected from muscularis
90% relief of dysphagia short and long term
? concomitant antireflux procedure: partial fundoplication
19. Diffuse Esophageal Spasm
Rare--cause is unknown; muscle hypertrophy; degenerative changes in Vagus branches
Symptoms: odynophagia, dysphagia, unexplained chest pain
Anxious individuals
Symptoms worsened by stress
Must differentiate from CAD
20. Simultaneous segmental contractions on x-ray
Corkscrew / rosary bead esophagus
Diverticulum: intermittent or epiphrenic
Endoscopy: usually normal
Peristalsis:>30% repetitive tertiary contractions
Duration and amplitude occasionally abnormal
LES: occas. hypertensive; occas. incomplete relaxation Spasm Upper GISpasm Manometry
21. Treatment
Nitroglycerin
Calcium channel blockers: decreases amplitude of contraction & reduces LES pressure
Control anxiety and precipitating factors
Esophageal myotomy: results not as good as in achalasia; good to excellent results in 67 - 70%
If LES is transected must do a partial fundoplication
Dilatation if hypertensive LES is documented
22. Nutcracker or Supersqueeze Esophagus
Normal peristalsis
Contraction amplitude is > 2 standard deviations above normal > 180 mmHg in distal esophagus
Duration of contractions >6 sec.
LES: occas. hypertensive; usually normal
Primary symptoms is chest pain
Strong emotional influence / hypochondriacal Nutcracker Esophagus Manometry
23. Treatment
Psychologic assessment and support
Calcium channel blockers
Dilatation or myotomy are of little or no benefit
Hypertensive LES
Resting pressure > 45 mmHg; normal relaxation and peristalsis
Conservative medical / psychiatric management
24. Idiopathic Gastroesophageal Reflux
Peristalsis and contraction amplitude are normal
LES is weak (gradient < 6 mmHg) allowing gastric acid to reflux and bathe the lining of the lower esophagus--responsible for 60 - 70 % of all GERD
Sphincter failure
Primary muscle dysfunction
25. Increased exposure to acid further weakens the LES leading to further reflux and mucosal damage
Esophageal contraction abnormalities with poor amplitude and aperistalsis
Correlation between the severity of sphincter hypotension and extent of functional abnormalities in the esophageal body
(DeMeester)
? correction cures abnormalities
26. Reflux Disease and Scleroderma
Seen in 90% of patients with scleroderma
Atrophy of smooth muscle components
Fibrous infiltration
Incompetence of LES with disappearance of propulsive and emptying mechanisms
Antireflux procedures not as successful though some improvement is seen Reflux
27. Idiopathic Gastroesophageal Reflux
Frequent association with Type I hiatal hernia
Alterations in the anatomy of the hiatus
Phrenoesophageal membrane
Secondary causes
Delay of gastric emptying
Pyloric stenosis
Gastric mass
Poor esophageal wall muscle tone (scleroderma)
28. Reflux: two factors must occur
Acid-peptic or pancreaticobiliary secretions must reach the esophagus with increased frequency
Esophagus must be unable to clear those refluxed materials back into the stomach
Treatment
Medical treatment
Surgical treatment if medical treatment fails
29. Diagnosis
Barium swallow
Fiberoptic / rigid endoscopy
Multiple biopsies if findings consistent with severe esophagitis, stricture, Barrett's epithelium, ulceration
Esophageal function test (manometry, acid reflux, perfusion and clearing tests, 24 hr pH monitoring)
30. Indications for surgery
Symptomatic after 3 months of medical therapy
Persistent esophagitis, stricture, aspiration, bleeding
Positive 24 hr pH study
Manometry suggesting dysfunctional LES and adequate esophageal motility(peak amplitude > 30 mmHg)
Barrett's mucosa if biopsies are benign (no CIS)
31. Operation of choice
Restoration of the anatomic and physiologic relationships of the LES at the GEJ
360 degree wrap (normal esophageal motility)
270 degree wrap (dysfunctional esophagus)
Esophageal resection (rare)
Totally unyielding (fibrotic) esophagus
Barrett's esophagus with CIS or frank malignancy
Gastroplasty: falling out of favor
Procedures
Nissen Fundoplication
Belsey Mark IV
Hill Fundoplication
Collis Gastroplasty
Collis-Belsey Procedure
-------------------------------------------------------------------------------
EXTENDED OUTLINEAnatomy and functional evaluation
1. Anatomy
a) Begins (transition from pharynx to esophagus) at lower end of sixth cervical vertebra/cricoid cartilage
b) Ends (transition to stomach) at 11th thoracic vertebra
c) Esophagus is midline, passing to the left in lower neck and upper thorax, then back to midline, then to left again in lower thorax to pass through diaphragmatic hiatus
d) Follows curve of vertebral column except to pass anteriorly to pass through diaphragmatic hiatus
e) Sites of perforation during rigid esophagoscopy:
i) Cricopharyngeus
ii) Terminal left anterior deviation
f) Measurements
i) Incisors to cardia = 38-40cm (men), 36-38 (women)
ii) Cricopharyngeus to cardia =23-30cm, avg. 25
iii) Incisors to cricopharyngeus = 14-15cm
iv) Incisors to tracheal bifurcation/indentation of aortic arch = 24-26cm
g) Anatomic relations of esophagus
i) Trachea and cervical spine
ii) Recurrent laryngeal nerves - in tracheoesophageal groove - left is closer to esophagus
iii) Above tracheal bifurcation, esophagus passes to the right of the aorta
iv) From arch down, esophagus lies to the right of the aorta
v) 8th vertebra - left wall of esophagus is covered only by mediastinal pleura - common site of perforation in Boerhaave’s syndrome
vi) Passing through diaphragmatic hiatus, phrenoesophageal membrane surrounds
vii) 2cm of abdominal esophagus between membrane and cardia - subjected to positive pressure
viii) Thoracic duct - through diaphragm behind aorta - in thorax, dorsal to esophagus, from 5th thoracic vertebra up, it passes to left, then departs from esophagus in neck to join L SCV at junction of IJV
h) Musculature of the esophagus
i) Opening is collared by cricopharyngeus muscle
ii) Outer longitudinal layer and inner circular layer
iii) Circular muscle is elliptical
iv) Upper esophagus is only striated muscle
v) At upper/middle 1/3 junction - 50% smooth muscle
i) Arterial supply of the esophagus
i) Cervical = inferior thyroid artery (mainly) + common carotid, SCA
ii) Thoracic = bronchial arteries (75% have one R and 1-2 L)
iii) Abdominal = branches of left gastric and inferior phrenic arteries
iv) After penetrating esophagus, arteries branch in T to form longitudinal anastomoses
v) Esophagus can be mobilized from stomach to aortic arch w/o devascularization
j) Venous drainage
i) Cervical = inferior thyroid
ii) Thoracic = bronchial, azygos and hemiazygous veins
iii) Abdominal = cardiac vein
k) Innervation
i) Parasympathetic = vagus
ii) Cricopharyngeus and cervical esophagus - recurrent laryngeal nerves
iii) RLN injury causes vocal cord paralysis and dysfunction of cricopharyngeus and of cervical esophageal motility, predisposing to aspiration
iv) Esophageal plexus receives fibers from vagus and from thoracic sympathetic chain
l) Lymphatic drainage
i) Submucosal plexus - lymph flow is longitudinal - extensive submucosal spread (of tumor) can occur
2. Normal structure and function
a) Pharyngeal phase of swallowing
i) Tongue is piston - propels food bolus as soft palate is closed
ii) Swallowing is reflex, once initiated
iii) Larynx is elevated and epiglottis covers opening of larynx
iv) Pharyngeal pressure increases to 45mm Hg
v) Food propelled by pressure gradient into thoracic esophagus
vi) Upper, striated portion of esophagus relaxes, then contracts within 0.5 seconds to twice its resting level of 30mm Hg
vii) A peristaltic wave of 30mm Hg begins in the esophagus
viii) Afferent nerves of pharynx are glossopharyngeal and superior laryngeal branch of vagus
ix) Efferent nerves arise from CN V, VII, X, XI, XII and C1-3
x) Motor disorders of pharyngeal swallowing:
a) Incomplete upper sphincter relaxation
b) Loss of skeletal portion of cervical esophagus
b) Esophageal phase of swallowing
i) Pressure gradient of -6mm Hg in thoracic esophagus to +6mm Hg intraabdominal
ii) Lower 1/3 of esophagus is most important
a) Peristaltic wave of 30-120 mm Hg
b) Rises to a peak in 1 sec, lasts 0.5 sec, then subsides in 1.5 sec
c) Wave moves down the esophagus at 2-4 cm/sec, reaches distal esophagus 9 sec after swallow starts
d) Vagal modulated wave
e) If vagi are preserved, muscle can be divided and propagate wave
f) Vagal fibers end in myenteric plexus
g) No known sympathetic innervation of the esophagus
iii) Pathologic states
a) Diffuse esophageal spasm - simutaneous contraction
b) Achalasia - failure of LES relaxation
c) Scleroderma - loss of contraction of smooth muscle portion of esophagus
3. The antireflux mechanism
a) LES
i) No distinct anatomic sphincter, but muscular architecture of cardia acts like a sphincter
ii) Gastric contraction results in increased LES pressure
b) Resting LES pressure
i) Correlates with incidence of GERD
ii) Truncal vagotomy has no effect
iii) Atropine (and other anti-cholinergics) reduces LES tone but does not cause GER
iv) In pharmacologic doses:
a) Secretin, cholecystokinin, glucagon, prostaglandins reduce LES pressure
b) Gastrin, bombesin, motilin augment it
v) Low LES tone in GERD is probably due to abnormal myogenic function
vi) Results of antireflux operations are independent of changes in resting LES pressure
vii) Myotomy can be performed along the length of the LES without resulting in reflux
c) Phrenoesophageal ligament
d) Intra-abdominal esophagus
i) Laplace’s law - pressure required to distend a soft tube is inversely proportional to its diameter
ii) Small-diameter esophagus requires high intragastric pressure to allow reflux
iii) LES competence directly proportional to length of intra-abdominal esophagus in cadaver studies by DeMester
4. GERD
a) Results from decrease in LES pressure, shortening of the intra-abdominal esophagus or both
b) Competence of cardia
i) Requires adequate LES pressure + intrabdominal length
ii) 80% prob of GERD when LES <5mmHG (independent of length)
iii) 80% prob of GERD when length <1cm (independent of pressure)
iv) Low incidence when pressure > 20mmHg and >2cm abd length
c) Gastric function
i) Delayed gastric emptying
ii) ­ intragastric pressure and distention shorten intraabdominal length
d) Overall LES length is also a factor in GERD
e) Esophageal clearance
i) Gravity, salivation and swallowing
ii) Pts w/complications of GERD (Barrett’s and stricture) have higher proportion of weak amplitude and simultaneous contractions
iii) ­ frequency of swallows (0.87à 2.59/min) during episodes of reflux
iv) Any impairment of motility may ­ exposure time
f) LES relaxation-abnormal will à increased exposure
g) Hiatal hernia
i) Phrenoesophageal ligament and snug hiatus prevent distention of abdominal esophagus
h) Antirreflux operations restore to normal the failed components of a mechanically defective sphincter
5. Objective assessment of esophagus
a) Esophageal and upper GI barium studies
i) ­ accuracy with video/cine
ii) ­ accuracy with solid and liquid boluses
iii) Intraluminal abnormalities, landmarks
iv) Some motor dysfunction - spastic contractions
v) Mucosal lesions better seen with double contrast
vi) GERD- reflux only seen in 40% of those with manometry proven
b) Esophagoscopy
i) Any patient who reports dysphagia
ii) Confirm structural abnormalities w/bx
iii) Hiatal hernia = a pouch lined with gastric rugal folds lying 2cm above crural indentation (identify w/a sniff)
iv) Esophagitis
a) Grade I= reddening w/o ulceration
b) Grade II= erosive and invasive, not circumferential
c) Grade III= confluence of erosions (cobblestone) - no stricturing
d) Grade IV= complications
v) Stricture
a) Multiple biopsies
b) Dilate
vi) Barrett’s
a) Difficulty visualizing squamo columnar jxn
b) Mucosa is red, more luxuriant
c) Biopsy proximal to lesion to determine junction w/nl squamous mucosa
d) Surveillance = 4 circumferential biopsies a t 2cm intervals
vii) Submucosal lesions - do not biopsy
c) The acid perfusion test
i) 0.1N HCl or H2O infused 15 cm above LES
ii) Pt reports symptoms
iii) Positive test is pt reporting symptoms w/acid relieved by saline
iv) Reduced sensitivity in pts w/stricture or Barrett’s
d) Manometry
i) Indications
a) Motor abnormality of esophagus suspected
b) Dysphagia or odynophagia w/o definite structural abnormality on Ba swallow
c) Confirm dx of achalasia, esophageal spasm, scleroderma
d) GERD - assess esophageal clearance prior to surgery
e) Determine LES pressure, total and intra abdominal length
ii) Pressure-measuring catheter is withdrawn rapidly or stepwise across cardia
iii) Measurements
a) Relaxation of LES to gastric levels during swallow
b) Respiratory inversion point - reference point for LES
c) Response to 10 pharyngeal swallows-wet swallows are more sensitive
iv) Achalasia (Fig 39-21)
a) LES does not fully relax
b) All waves in body are simultaneous
c) No primary peristaltic waves are seen
d) Resting pressure of body is usually elevated
v) Scleroderma (Fig 39-22)
a) All muscular function of distal esophagus is obliterated
b) No high pressure zone
c) No contractions in body (lower 2/3 of esophagus)
vi) Simultaneous, repetitive or broad-based powerful contractions
a) Partial obstruction
b) Esophageal spasm
e) 24-hour esophageal motility monitoring
i) Advantages
a) Multiplies amount of data
b) Various physiologic conditions
ii) Limitations of stationary monitoring
a) Pt is supine
b) Limited to 10 swallows
iii) Technique
a) Drugs are stopped 48h before test
b) 3 transducers - 5, 10, 15 cm above upper border of LES
c) Pt diary of eating, position, sleeping, symptoms
iv) Diagnostic criteria (Table 39-2)
v) Little correlation with stationary manometry - especially for normal or nutcracker by ambulatory
vi) Primarily useful in pts with noncardiac chest pain
a) Amplitude and duration of contractions associated w/ pain are similar to asymptomatic
b) Frequency of contractions prior to episodes is increased
c) Esophageal claudication
d) Long esophageal myotomy can eliminate ability of esophagus to produce these bursts of abnormal activity
vii) Other findings
a) Esophageal contractility deteriorates with mucosal injury
b) Assess esophageal clearance function = peristaltic contractions with amplitude > 30mm Hg
f) 3-D imaging of LES
i) Overall length or intra abdominal length below 5th percentile can nulify normal LES pressure
ii) Increases the sensitivity of esophageal manometry in identifying pts who will benefit from “early” antireflux surgery (i.e., before the development of mucosal injury)
g) Esophageal pH tests
i) pH electrode withdrawl test
a) Normal is sharp rise in pH from stomach to 5-7 in esophagus
b) 20% false poitive - abandoned
ii) SART
a) pH electrode 5cm above LES - 0.1N Hcl infused into stomach - pt performs maneuvers
b) > 2 drops in pH = abnormal cardia
iii) Acid clearance test
a) Performed after SART
b) Acid infused into esophagus
c) Normal=pH > 5 with < 10 swallows
iv) 24-hour pH monitoring
a) Most sensitive method for reflux-related problems
b) Indications
(1) GERD symptoms, other tests equivocal
(2) Prior to antireflux operation
(3) Atypical GERD symptoms
(4) Dysphagia and motor disorder (?GERD)
(5) Recurrent symptoms after esophageal or gastric surgery
c) Technique
(1) pH electrode 5cm above LES
(2) Acid reflux = pH <4
(3) Alkaline reflux = pH >7
(4) Restrict intake to food pH 5-6
d) Measure
(1) Cumulative time pH < 4 as percentage of time supine, total, upright
(2) Frequency of episodes of pH<4/24h
(3) Duration of longest episode (
4) Number of episodes > 5 min
h) Radionuclide studies
i) Localization of Barrett’s - not used
ii) Dx and quantitation of GERD - not physiologic
iii) Measure esophageal transit - ?screening test prior to manometry
iv) Measurement of gastric emptying
i) Bilirubin monitoring with fiberoptic probe
i) Complications are related to acid and alkaline reflux
ii) 5cm above LES
iii) Uses bilirubin as a marker of exposure to duodenal contents

Read More

Bone Age Tool

Download from link for mac users

http://homepage.mac.com/d2p/radiology/boneage.html

Calculate online by clicking on the link

http://vl.academicdirect.ro/medical_informatics/bone_age/v1.0/

Read More

Hiatus hernia

When a hiatus hernia occurs , a portion of the stomach is able to slide upwards through the opening in the diaphragm, beside the oesophagus, into the chest.



There are 2 main types of hiatus hernia.



Sliding hiatus hernia: this is the most common type of hiatus hernia. It occurs when the junction between the oesophagus and the stomach and the upper part of the stomach protrude up through the oesophageal opening in the diaphragm into the chest cavity. The herniated portion of the stomach can slide back and forth, into and out of the chest.



Rolling hiatus hernia: this is sometimes called a para-oesophageal hiatus hernia by doctors. In this case, part of the stomach bulges into the chest out of the weakest part of the diaphragm, which is the oesophageal opening. The junction of the oesophagus and stomach stays down within the abdomen, and the top part of the stomach (the fundus) bulges up into the chest cavity. This type of hernia normally remains in one place, sitting next to the oesophagus, and does not move in or out when you swallow.

Read More

Implanon

IMPLANON™ (etonogestrel implant) is indicated for women for the prevention of pregnancy. IMPLANON™ is a long-acting (up to three years), reversible, contraceptive method. IMPLANON™ must be removed by the end of the third year and may be replaced by a new IMPLANON™ at the time of removal, if continued contraceptive pro- tection is desired.
In clinical trials involving 923 subjects and 1854 women-years of IMPLANON™ use, the total exposure in 28-day cycles by year was
Year 1: 10,867 cycles
Year 2: 8595 cycles
Year 3: 3492 cycles
The clinical trials excluded women who
Weighed more than 130% of their ideal body weight
Were chronically taking medications that induce liver enzymes
Among women aged 18-35 years of age at entry, six pregnancies during 20,648 cycles of use were reported. Two pregnancies occurred in each of Years 1, 2 and 3. Each conception was likely to have occurred shortly before or within two weeks after IMPLANON™ removal. With these six pregnancies, the cumulative Pearl Index was 0.38 pregnancies per 100 women-years of use.
The efficacy of IMPLANON™ does not depend on patient self-administration. IMPLANON™ may be less effective in women who are overweight or who are taking medications that induce liver enzymes.
See CLINICAL PHARMACOLOGY, Special Populations, Overweight Women, and PRECAUTIONS: DRUG INTERACTIONS.
Also see
http://emc.medicines.org.uk/emc/assets/c/html/DisplayDoc.asp?DocumentID=5382

DOSAGE AND ADMINISTRATION
All healthcare providers performing insertions and/or removals of IMPLANON™ (etonogestrel implant) must receive instruction and training and where appropriate, supervision prior to inserting or removing IMPLANON™. Insert IMPLANON™ subdermally in the inner side of the upper arm (non-dominant arm) about 6-8 cm (21/2-3 inches) above the elbow crease overlying the groove between the biceps and the triceps. See INSTRUCTIONS FOR INSERTION AND REMOVAL. IMPLANON™ must be inserted by the expiration date stated on the packaging. Remove IMPLANON™ no later than three years after the date of insertion.
When to Insert IMPLANON™
IMPORTANT: Rule out pregnancy before inserting IMPLANON™.
Timing of insertion depends on the patient's recent history, as follows
No preceding hormonal contraceptive use in the past month
Counting the first day of menstruation as “Day 1”, IMPLANON™ must be inserted between Days 1 through 5, even if the woman is still bleeding.
Switching from a combination hormonal contraceptive IMPLANON™ may be inserted
Anytime within seven days after the last active (estrogen plus progestin) oral contraceptive tablet
Anytime during the seven-day ring-free period of NuvaRing® (etonogestrel/ethinyl estradiol vaginal ring)
Anytime during the seven-day patch-free period of a transdermal contraceptive system
Switching from a progestin-only method
There are several types of progestin-only methods. IMPLANON™ insertion must be performed as follows
Any day of the month when switching from a progestin-only pill, do not skip any days between the last pill and insertion of IMPLANON™
On the same day as contraceptive implant removal
On the same day as removal of a progestin-containing IUD
On the day when the next contraceptive injection would be due
Following first trimester abortion or miscarriage
IMPLANON™ may be inserted immediately following a complete first trimester abortion. If IMPLANON™ is not inserted within five days following a first trimester abortion, follow the instructions under “No preceding hormonal contraceptive use in the past month.”
Following delivery or a second trimester abortion
• IMPLANON™ may be inserted between 21 to 28 days postpartum if not exclusively breast feeding or between 21 to 28 days following second trimester abortion. If more than four weeks have elapsed, pregnancy should be excluded and the patient should use a non-hormonal method of birth control during the first seven days after the insertion. If the patient is exclusively breast feeding, insert IMPLANON™ after the fourth postpartum week (see Nursing Mothers section under PRECAUTIONS)
If inserted as recommended above, backup contraception is not necessary. If deviating from the recommended timing of insertion, rule out pregnancy and use backup non-hormonal contraception for seven days after IMPLANON™ insertion.

HOW SUPPLIED
One IMPLANON™ (etonogestrel implant) package consists of a single rod implant containing 68 mg etonogestrel that is 4 cm in length and 2 mm in diameter. IMPLANON™ is pre-loaded in the needle of a disposable applicator. The applicator consists of acrylonitrile-buta- diene-styrene body with a stainless steel needle and a polypropylene shield. The sterile applicator containing IMPLANON™ is packed in a blister pack.
NDC 0052-0272-01
Storage
Store IMPLANON™ (etonogestrel implant) at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]. Protect from light. Avoid storing IMPLANON™ in direct sunlight or at temperatures above 30ºC (86ºF).
REFERENCES FURNISHED UPON REQUEST
INSTRUCTIONS FOR INSERTION AND REMOVAL
The basis for successful use and subsequent removal of IMPLANON™ (etonogestrel implant) is a correct and carefully performed subdermal insertion of the single rod implant in accordance with the instructions. If the implant is placed improperly leading to deep location or migration, it will be more difficult to remove than a correctly placed subdermal implant. All healthcare providers performing insertions and removals of IMPLANON™ must receive instruction and training, and where appropriate, supervision prior to inserting or removing IMPLANON™.
Information concerning the insertion and removal of IMPLANON™ will be sent upon request free of charge [Organon USA Inc., telephone: 1-877-IMPLANON (1-877-467-5266)].
INSERTION PROCEDURE
Prior to inserting IMPLANON™ (etonogestrel implant) carefully read the instructions for insertion and removal as well as the full prescribing information.
Place IMPLANON™ subdermally. Both you and your patient should be able to feel IMPLANON™ under her skin after placement.
Follow instructions carefully. All healthcare providers must receive training before inserting or removing IMPLANON™. Proper IMPLANON™ insertion will facilitate removal. Correct timing of insertion is important. (See When to Insert IMPLANON™ in the DOSAGE AND ADMINISTRATION section.) Perform a history and physical examination, including a gynecologic examination, before IMPLANON™ insertion. Ensure that the patient understands the risks and benefits of IMPLANON™ before insertion. Provide the patient with a copy of the Patient labeling included in packaging. Have the patient review and complete a consent form and maintain it with the patient's chart.
Exclude pregnancy before insertion.
Insert IMPLANON™ under aseptic conditions.
The following equipment is needed for IMPLANON™ insertion
An examination table for the patient to lie on
Sterile surgical drapes, talc-free sterile gloves, antiseptic solution, sterile marker (optional)
Local anesthetic, needles, and syringe
Sterile gauze, adhesive bandage, pressure bandage
An applicator and its parts are shown in the following diagrams (Figures 3a and 3b).
Figure 3a (Not to scale)
Figure 3b Grooved tip of obturator (enlarged)
The procedure used for IMPLANON™ insertion is opposite from that of an injection. The obturator keeps IMPLANON™ in place while the cannula is retracted. The obturator must remain fixed in place while the cannula with needle is retracted from the arm. Do not push the obturator.
1. Confirm that the patient does not have allergies to IMPLANON™, as well as the antiseptic and anesthetic to be used during insertion.
2. Have the patient lie on her back on the examination table with her non-dominant arm flexed at the elbow and externally rotated so that her wrist is parallel to her ear or her hand is positioned next to her head (Figure 4).
3. Identify the insertion site, which is 6-8 cm (21/2 to 3 inches) above the elbow crease at the inner side of the upper arm overlying the groove between the biceps and the triceps of her nondominant arm.
4. Mark the insertion site with a sterile marker. Make two marks: first, mark the spot where the IMPLANON™ rod will be inserted, and second, mark a spot about 6-8 cm (21/2 to 3 inches) proximal to the first mark (Figure 5). This second mark will later serve as a direction guide during IMPLANON™ insertion.
5. Clean the insertion site with an antiseptic solution.
6. Anesthetize the insertion area (for example, with anesthetic spray or by injecting 2 cc of 1% lidocaine just under the skin along the planned insertion tunnel).
7. Carefully remove the IMPLANON™ applicator from its blister. Keep the shield on the needle and look for the IMPLANON™ rod, seen as a white cylinder inside the needle tip.
8. If you don't see the IMPLANON™ rod, tap the top of the needle shield against a firm surface to bring the implant into the needle tip.
9. Following visual confirmation, lower the IMPLANON™ rod back into the needle by tapping it back into the needle tip. Then remove the needle shield, while holding the applicator upright.
10. Note that IMPLANON™ can fall out of the needle. Therefore, after you remove the needle shield, keep the applicator in the upright position until the moment of insertion.
11. Keep the IMPLANON™ needle and rod sterile. If contamination occurs, use a new package of IMPLANON™ with a new sterile applicator.
12. Apply counter-traction to the skin around the proposed insertion (Figure 6).
13. At a slight angle (not greater than 20º), insert only the tip of the needle with the beveled side up into the insertion site (Figure 7).
14. Lower the applicator to a horizontal position. Lift the skin up with the tip of the needle, but keep the needle in the subdermal connective tissue (Figure 8).
15.While “tenting” (lifting) the skin, gently insert the needle to its full length. Keep the needle parallel to the surface of the skin dur- ing insertion (Figure 9).
16. If IMPLANON™ is placed too deeply, the removal process can be difficult or impossible. If the needle is not inserted to its full length, the implant may protrude from the insertion site and fall out.
17. Break the seal of the applicator by pressing the obturator support (Figure 10).
18. Turn the obturator 90º in either direction with respect to the needle (Figure 11).
19. While holding the obturator fixed in place on the arm, fully retract the cannula (Figure 12). Note: This procedure is opposite from an injection. Do not push the obturator. By holding the obturator fixed in place on the arm and fully retracting the cannula, IMPLANON™ will be left in its correct subdermal position. Do not simultaneously retract the obturator and cannula from the patient's arm.
20. Confirm that IMPLANON™ has been inserted by checking the tip of needle for the absence of IMPLANON™. After IMPLANON™ insertion, the grooved tip of the obturator will be visible inside the needle (Figure 13).
In this figure, the right hand is holding the obturator in place while the left hand is retracting the cannula.
21. Always verify the presence of IMPLANON™ in the patient's arm immediately after insertion by palpation. By palpating both ends of the implant, you should be able to confirm the presence of the 4 cm rod.
22. Place a small adhesive bandage over the insertion site. Request that the patient palpate IMPLANON™.
23. If you cannot feel IMPLANON™ as a 4 cm long rod, confirm its presence using other methods. Suitable methods to locate IMPLANON™ are: ultrasound (US) with a high-frequency linear array transducer (10 MHz or greater) or magnetic resonance imaging (MRI). Please note that the IMPLANON™ rod is not radio-opaque and cannot be seen by X-ray or CT scan. If ultrasound and MRI fail, call 1-877-IMPLANON (1-877-467-5266) for information on the procedure for measuring ENG blood levels.
Until you confirm proper IMPLANON™ insertion, your patient must use a non-hormonal contraceptive method.
24. Apply a pressure bandage with sterile gauze to minimize bruising. The patient may remove the pressure bandage in 24 hours and the small bandage over the insertion site in three to five days.
25. Complete the USER CARD and give it to the patient to keep. Also, complete the Patient Chart Label and affix it to the patient's medical record.
26. The applicator is for single use only. Dispose of the applicator in accordance with the Center for Disease Control and Prevention guidelines for handling of hazardous waste.
REMOVAL PROCEDURE
Before initiating the removal procedure, the healthcare provider may consult the USER CARD that is kept by the patient and/or the Patient Chart Label. The arm in which IMPLANON™ (etonogestrel implant) is located should be indicated on the USER CARD and the Patient Chart Label. IMPLANON™ should have been inserted in the medial aspect of the upper non-dominant arm. Prior to removing IMPLANON™, carefully read the instructions for removal. Find IMPLANON™ by palpation. If IMPLANON™ cannot be palpated, use either ultrasound with a high-frequency linear array transducer (10 MHz or greater) or magnetic resonance imaging to localize the implant. Consider conducting difficult removals with ultrasound guidance. Only remove a non-palpable implant once the location of IMPLANON™ has been established. If these imaging methods fail, call 1-877-IMPLANON (1-877-467-5266) for further instructions.
The patient's position for removal is similar to the position for insertion. Use aseptic technique.
The following equipment is needed for removal
An examination table for the patient to lie on
Sterile surgical drapes, talc-free sterile gloves, antiseptic solution, sterile marker (optional)
Local anesthetic, needles, and syringe
Sterile scalpel, forceps (straight and curved mosquito)
Skin closure, sterile gauze, adhesive bandage and pressure bandages
1. IMPLANON™ must only be removed by a healthcare provider who has been instructed and trained in the IMPLANON™ removal technique.
2. The arm in which IMPLANON™ is located should be indicated on the USER CARD and the Patient Chart Label. IMPLANON™ should be in the medial aspect of the upper non-dominant arm.
3. After confirming that the patient does not have any allergies to the antiseptic, wash the patient's arm and apply an antiseptic. Locate IMPLANON™ by palpation and mark the end closest to the elbow, for example, with a sterile marker (Figure a).
4. After determining the absence of allergies to the anesthetic agent or related drugs, anesthetize the arm, for example, with 0.5 to 1 cc 1% lidocaine at the site where the incision will be made (near the tip of IMPLANON™ that is closest to the elbow) (Figure b). Be sure to inject the local anesthetic under IMPLANON™ to keep the implant close to the skin surface.
5. Make a 2-3 mm incision in the longitudinal direction of the arm at the tip of the implant closest to the elbow (Figure c).
6. Gently push IMPLANON™ toward the incision until the tip is visible. Grasp the implant with forceps (preferably curved mosquito forceps) and pull it out gently (Figure d).
7. If IMPLANON™ is encapsulated, make an incision into the tissue sheath and then remove IMPLANON™ with the forceps (Figures e and f).
8. If the tip of the implant is still not visible after gently pushing it towards the incision (as in step 6), gently insert a forceps into the incision and grasp the implant (Figures g and h). Turn the forceps around (Figure h).
9. With a second forceps carefully dissect the tissue around IMPLANON™ and then remove IMPLANON™ (Figure i). Be sure to remove the IMPLANON™ rod entirely. Confirm that the entire rod, which is 4 cm long, has been removed by mea- suring its length.
If the patient would like to continue using IMPLANON™, insert a new IMPLANON™ rod immediately after the old IMPLANON™ rod is removed. The new IMPLANON™ can be inserted in the same arm, and through the same incision, or a new IMPLANON™ can be inserted in the other arm. If the patient does not wish to continue using IMPLANON™ and does not want to become pregnant, recommend another contraceptive method.
10. After removing IMPLANON™, close the incision with a butterfly closure and apply an adhesive bandage.
11. Apply a pressure bandage with sterile gauze to minimize bruising.
Manufactured for Organon USA Inc. Roseland, NJ 07068 by N.V. Organon, Oss, The Netherlands. FDA Rev date: 1/18/2007

Read More

Website allows users to calculate radiation exposure during scans.

Website allows users to calculate radiation exposure during scans.

In her column in Chicago's Daily Herald (2/24), Anna Marie Kukec wrote that "[s]ome medical groups" have expressed "concerns over radiation exposure" during scans. This "led American Imaging Management, a subsidiary of WellPoint Inc., last week to launch a website" that "helps calculate radiation exposure and explains results." The site allows users to calculate the "millisivert measurement of radiation dosage" by "type of scan." The company, which "is a subsidiary of WellPoint Inc.," plans to "introduc[e] an educational campaign with physicians to raise awareness of radiation issues related to imaging in order to promote more informed decision making between physicians and their patients across the country."

Read More

The Use of Ultrasonography in the Diagnosis of Ectopic Pregnancy: A Case Report and Review of the Literature

An ectopic pregnancy is a potentially life-threatening gynecologic emergency that requires urgent intervention. Because the vast majority of ectopic pregnancies are tubal,[1] this discussion concentrates on this specific type of ectopic pregnancy. There is ongoing debate in regard to the best method to investigate and diagnose (tubal) ectopic pregnancy.[2]

In all sexually active women of reproductive age who present with lower abdominal pain, with or without vaginal bleeding, an ectopic pregnancy must be excluded. A qualitative urine dipstick test for beta-hCG (urinary pregnancy test) must be carried out.[4,5] This is a quick, easy, and sensitive test. It has a sensitivity of 99% at a urine beta-hCG level greater than 25 IU/L.[4] If a woman has a negative urinary pregnancy test, this almost invariably means that she does not have an ectopic pregnancy.[4] However, if it is positive the woman should have a USS.[4,5]

Gracia and Barnhart[6] compared different methods of diagnosing ectopic pregnancy using combinations of transvaginal ultrasound plus biochemistry (serum progesterone and serum beta-hCG), ultrasound only, and clinical examination without ultrasound. The study found that the most accurate method of diagnosing ectopic pregnancy was using a combination of ultrasound followed by beta-hCG.

A recently published review by Sawyer and Jurkovic[2] found that the most accurate way to diagnose an ectopic pregnancy is the use of a combination of ultrasonography, serum beta-hCG, and histology, either following laparoscopy or dilatation and curettage (D&C). However, unlike ultrasonography, neither biochemistry nor histology are available immediately, and when presented with a pregnant woman with pain and/or vaginal bleeding, clinicians must urgently exclude an ectopic pregnancy. As such, the initial investigation should be ultrasonography.

In addition to having a transabdominal ultrasound scan, a symptomatic woman with a positive urinary pregnancy test should also have a transvaginal ultrasound scan (TVS) performed. The use of TVS in the diagnosis of ectopic pregnancy has become widely accepted and practiced. Transvaginal ultrasonography has transformed the assessment of problems in early pregnancy.[5] It is suggested that transvaginal ultrasonography is the "ultimate diagnostic tool" in the diagnosis of ectopic pregnancy.[7] In fact, Condous upholds that "transabdominal ultrasonography is an outdated modality which is not diagnostic of ectopic pregnancy and should no longer be used.[4]" However, transabdominal scans are still very informative because TVS can miss some suprapubic pathology. Comparing the 2 ultrasonographic modalities, it has been said that the diagnostic reliability of transabdominal ultrasonography is around 70%, whereas that of TVS, under ideal conditions, is more than 90%.[8]

Shalev and colleagues[7] found that the use of TVS in the diagnosis of an ectopic pregnancy has a sensitivity of 87%, specificity of 94%, and positive predictive value of 92.5%. Another study[9] gave a sensitivity of 93%, specificity of 99%, and positive predictive value of 98%, and when a TVS finding of an adnexal mass was combined with serum beta-hCG, this increased the sensitivity to 97%, with equivalent specificity and positive predictive value.

The possible adnexal findings on USS in an ectopic pregnancy are[1,10]:

1. A tubal ring, ie, an empty gestational sac;
2. A gestational sac with a fetal pole and fetal heartbeat;
3. A gestational sac containing a yolk sac or embryo; and
4. An adnexal mass other than a simple cyst.

A retrospective study[11] of ultrasonographic images found that a tubal ring (an adnexal mass with a concentric echogenic rim of tissue [a gestational sac] surrounding a hypoechoic [empty] center) was present in 68% of ectopic pregnancies in which the tube had not ruptured. Brown and Doubilet[10] identified the 4 aforementioned ultrasonographic findings for the diagnosis of ectopic pregnancy. They concluded that the most appropriate way to identify an ectopic pregnancy is with any noncystic adnexal mass. However, it must be noted that the absence of adnexal findings on TVS does not exclude an ectopic pregnancy, and serial serum beta-hCG levels should be measured.[1]

Occasionally a "pseudosac" may be seen in the uterus (Figure 1). This is an intrauterine fluid collection produced by the ectopic pregnancy, which can mimic a gestational sac giving a false picture of an intrauterine pregnancy.


Sometimes there are no conclusive adnexal findings, and the diagnosis of ectopic pregnancy may be based on other ultrasound features, such as hematoperitoneum,[2,12] hematosalpinx,[2,12] and free fluid in the peritoneum or the pelvis, for example, in the pouch of Douglas .[12]

The diagnosis of ectopic pregnancy should be based on the positive findings of an adnexal mass with TVS rather than the absence of an intrauterine gestational sac (ie, an "empty uterus").[4] The CEMD report describes a potentially preventable death in which a woman who had an empty uterus on USS was misdiagnosed with complete miscarriage. She died 3 weeks later.[3] The differential diagnosis of an empty uterus with a positive beta-hCG is complete miscarriage, an early pregnancy (less than 5 weeks), or ectopic pregnancy.[1]

Ultrasound reports that read "empty uterus, ectopic pregnancy cannot be excluded" are not helpful.[4] If an ectopic pregnancy is present and scanning skills are highly developed, between 87% and 93% should be identified with TVS before surgery.[7,9,13] If there are no adnexal findings on TVS in the absence of an intrauterine gestational sac, then ectopic pregnancy must still be excluded, by measuring serial serum beta-hCG levels.[4,5]

Diagnosing ectopic pregnancy earlier with TVS has changed the available management options. Early diagnosis allows the clinician to consider conservative options, such as methotrexate, in patients who are hemodynamically stable and in whom the ectopic pregnancy is small.[1,14] It has also reduced the associated mortality, with shock and collapse and subsequent emergency laparotomy being the exception rather than the rule in modern practice.[4] The use of TVS in the diagnosis of ectopic pregnancy has meant that laparoscopy can be reserved for its treatment, rather than as a diagnostic tool.[2]

The reported case highlights an example of a situation in which an ectopic pregnancy was inadequately excluded and a misdiagnosis of a complete miscarriage was made. The error that was made is that an ectopic pregnancy was excluded on the basis of the lack of any adnexal masses on TVS and the absence of an intrauterine gestational sac.

As stated above, the lack of adnexal masses on TVS does not rule out the presence of an ectopic pregnancy. An empty uterus with a positive urinary beta-hCG is not diagnostic of a complete miscarriage. Both findings, as this case illustrates, do not eliminate the possibility of an ectopic pregnancy. Therefore, women with suspected complete miscarriages in whom ectopic pregnancy cannot be excluded must be followed up by close monitoring of their serial serum beta-hCG levels.

On the basis of this review, the following management algorithm is recommended to evaluate a sexually active woman of reproductive age who presents with lower abdominal pain and/or vaginal bleeding for the possibility of an ectopic pregnancy. First, a beta-hCG urine dipstick test must be performed urgently. If this is positive, she must have a USS. If there are adnexal masses suggestive of an ectopic pregnancy, she must be treated for this. However, even if there are no adnexal masses on TVS, in the absence of an intrauterine gestational sac ectopic pregnancy cannot be excluded, and she must have serial serum beta-hCG measurements.[4,5]

References

Drife J, Magowan B, eds. Clinical Obstetrics and Gynaecology. London, United Kingdom: Saunders; 2004:169-171.
Sawyer E, Jurkovic D. Ultrasonography in the diagnosis and management of abnormal early pregnancy. Clin Obstet Gynecol. 2007;50:31-54. Abstract
Drife J, Lewis G, eds. Why Mothers Die 2000-2002 - The Sixth Report of Confidential Enquiries into Maternal Deaths in the United Kingdom. London, United Kingdom: Royal College of Obstetricians and Gynaecologists; 2004.
Condous G. Ectopic pregnancy - risk factors and diagnosis. Aust Fam Physician. 2006;35:854-857. Abstract
Murray H, Baakdah H, Bardell T, Tulandi T. Diagnosis and treatment of ectopic pregnancy. CMAJ. 2005;173:905-912. Abstract
Gracia C, Barnhart K. Diagnosing ectopic pregnancy: decision analysis comparing six strategies. Obstet Gynecol. 2001;97:464-470. Abstract
Shalev E, Yarom I, Bustan M, Weiner E, Ben-Shlomo I. Transvaginal sonography as the ultimate diagnostic tool for the management of ectopic pregnancy: experience with 840 cases. Fertil Steril. 1998;69:62-65. Abstract
Gurel S, Sarikaya B, Gurel K, Akata D. Role of sonography in the diagnosis of ectopic pregnancy. J Clin Ultrasound. 2007;35:509-517. Abstract
Cacciatore B, Stenman UH, Ylostalo P. Diagnosis of ectopic pregnancy by vaginal ultrasonography in combination with a discriminatory serum hCG level of 1000 IU/L. Br J Obstet Gynaecol. 1990;97:904-908. Abstract
Brown DL, Doubilet PM. Transvaginal ultrasonography for diagnosing ectopic pregnancy: positivity criteria and performance characteristics. J Ultrasound Med. 1994;13:259-266. Abstract
Fleischer AC, Pennell RG, McKee MS, et al. Ectopic pregnancy: features at transvaginal sonography. Radiology. 1990;174:375-378. Abstract
Bourgon DR. Ectopic prgenancy. eMedicine. December 2, 2005. Available at: http://www.emedicine.com/radio/topic231.htm Accessed January 15, 2008.
Condous G, Okaro E, Khalid A, et al. The accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy prior to surgery. Hum Reprod. 2005;20:1404-1409. Abstract
Sowter MC, Farquhar CM, Petrie KJ, Gudex G. A randomised trial comparing single dose systemic methotrexate and laparoscopic surgery for the treatment of unruptured tubal pregnancy. Br J Obstet Gynaecol. 2001;108:192-203.

Read More

CT scan can harm kidneys, but cheap drug can help

Medical Research News
Published: Wednesday, 20-Feb-2008


As more and more Americans undergo CT scans and other medical imaging scans involving intense X-rays, a new study suggests that many of them should take a pre-scan drug that could protect their kidneys from damage.
The inexpensive drug, called N-acetylcysteine, can prevent serious kidney damage that can be caused by the iodine-containing "dyes" that doctors use to enhance the quality of such scans.
That "dye," called contrast agent, is usually given intravenously before a CT scan, angiogram or other test. But the new study shows that taking an N-acetylcysteine tablet before receiving the contrast agent can protect patients - and that it works better than other medicines that have been proposed for the same purpose.
People whose kidneys are already vulnerable, including many older people and those with diabetes or heart failure, are the most at risk from contrast agents, and have the most to gain from taking the drug.
Researchers from the University of Michigan Health System performed the study, which is published in the Annals of Internal Medicine. It is a meta-analysis of data from 41 randomized controlled studies that evaluated various drugs for their kidney-protecting effects. It was led by Aine Kelly, M.D., M.S., an assistant professor in the Department of Radiology at the U-M Medical School.
Only N-acetylcysteine clearly prevented contrast-induced nephropathy, the medical name for kidney damage caused by contrast agents. Theophylline, another drug that has been seen as a possible kidney-protecting agent, did not reduce risk significantly. Other drugs had no effect, and one, furosemide, raised kidney risk.
"Our goal is to improve the safety and quality of these common tests by studying drugs that reduce the risk of kidney failure," says senior author Ruth Carlos, M.D., associate professor of radiology.
Mild to moderate kidney damage occurs in one in four high-risk people who have CT scans, and in as many as one in ten people with normal kidney function. In some cases, it causes acute kidney failure.
"Millions of people receive contrast agent each year, including most heart patients who have angioplasties and stents, as well as those having a CT scan. Contrast agent helps physicians see the things we need to see, but it also does pose a hazard to some people," says Kelly. "This drug, which is quick, convenient, inexpensive and widely available, with no major side effects, appears to be the best choice to protect those whose kidneys are most at risk."
Only studies that involved intravenous iodine-containing contrast agents, and compared a drug with a water or saline control, were included in the analysis. Oral "milkshake" barium contrast agents, used in CT scans of the digestive system, do not cause kidney damage, and were not included.
The study also did not assess potential ways to protect against kidney damage from gadolinium contrast agents used in MRI (magnetic resonance imaging) scans. Since May 2007, those contrast agents have carried a warning from the U.S. Food and Drug Administration about risk to kidneys.
Kelly, Carlos and their colleagues performed the study to try to get a firm answer to a question that has puzzle medical imaging specialists for years.
Although many drugs have been tried for prevention of iodine-related contrast-induced nephropathy, contradictory evidence has emerged from studies of how well they work. The result has been widespread variation in what hospitals and medical imaging centers do before scanning a patient.
Although a prospective trial comparing N-acetylcysteine directly to other drugs should be conducted to verify the U-M team's findings, the team hopes its new study will help guide both clinicians and patients.
In fact, Kelly says, patients who know they have weakened kidneys - also called impaired renal function - should speak up when their doctor orders a CT scan, angiogram or angioplasty, and make sure they get a tablet of N-acetylcysteine beforehand.
And, since most kidney problems cause no symptoms, even healthy people might want to ask their doctors to test their blood creatinine levels before sending them for a scan.
Creatinine levels go up when the kidneys aren't operating efficiently. Contrast-induced nephropathy is defined as a 25 percent or greater increase in creatinine within 48 hours of receiving contrast agent. The new study evaluated the impact of pre-scan medicines by looking at their impact on patients' creatinine levels, as a surrogate for kidney function.
The problem of contrast-induced nephropathy is a relatively recent one - a byproduct of the dramatic increase in the use of CT scans and X-ray guided procedures such as angioplasty.
The benefit of these scans is not in question: Intense X-rays can reveal valuable information about injuries, diseases, and patients' response to treatment. Iodine-containing agents allow doctors to improve the scans even further, giving better "contrast" between the blood vessels and tissue, because X-rays are scattered differently by iodine. But as the iodine is carried by the blood to the kidneys, and filtered out into the urine, the iodine can upset the delicate balance that keeps the kidneys functioning.
In recent years, manufacturers of contrast agents have begun to offer different formulations that may pose less risk to patients' kidneys. More expensive low-iodine and iodine-free agents are available to especially vulnerable patients, and to people who are allergic to iodine. But for everyone else, medical imaging specialists have tried to find ways to prevent the damage.
N-acetylcysteine is already widely used to clear mucus in cystic fibrosis patients, and to treat overdoses of acetaminophen. It's also being studied for other uses.
Tablets of prescription-strength N-acetylcysteine are inexpensive - about 25 cents for a 500 milligram tablet - and stocked by most pharmacies. It has few side effects. Over-the-counter supplement forms of the drug should not be used for pre-scan kidney protection.

In addition to Kelly and Carlos, the study's authors are Ben Dwamena, M.D., and Paul Cronin, M.B.B.Ch., both assistant professors of radiology, and Steven J. Bernstein, M.D., MPH, professor of internal medicine.
The study was funded by the National Institutes of Health and the National Cancer Institute, and by Kelly's GE-Association of University Radiologists Radiology Research Academic Fellowship. None of the authors has financial connections with manufacturers of the drugs or contrast agents studied.

Reference: Annals of Internal Medicine, 19 February 2008, Volume 148 Issue 4

Read More

Administration of Intravenous Radiocontrast to patients with asthma

History
Iodinated contrast media were first introduced in 1929 as sodium Iodide (1,2). In the 1950’s tri-iodinated benzoic acid salts were introduced and then in the 1970’s, the currently used low osmolarity non-ionic contrast media were developed.

Pathophysiology
Iodine has a high atomic number of 53, similar to that of barium.(1) After intravenous injection, 70% of the dose diffuses into the extracellular space within 5 minutes and complete equilibrium is achieved by 2 hours. It is filtered by the renal glomerulus and has no tubular reabsorption having a half life of 2 hours if normal renal function.(2) Iodine salt is found readily in modern food and drinking water.(1) Although Iodine allergy does occur, it would result in allergy to common salt and true allergy is very rare.

ADVERSE DRUG REACTIONS
Intravenous contrast is the commonest drug used in Radiology and every contrast examination is performed at some risk to the patient.

Adverse reactions to contrast media can result by multiple different mechanisms
Drug allergy
Pseudoallergic “anaphylactoid”
Drug Intolerance
Overdose
Drug Interaction
Reactions may be dose dependent or idiosyncratic.

Most Adverse Drug Reactions (ADR) are not allergic in nature but rather due to the chemical composition and are directly related to the osmolarity. The exact mechanism is not clear however the osmotic contrast bolus interrupts homeostasis with the degree of disruption directly relating to the risk of adverse event.( 1 ,2, 3,4) Use of low osmolarity non-ionic contrast significantly decreases the physiologic disturbances.(4)


Osmolarity
Plasma
300
Ionic
1000-2400
Non-ionic
750

Allergic type reactions are usually unpredictable and involve multiple mediators.(2)
Anaphylactoid reactions are more common than true IgE mediated anaphylactic reactions and there is no anti-contrast antibody detected in the majority of cases making predictive skin testing unhelpful.(2,3)

Most adverse reactions will occur within the first 60 minutes with the greatest risk in the first 5 minutes. Delayed contrast reactions do occur with some events recorded up to 7 days post contrast. These are often not reported and sometimes difficult to relate directly to the contrast injection and although reported at 2-8%, the exact incidence is unknown.(2,5)

Ionic versus Non-ionic contrast
There is no doubt from the literature that non-ionic contrast is significantly safer than ionic contrast when considering ADR's of all levels of severity. (1,2, 4,6,7,8,9,10,11,12,13) Fatal reactions are very rare and there is less of a statistically significant difference between the two types of contrast. (7) A detailed review of this topic is beyond the scope of this paper however a brief review of the major studies in the literature is included. Non-ionic contrast is the standard in this institution.

There is some variation in the literature between quoted incidence of ADR’s. This is due to a number of reasons but mostly to the fact that there is no standard definition of an ADR or its severity. Many studies do not separate the osmolality related ADR’s from anaphylactoid or anaphylactic reactions.


Ionic
Non-ionic
Total


Mild
8-15%
0.2-3%
Moderate
1-2%

Severe
0.1-0.22%
0.04%
Life threatening
0.04%
0.004%
Fatal
0.0006% 1: 170,000
0.0006% 1:170000
(1,2,4,7,11)
The risk of fatal reaction does not differ between contrast types. The risk of death from contrast is similar to that of the risk of death from exposure to penicillin. (1)

History of allergy or atopy
A history of allergy in some form is associated with a 1.5-3 fold relative risk increase for an ADR. (2,4,11) Despite the long held belief, there is no proven association between seafood allergy and reaction to non-ionic intravenous contrast. Seafood allergy results from hypersensitivity to a protein within the seafood and has no association with iodine. As such there is no higher relative risk in a patient with seafood allergy than with allergy to any other food product. (1,8)

Anxiety as a risk factor
There appears to be an association between the level of patient anxiety and the risk of an allergic type ADR. (1,2) This should be considered when interacting with patients prior to contrast administration.

ASTHMA AND INTRAVENOUS CONTRAST

The issue of administration of intravenous contrast to patients with a history of asthma arises frequently. There does not appear to be a standard approach within the Royal Brisbane Hospital (RBH).
A history of asthma is associated with a 5-6 fold increase in relative risk of ADR to contrast.( 2,4,14) Despite this, although the incidence of childhood asthma is double that of adults at 13-20%, children have a much lower rate of ADR to contrast media.(14)


Role of pretreatment
The risk of recurrent anaphylactoid reaction after intravenous contrast is variably quoted from 17-35%.(15) There are many case reports regarding ADR to contrast despite pretreatment regimes and there is no doubt that steroid pretreatment does not exclude the potential for life threatening allergic ADR’s.( 1 ,2,3,6,16) The quoted figures for breakthrough reactions despite steroid pretreatment range from 6-40%.(9,16)
Patients with a previous history of contrast related allergy have a 5 fold increase relative risk for recurrent adverse event.(2)

There is no support in the literature for the use of antihistamines or adrenaline for pretreatment.(2,15)

Current American College of Radiology Guidelines recommend the use of non-ionic contrast but describe no role for pretreatment. (6)

At the Great Ormond Street Hospital for Children, there is an established protocol for asthmatic patients receiving non-ionic contrast. Pretreatment is administered only if there is a history of previous contrast reaction, chronic steroid dependent asthma or active wheeze on presentation. Asthmatic patients on bronchodilators or inhaled steroids do not receive pretreatment.(14)

LANDMARK STUDIES

There is a noticeable paucity of literature addressing the issue of Adverse Drug Reaction (ADR) to intravenous contrast in the last two decades since the introduction of non-ionic contrast. Most studies relate to the use of ionic contrast and have little relevance to current clinical practice.

Lasser et al 1987 The New England Journal of Medicine(11)
Prospective multi-institutional randomised study of 6763 patients with a previous history of an immediate generalised contrast reaction. Randomised to oral methylprednisalone pretreatment at 12 and 2 hours prior, at 2 hours prior and placebo groups. Patients were given ionic contrast only. The single dose pretreatment regime showed no benefit at interim analysis and was subsequently discontinued.

Conclusion
- No difference between placebo and steroid pretreatment at 2 hours prior.
- Statistical benefit of dual dose steroid pretreatment for overall, minor and severe reactions but not for moderate reactions.
- Non-ionic contrast without pretreatment is safer than ionic contrast with pretreatment BUT cheaper to pretreat and use ionic contrast than use non-ionic contrast.


Limitations
- Looked at ionic contrast only – not relevant in current practice.
- Too small study group for statistical difference between moderate ADR.
- Asthma was inadvertently not assessed due to an error in the data sheet.


Palmer et al 1988 Australasian Radiology (4,12)
A recommended guideline for selective use of non-ionic contrast in high risk patients was issued by the Royal Australasian College of radiologists in 1986. A prospective survey of ADR was performed between 1986 and 1988.

Reactions graded
Mild – skin reaction / not require treatment
Moderate – require treatment but not admission
Severe – required urgent treatment and admission

109,546 patients included in the survey.


IONIC CONTRAST

NON-IONIC CONTRAST

ADR
High risk patient
Low risk patient
High risk patient
Low risk patient
Mild
7.2%
3.2%
1.1%
.97%
Moderate
2.7%
0.3%
.1%
.09%
Severe
0.36%
.09%
.03%
0
Death
0
.0025%
0
0
Incidence Mod-severe

1:32

1:251

1:718

1:1084

Conclusions
- non-ionic contrast is safer in all groups

Lasser et al 1993 American Journal Radiology(17)
Prospective randomised multi-institutional study of 1411 patients requiring intravenous contrast for CT or IVP over a 3 year period. Assessed with intention to treat
All patients received non-ionic contrast. The study group received oral methylprednisalone at 6-24 hours and at 2 hours prior and was compared with placebo. Reactions were graded as mild, moderate and severe and were not restricted to allergic type symptoms or signs.

Conclusion
- Overall reaction rate fell from 5% to 2% with predominant effect seen in mild reactions.
- There was no significant reduction in moderate and severe reactions.

Limitations
- small study number despite the duration of the study and multiple institutions.
- study ceased early due to lack of funds.
- Because Moderate and Severe reactions are very uncommon, a very large study group would be required to see a significant difference.





Katayama et al 1990 Radiology(13)
Nationwide Japanese prospective study to compare the use of ionic and non-ionic intravenous contrast. 352,817 contrast injections with equal percentage of ionic and non-ionic contrast used.

ADR
Ionic
Non-ionic
Total
21428 (12.66%)
5276 (3.13%)
Severe
367 (0.22%)
70 (0.04%)
Very Severe
63 (0.04%)
6 (0.004%)
Fatal
1 - ? association
1 - ? association
All differences had P < 0.01

No difference was found with age and sex.

Past history of contrast reaction:

Ionic
Non-ionic
Overall recurrence rate
44%
11.2%
Recurrence of severe reaction
0.73%
0.18%

History of allergy or atopy:

Ionic

Non-ionic


All ADR
Severe ADR
All ADR
Severe ADR
Hx of allergy
23.3%
0.53%
6.8%
0.1%
No Hx allergy
11.7%
0.13%
2.7%
0.03%

History of asthma:
Ionic – 1.88% have severe reactions
Non-ionic – 0.23% have severe reactions

Effect of pretreatment:
Hx Allergy
PreRx
Ionic

Non-ionic



ADR
Severe
ADR
Severe
With
PreRx
34.5%
0.28%
14%
0.1%

Not
22.2%
0.56%
6.3%
0.1%
Without
PreRx
17.8%
0.36%
4.7%
0.06%

Not
11.3%
0.17%
2.6%
0.03%

Conclusions
- Non-ionic contrast reduces prevalence of ADR’s at all levels of risk
- Patients with a history of allergy and given non-ionic contrast had less ADR than patients without a history of allergy and given ionic contrast.
- Steroid pretreatment is beneficial only for ionic contrast and history of allergy
- There is no benefit of steroid pretreatment when non-ionic contrast is used



REFERENCES

1. Shymko, M.: Reactions to iodinated contrast. Radiologic Technology72(4): 381-2.
2. Morcos, S., Thomsen, H.: Adverse Reactions to Iodinated contrast media. European Radiology (2001)11: 1267-75.
3. Dewachter, P., Mouton-Faivre, F., Felden, F.: Allergy and contrast media. Allergy (2001) Mar 56(3): 250-1.
4. Palmer, F. The R.A.C.R. Survey of Intravenous Contrast Media Reactions. A preliminary report. Australasian Radiology 1988 32: 8-11.
5. Newman, B. Delayed Adverse reaction to non-ionic contrast agents. Paediatric Radiology (2001) 31: 597-9.
6. Taragin, B., Newhouse, J. Question and Answer. American Journal of Roentgenology (2001) 177: 1211-2.
7. Cochran, S., Bomyea, K., Sayre, J. Trends in Adverse Events after IV Administration of Contrast Media. American Journal of Roentgenology (2001) 176: 1385-8.
8. Leder, R. The safe administration of intravenous contrast material for urologists and radiologists. Current opinion in Urology 2000 10: 95-7.
9. Dunnick, N., Cohan, R. Cost, Corticosteroids and Contrast Media. American Journal of Roentgenolegy 1994 162: 257-9.
10. Federle, M., Willis, L., Swanson, D. Ionic versus Non-ionic contrast media: A prospective study of the effect of rapid bolus injection on nausea and anaphylactoid reactions. Journal of Computed Assisted Tomography 22(3): 341-5.
11. Lasser, M., Berry, C. et al. Pretreatment with corticosteroids to alleviate reactions to Intravenous Contrast Material. The New England Journal of Medicine 1987 317(14): 845-9.
12. Palmer, F. The R.A.C.R. Survey of Intravenous contrast media reactions. Final Report. Australasian Radiology 1988 32: 426-8.
13. Katayama, H., Yagamuchi, K. Adverse Reactions to Ionic and Non-ionic Contrast Media. Radiology (1990) 175(3): 621-8.
14. McHugh, K., Shaw, M. Prophylaxis in asthmatic patients prior to intravenous contrast. Paediatric radiology (1990) 29(1): 78.
15. Greenberger, P., Patterson, R., Tapio, C. Prophylaxis against repeated radiocontrast Reactions in 857 cases. Archives of Internal Medicine (1985) 145: 2197-200.
16. Freed, K., Leder., et al, Breakthrough adverse reactions to low-osmolar contrast media after steroid premedication. American Journal of Roentgenology (2001) 176: 1389-92.
17. Lasser, E., Berry. et al. Pretreatment with corticosteroids to prevent adverse reactions to non-ionic contrast media. American Journal of Roentgenology (1994) 162: 523-6.




SUMMARY OF LITERATURE REVIEW

The incidence of severe or life threatening Adverse Drug reaction (ADR) to contrast is very low.

Most ADR's are due to osmotically induced physiologic disturbances.
True allergic reactions are uncommon and anaphylactoid reactions predominate.
Non anaphylactoid reactions (nausea, vomiting and flushing) are significantly less common with non-ionic contrast and not associated with an increase risk of anaphylactoid reaction.

There is no doubt regarding the safety of non-ionic contrast relative to ionic contrast.

Patients with an allergic history have a 3 fold increase relative risk for allergic type ADR.
Allergy to seafood is NOT directly related to risk of contrast ADR.

Pretreatment

Patients with a previous anaphylactoid contrast reaction have up to a 40% risk of recurrent contrast reaction.
Pretreatment with corticosteroids is associated with a breakthrough rate of up to 40% and breakthrough reactions may be lifethreatening.

There is no evidence base for pretreatment with antihistamine or adrenaline.

Contrast in asthmatics

Patients with asthma have a 5 fold increase in relative risk for allergic type ADR.
If non-ionic contrast is used, pretreatment has no significant effect on the risk of anaphylactoid reaction.

There is no evidence in the literature to support routine premedication of asthmatics prior to administration of intravenous non-ionic contrast.
Patients on bronchodilators and inhaled steroids do not benefit from steroid pretreatment.

TAKE HOME MESSAGE

Most adverse drug reactions will occur unexpectedly despite risk assessment.
Pretreatment will not prevent severe adverse drug reactions
All staff should be skilled in the detection and immediate management of anaphylaxis.

Read More

Who Is at Risk for Contrast- Induced Nephropathy?

Who Is at Risk for Contrast- Induced Nephropathy?
by Richard Solomon MD

Identifying high-risk patients is the first step in a programmatic approach to preventing contrast-induced nephropathy.
A number of risk factors for contrast-induced nephropathy have now been identified through the analysis of information from large databases. Most of the data come from the cardiac literature and involve patients diagnosed with and without interventional procedures. The clinical risk factors correspond to recognized pathophysiological mechanisms of acute renal failure (Table 1).
PATIENT-RELATED FACTORS
PROCEDURE-RELATED FACTORS
§ Baseline renal insufficiency
§ Diabetes mellitus with renal insufficiency
§ Volume depletion
§ Hypoalbuminemia
§ Hypotension (mean arterial pressure < 100 mm Hg)
§ Intra-aortic balloon pump dependent
§ Urgent catheterization
§ Low-output class IV heart failure
§ Concomitant exposure to other nephrotoxins (nonsteroidal anti-inflammatory drugs and cyclosporin A)
§ Multiple contrast injections within 72 hours
§ Intra-arterial injection site
§ High volume of contrast
§ Type of contrast
Table 1. Risk factors for contrast-induced nephropathy.
The most important risk factor is chronic kidney disease. The National Kidney Foundation has staged chronic kidney disease (Table 2). The glomerular filtration rate (GFR) is the yardstick by which the various stages are defined because the GFR reflects kidney function. The serum creatinine is derived from the GFR. Because of marked differences in the production of creatinine among individuals, a given serum creatinine level will not reflect the same GFR across individuals. Since measuring the GFR (estimated using creatinine clearance) is tedious, inaccurate because of collection errors, and thus clinically inappropriate for the vast majority of patients, formulas have been developed to determine the estimated GFR (eGFR) based on the serum creatinine level. These formulas have been based on work with large groups of patients, with GFR measured via iothalamate clearance and validated for a number of different types of patients. The Modification of Diet in Renal Disease formula is the most widely accepted; it has the advantage that only the patient's age, gender, race, and serum creatinine are required for the calculation. 1 Calculators are available on Web sites 2-5 and are also distributed by a number of organizations as a slide rule. Many authorities agree that the risk of contrast-induced nephropathy (CIN) increases as the eGFR falls below 60 mL per min per 1.73 m 2 (stage III).
STAGE
DESCRIPTION
GFR (mL/min/1.73 m2)
1
Chronic kidney damage with normal or elevated GFR
> 90
2
Mildly decreased GFR
60 to 89
3
Moderately reduced GFR
30 to 59
4
Severely reduced GFR
15 to 29
5
Kidney failure
< 15 or dialysis
Table 2. National Kidney Foundation-Kidney Disease Outcome Quality Initiative staging classification of chronic kidney disease; GFR=glomerular filtration rate.
Reduction in blood flow to the kidney will also enhance the risk of CIN. This occurs with hypotension (from any cause) and with intravascular volume depletion due to trauma, acute gastrointestinal losses, chronic use of diuretics, congestive heart failure, and cirrhosis. Pharmaceuticals such as nonsteroidal anti-inflammatory drugs may also contribute to a reduction in renal blood flow.
Procedure-related risk factors involve the contrast agent itself: its chemical characteristics (osmolality, ionicity, viscosity, and similar factors); the volume administered; and timing. The route of administration may also be important, although compelling evidence for a lower rate of CIN with intravenous (IV) use is not available.
Identifying high-risk patients is the first step in a programmatic approach to preventing CIN. A number of profiles have been developed to make the process more formula based.
Because the characteristics of patients undergoing coronary catheterization with percutaneous coronary intervention differ significantly from those of patients undergoing contrast-enhanced CT examinations, these profiles differ (Figure 1).
After the identification of high-risk patients, the next step is to determine whether the diagnostic information needed for their care can be obtained without the use of contrast. For some diagnostic questions, MR angiography with gadolinium chelates, interventional angiography with carbon dioxide, or ultrasound may be appropriate.
Figure 1. Identifying high-risk patients in CT use of contrast; eGFR=estimated glomerular filtration rate; EF=ejection fraction, NSAID-nonsteroidal anti-inflammatory drug, ACEI=angiotensin-converting enzyme inhibitor, and ARB=angiotensin receptor blocker. Adapted with permission from AJR Am J Roentgenol (reference #13)
When iodinated contrast is to be administered, efforts to protect the patient from the nephrotoxic effects of the contrast medium are required. Current recommendations are derived from randomized controlled trials, predominately in the cardiac literature. Volume expansion with diuresis (more than 150 mL per hour)6 is the most widely recommended therapy. There are a variety of approaches used in clinical trials that must be accommodated by clinical practice. In general, patients should not avoid oral intake unless this restriction is required by anesthesia administration; even then, the interval of intake restriction before contrast exposure should be as short as possible. IV fluids, in the form of 0.45% or 0.9% sodium chloride solution, should be started 12 hours before contrast exposure, if possible, at a rate of 1 mL per kg per hour. 7,8 The infusion, however, needs to be individualized to suit the clinical situation. For patients who are not in heart failure, a more rapid infusion augmented by oral water may suffice, although data are lacking concerning this. Isotonic sodium bicarbonate, infused at a rate of 3 mL per kg per hour for 1 hour before contrast exposure, was also shown to be effective in reducing the incidence of CIN. 9 This may be particularly useful in emergency situations and in patients with congestive heart failure. The use of diuretic agents (loop diuretics, mannitol, and dopamine) is discouraged because of either their lack of effect or their association with an increased risk of CIN. 8 IV fluids should be continued for 8 to 12 hours after contrast exposure at 1 mL per kg per hr.
At present, there is no role for the systemic administration of vasodilatory agents. Antioxidants such as N-acetylcysteine (NAC) and ascorbic acid have been effective in some, but not all, studies. The differences between studies may reflect differences in the dose, timing, and route of administration of NAC. Only one study 10 has reported on the use of NAC in patients with renal insufficiency receiving contrast-enhanced CT. The drug was effective when it was administered starting the day before exposure to contrast and was continued on the day of exposure.
The choice of contrast is also important. Low-osmolality and iso-osmolality contrast media are associated with a lower incidence of CIN, compared with high-osmolality contrast. There are too few head-to-head comparison trials to permit recommending one agent over another. 11 When contrast administration is combined with the prophylactic strategies of volume expansion and antioxidant therapy, the incidence of CIN is reduced for all agents. 12
The diagnosis of CIN can only be made if a second serum creatinine level is obtained 48 to 72 hours after contrast exposure. This is not an problem with hospital inpatients, but is difficult with outpatients. In high-risk patients, every effort should be made to obtain the follow-up serum creatinine level.
Richard Solomon, MD, is professor of medicine and chief of the Division of Nephrology, University Health Center, Fletcher Allen Health Care, Burlington, Vt.
References:
1. Levey A, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461-470.
2. Available at: www.nkdep.nih.gov/healthprofessionals/tools. Accessed October 8, 2005.
3. National Kidney Foundation. GFR calculator. Available at: www.kidney.org/kls/professionals/gfr_calculator.cfm. Accessed October 8, 2005.
4. Fadem SZ. MDRD GFR calculator. Available at: www.nephron.com/mdrd/default.html. Accessed October 8, 2005.
5. Hypertension, Dialysis, and Clinical Nephrology. Calculators and modeling aids. Available at: www.hdcn.com/calc.htm. Accessed October 8, 2005.
6. Stevens M, McCullough PA, Tobin K, et al. A prospective randomized trial of prevention measures in patients at high risk for contrast nephropathy. J Am Coll Cardiol. 1999;33:403-411.
7. Mueller C, Guerkle G, Buettner H, et al. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angiography. Arch Intern Med. 2002;162:329-336.
8. Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med. 1994;331:1416-1420.
9. Merten G, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004;291:2328-2334.
10. Tepel M, Van Der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med.
11. Solomon R. The role of osmolality in the incidence of contrast induced nephropathy: a systematic review of angiographic contrast media in high risk patients. Kidney Int. In press.
12. Briguori C, Colombo A, Airoldi F, et al. Nephrotoxicity of low-osmolality versus iso-osmolality contrast agents: impact of N-acetylcysteine. Kidney Int. In press.
13. Gleeson T, Bulugahapitiya S. Contrast-induced nephropathy. AJR Am J Roentgenol. 2004;183:1673-1689.
14. Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol. 2004;44:1393-1399.

Read More

Dilatation of the Virchow-Robin Space Is aSensitive Indicator of Cerebral MicrovascularDisease: Study in Elderly Patients withDementia

Tufail F. Patankar, Dipayan Mitra, Anoop Varma, Julie Snowden, David Neary, and Alan Jackson

BACKGROUND AND PURPOSE: Virchow-Robin spaces (VRSs) are CSF spaces that accompanyblood vessels as they perforate the brain substance. Dilatation of VRS is associated with microangiopathy. Microvascular disease has a major etiologic and pathogenetic role in dementias.To our knowledge, no investigators have looked at the relationship between dilated VRS onMR imaging and cerebral microvascular disease. The aim of our study was to test thehypothesis that dilatation of VRS is associated with subcortical vascular dementia.

METHODS: We recruited 75 patients with Alzheimer’s disease (n 35), ischemic vasculardementia (n 24), or frontotemporal dementia (n 16) and 35 healthy volunteers. Weassessed deep white matter and periventricular hyperintensities and the severity of VRSdilatation, as scored on MR images. Statistical group comparisons and multiple regressionanalyses were performed to quantify the relationship between imaging features and diagnoses.
RESULTS: White matter lesions were more common in patients with ischemic vasculardementia than in those with Alzheimer’s disease or healthy volunteers (P < .01). VRS scoreswere significantly higher in patients with vascular dementia than in patients with AD (P <.001), patients with FTD (P < .01), or healthy volunteers (P < .001). VRS scores accounted for29% of the variance in the regression model, and scores for periventricular hyperintensityaccounted for 2%.
CONCLUSION: VRS dilatation is common in diseases associated with microvascular abnormalityand can be used as a diagnostic tool to differentiate vascular dementias from degenerativedementias.

Read More

Leukoaraiosis and Ischemia

David G. Munoz, MD, FRCPC
From the University of Toronto, Department of Laboratory Medicine & Pathobiology, Toronto, ON, Canada.

Although Alois Alzheimer had described in 1902 a baffling extensive and severe degeneration of the cerebral white matter (misnamed Binswanger disease), over half a century of regular examination of brains by histological techniques failed to recognize the common occurrence of bilateral, patchy or confluent, white matter lesions revealed first as hypodense areas by computed tomography and later with much improved definition as hyperintensities in T2 and FLAIR sequences in magnetic resonance.1 Even in retrospect, it is hard to identify on histological sections the exact location of lesions so brightly demonstrated on magnetic resonance images. The name leukoaraiosis will be used in this editorial to designate these white matter lesions, as opposed to others related to demyelinating, infectious, toxic, or metabolic processes.2
Having named the finding we were left with an existentialist lesion in search of significance. As a marker, leukoaraiosis is a prognostic factor for stroke and myocardial infarction.3,4 Its consequences, even in samples restricted to nondisabled elderly, include impaired cognitive function,5,6 mediated by deterioration in information processing speed and executive functions,7 as well as reduced motor function,8 and possibly late onset-depression.9
But how are the lesions produced? Epidemiological studies suggest association with aging and vascular risk factors such as hypertension and diabetes,10,11 whereas histological studies indicate association with arteriolosclerosis of small blood vessels in the brain, consisting of replacement of mural smooth muscle by fibrohyaline material which eventually results in thickening of the wall and sometimes narrowing of the lumen.12,13 Several mechanisms are consistent with these findings: certainly ischemia–insufficient oxygen and nutrient delivery- is a possibility, but credible alternatives include alterations of the blood–brain barrier permeability either during hypertensive episodes or in relation to impaired venous return in the deep white matter. This would lead to vasogenic edema and leakage of molecules toxic to axons and their associated cells. Even disturbances in the circulation of cerebrospinal fluid could be involved.14 Depressed regional cerebral blood flow and acetazolamide reactivity has been shown in white matter hyperintensities,15 but it has proven difficult to demonstrate reduced regional cerebral blood flow combined with increased extraction fraction, which would constitute the imaging proof of ischemia. The term "incomplete infarct" does not advance our understanding of the process: it provides no more than a tattered cloak to hide the shame of our naked ignorance.
No animal model of leukoaraiosis is available. This is a common problem. Humans are often the only species to suffer a disease, and the range of ethical experimentation is very limited as compared with animals. Fernando et al16 have bridged the gap by taking brains from autopsies of demented and nondemented elderly donors, and treating them in parallel with both patients in whom magnetic resonance identifies the lesions, and laboratory animals in which immunohistochemically detected markers can be related to experimentally induced ischemia. Specifically the hypoxia-inducible factors HIF1 and HIF2, as well as the candidate markers of hypoxia proteins neuroglobin and MMP7 are expressed in glial cells in deep subcortical white matter lesions at a significantly higher level than in normal white matter. The cellular distribution is worth mentioning, as these markers are overexpressed in astrocytes and microglia, but apparently not in oligodendrocytes. The correlation of hypoxia markers in the lesions with amyloid angiopathy load strongly suggest that when present the latter is also involved in the genesis of leukoaraiosis, despite affecting leptomeningeal and cortical blood vessels, in contrast to the basal ganglionic and white matter preference of arteriolosclerosis.
Leukoaraiosis may have a different etiology in periventricular white matter given that only one of the markers of hypoxia studied was increased in lesions in this area. On the other hand, denudation of the lining of the ventricles was more common in cases with periventricular, but not deep white matter lesions, suggesting that fluid accumulation associated with disruption of the ependyma is involved in the genesis of the former.
The article convincingly demonstrates that leukoaraiosis is associated with persistent tissular ischemia. Several questions remain in relation both to the effects and the genesis of ischemia.
Yes, ischemia is involved, but how does it produce the observed lesions? We do not even know which of the 3 ultrastructural substrates observed in experimental ischemia (swollen astrocytic processes, separation of myelin from axolemma, and enlarged extracellular spaces14) is responsible for the histological appearance of rarefaction in human leukoaraiosis.17 The microglial activation demonstrated in the lesions points to inflammatory cytokines as possible mediators of the effects of ischemia on tissue. What is the contribution of alternative mechanisms, such as disruption of the blood–brain barrier, a process suggested by the presence of plasma proteins in clasmatodendritic astrocytes18,19? It is even possible that ischemia is secondary to alterations in blood–brain barrier permeability.20
Information on the detailed time scale of development of single lesions in leukoaraiosis would provide an important clue to the previous question, but this intelligence is missing, despite the many population studies detailing progression of leukoaraiosis over a period of years.21,22 Full development of a stable lesion over a few days would be expected if ischemia is the primary factor. In that case, would a prolonged period of marginal oxygen delivery before a sudden drop in perfusion pressure be relevant? Ischemic preconditioning, the increased resistance to ischemia after subthreshold ischemic insults, documented in animal and human brain,23,24 is associated with expression of HIF1,25 the protein Fernando et al found in deep subcortical leukoaraiosis.16 It may be worthwhile investigating whether leukoaraiosis could be explained as a manifestation of the ischemic preconditioning phenomenon.
Finally, what triggers ischemia? Is it a failure of cerebral blood flow autoregulation, or simple narrowing of the vascular lumen? Are microemboli or microthrombi involved? What is the importance of endothelial and hemostatic activation?26 Although the Fernando et al study was not focused on these issues, they demonstrate vascular endothelial activation, but absent reduction of the diameter of the lumen.
Leukoaraiosis remains one of the most accessible markers of the pounding aging and vascular risk factors inflict on the brain. It is likely that the further dissection of its causes and consequences will reveal basic mechanisms of the processes that steal the cerebral function of so many of our elders.
Footnotes
The opinions in this editorial are not necessarily those of the editors or of the American Heart Association.
References

Pantoni L, Garcia JH. The significance of cerebral white matter abnormalities 100 years after Binswanger’s report. A review. Stroke. 1995; 26: 1293–1301.[Abstract/Free Full Text]
Hachinski VC, Potter P, Merskey H. Leukoaraiosis. Arch Neurol. 1987; 44: 21–23.[Abstract]
Inzitari D, Di Carlo A, Mascalchi M, Pracucci G, Amaducci L. The cardiovascular outcome of patients with motor impairment and extensive leukoaraiosis. Arch Neurol. 1995; 52: 687–691.[Abstract]
Kuller LH, Longstreth WT Jr, Arnold AM, Bernick C, Bryan RN, Beauchamp NJ Jr. White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. Stroke. 2004; 35: 1821–1825.[Abstract/Free Full Text]
Garde E, Mortensen EL, Krabbe K, Rostrup E, Larsson HB. Relation between age-related decline in intelligence and cerebral white-matter hyperintensities in healthy octogenarians: a longitudinal study. Lancet. 2000; 19: 356:628–634.
van der Flier WM, van Straaten EC, Barkhof F, Verdelho A, Madureira S, Pantoni L, Inzitari D, Erkinjuntti T, Crisby M, Waldemar G, Schmidt R, Fazekas F, Scheltens P. Small vessel disease and general cognitive function in nondisabled elderly: the LADIS study. Stroke. 2005; 36: 2116–2120.[Abstract/Free Full Text]
Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Jolles J, Koudstaal PJ, Hofman A, Breteler MM. Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain. 2005; 128: 2034–2041.[Abstract/Free Full Text]
Sachdev PS, Wen W, Christensen H, Jorm AF. White matter hyperintensities are related to physical disability and poor motor function. J Neurol Neurosurg Psychiatry. 2005; 76: 362–367.[Abstract/Free Full Text]
Artero S, Tiemeier H, Prins ND, Sabatier R, Breteler MM, Ritchie K. Neuroanatomical localisation and clinical correlates of white matter lesions in the elderly. J Neurol Neurosurg Psychiatry. 2004; 75: 1304–1308.[Abstract/Free Full Text]
Murray AD, Staff RT, Shenkin SD, Deary IJ, Starr JM, Whalley LJ. Brain white matter hyperintensities: relative importance of vascular risk factors in nondemented elderly people. Radiology. 2005; 237: 251–257.[Abstract/Free Full Text]
de Leeuw FE, de Groot JC, Oudkerk M, Witteman JC, Hofman A, van Gijn J, Breteler MM. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain. 2002; 125: 765–772.[Abstract/Free Full Text]
Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, Radner H, Lechner H. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993; 43: 1683–1689.[Abstract/Free Full Text]
van-Swieten JC, van-den-Hout JH, van-Ketel BA, Hijdra A, Wokke JH, van-Gijn J. Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain Res. 1991; 114: 761–774.
Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke. 1997; 28: 652–659.[Abstract/Free Full Text]
Marstrand JR, Garde E, Rostrup E, Ring P, Rosenbaum S, Mortensen EL, Larsson HB. Cerebral perfusion and cerebrovascular reactivity are reduced in white matter hyperintensities. Stroke. 2002; 33: 972–976.[Abstract/Free Full Text]
Fernando MS, Simpson J, Matthews FE, Brayne C, Lewis C, Barber R, Kalaria RN, Forster G, Esteves F, Wharton SB, Shaw PJ, O’Brien JT, Ince PG; on behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group. White matter lesions in an unselected cohort of the elderly: II. Molecular pathology suggests origin from chronic hypoperfusion injury. Stroke. 2006; 37: 1391–1398.[Abstract/Free Full Text]
Munoz DG, Hastak SM, Harper B, Lee D, Hachinski VC. Pathologic correlates of increased signals of the centrum ovale on magnetic resonance imaging. Arch Neurol. 1993; 50: 492–497.[Abstract]
Akiguchi I, Tomimoto H, Suenaga T, Wakita H, Budka H. Blood-brain barrier dysfunction in Binswanger’s disease: an immunohistochemical study. Acta Neuropathol (Berl). 1998; 95: 78–84.[CrossRef][Medline] [Order article via Infotrieve]
Sahlas DJ, Bilbao JM, Swartz RH, Black SE. Clasmatodendrosis correlating with periventricular hyperintensity in mixed dementia. Ann Neurol. 2002; 52: 378–381.[CrossRef][Medline] [Order article via Infotrieve]
Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke. 2003; 34: 806–812.[Abstract/Free Full Text]
Longstreth WT Jr, Arnold AM, Beauchamp NJ Jr, Manolio TA, Lefkowitz D, Jungreis C, Hirsch CH, O’Leary DH, Furberg CD. Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke. 2005; 36: 56–61.[Abstract/Free Full Text]
Streifler JY, Eliasziw M, Benavente OR, Alamowitch S, Fox AJ, Hachinski V, Barnett HJ. Development and progression of leukoaraiosis in patients with brain ischemia and carotid artery disease. Stroke. 2003; 34: 1913–1916.[Abstract/Free Full Text]
Lu GW, Yu S, Li RH, Cui XY, Gao CY. Hypoxic preconditioning: a novel intrinsic cytoprotective strategy. Mol Neurobiol. 2005; 31: 255–271.[Medline] [Order article via Infotrieve]
Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003; 26: 248–254.[CrossRef][Medline] [Order article via Infotrieve]
Sharp FR, Ran R, Lu A, Tang Y, Strauss KI, Glass T, Ardizzone T, Bernaudin M. Hypoxic preconditioning protects against ischemic brain injury. NeuroRx. 2004; 1: 26–35.[CrossRef]
Markus HS, Hunt B, Palmer K, Enzinger C, Schmidt H, Schmidt R. Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study. Stroke. 2005; 36: 1410–1414.[Abstract/Free Full Text]

Read More