Q. My baby seems to sweat a lot. When he wakes up in the morning, his hair is wet and his back is often sweaty when I am breastfeeding him. He seems fine otherwise and doesn't seem hot. Is it normal to sweat so much?
Excessive sweating can be normal, but it can also be a sign of some serious medical conditions, so an evaluation by your pediatrician would be a good idea.
When caused by a medical problem, you would typically expect other symptoms though, such as trouble feeding, fast breathing, or poor weight gain. For example, sweating while feeding can be a symptom of congestive heart failure. These infants may get tired while feeding, and have a fast respiratory rate, a frequent cough, and poor weight gain. So if your baby had a heart problem, you would expect other symptoms besides sweating.
Having an overactive thyroid, or hyperthyroidism, can also cause excessive sweating, but again, you would expect some of those other symptoms.
Keep in mind that overbundling or overdressing your child and keeping your home too warm, could also cause excessive sweating. Since getting overheated is a risk factor for SIDS, you should make sure that your baby is not getting overheated by:
keeping your home at a temperature that is comfortable for an adult that is lightly clothed
not over-bundling your baby, but instead dressing him with one extra layer than you are wearing yourself
Showing posts with label scfhs. Show all posts
Showing posts with label scfhs. Show all posts
15.11.09
answer to the saudi medical council question examination
Congenital toxoplasmosis is a group of symptoms that occur when an unborn baby (fetus) is infected with the parasite Toxoplasma gondii.
Causes
The fetus can become infected with toxoplasmosis if the mother becomes infected with toxoplasmosis during the pregnancy. The infection may spread to the fetus during the pregnancy itself, or during labor or delivery.
For the mother, the toxoplasmosis infection is generally mild, and she may not be aware of it. Infection of the fetus, however, can cause severe problems. Infection early in pregnancy results in more severe problems than later infection.
Symptoms
Up to half of the fetuses who become infected with toxoplasmosis during the pregnancy ae born early (prematurely). Congenital toxoplasmosis can damage the baby's eyes, nervous system, skin, and ears.
Often, there are signs of infection in the baby at birth. However, newborns with milder infections may not have symptoms or problems for months or even years. If they are not treated, almost all develop problems (especially in the eyes) when they become adolescents.
Symptoms may include:
Enlarged liver and spleen
Diarrhea or vomiting
Eye damage from inflammation of the retina or other parts of the eye
Feeding problems
Hearing loss
Jaundice
Low birth weight (intrauterine growth restriction)
Skin rash (petechiae or ecchymosis) at birth
Brain and nervous system damage may be severe or very mild, and may include:
Seizures
Abnormal brain and nervous system (neurologic) function
Exams and Tests
The physical examination may show signs of:
Anemia
Cerebral calcifications
Chorioretinitis
Larger head size (hydrocephalus)
Swollen lymph nodes (lymphadenopathy)
Macrocephaly or microcephaly
Signs and symptoms that occur late in the disease include:
Hearing loss
Mental retardation
Seizures
Neurological problems
Visual impairment
Prenatal tests include:
Amniotic fluid testing and fetal blood testing
Antibody titer
Ultrasound of the abdomen
Postnatal diagnosis:
Antibody studies on cord blood and cerebrospinal fluid
CT scan of the brain
MRI scan of the brain
Neurological exams
Standard eye exam
TORCH screen
Treatment
Spiramycin can treat infection in the pregnant mother.
Pyrimethamine and sulfadiazine can treat fetal infection (diagnosed during the pregnancy).
Treatment of infants with congenital toxoplasmosis typically includes pyrimethamine, sulfadiazine, and leucovorin for one year. Infants are also sometimes given steroids if their vision is threatened or if the protein level in the spinal fluid is high.
Outlook (Prognosis)
The outcome depends on the severity of the congenital toxoplasmosis.
Possible Complications
Hydrocephalus
Blindness or severe visual disability
Severe mental retardation or other neurological problems
When to Contact a Medical Professional
Call for an appointment with your health care provider if you are pregnant and think you are at risk for toxoplasmosis (for example, if you have a cat and are the person who cleans the litter box).
Call for an appointment with your health care provider if you are pregnant and have not received any prenatal care.
Prevention
Prospective or expectant mothers can be tested to find out if they are at risk for toxoplasmosis.
Pregnant women who have cats as house pets may be at increased risk of developing toxoplasmosis. They should avoid contact with any materials that are potentially infected with cat feces, or that could be contaminated by insects exposed to cat feces (cockroaches, flies, etc.).
Cook meat until it is well done, and wash your hands after handling raw meat.
Causes
The fetus can become infected with toxoplasmosis if the mother becomes infected with toxoplasmosis during the pregnancy. The infection may spread to the fetus during the pregnancy itself, or during labor or delivery.
For the mother, the toxoplasmosis infection is generally mild, and she may not be aware of it. Infection of the fetus, however, can cause severe problems. Infection early in pregnancy results in more severe problems than later infection.
Symptoms
Up to half of the fetuses who become infected with toxoplasmosis during the pregnancy ae born early (prematurely). Congenital toxoplasmosis can damage the baby's eyes, nervous system, skin, and ears.
Often, there are signs of infection in the baby at birth. However, newborns with milder infections may not have symptoms or problems for months or even years. If they are not treated, almost all develop problems (especially in the eyes) when they become adolescents.
Symptoms may include:
Enlarged liver and spleen
Diarrhea or vomiting
Eye damage from inflammation of the retina or other parts of the eye
Feeding problems
Hearing loss
Jaundice
Low birth weight (intrauterine growth restriction)
Skin rash (petechiae or ecchymosis) at birth
Brain and nervous system damage may be severe or very mild, and may include:
Seizures
Abnormal brain and nervous system (neurologic) function
Exams and Tests
The physical examination may show signs of:
Anemia
Cerebral calcifications
Chorioretinitis
Larger head size (hydrocephalus)
Swollen lymph nodes (lymphadenopathy)
Macrocephaly or microcephaly
Signs and symptoms that occur late in the disease include:
Hearing loss
Mental retardation
Seizures
Neurological problems
Visual impairment
Prenatal tests include:
Amniotic fluid testing and fetal blood testing
Antibody titer
Ultrasound of the abdomen
Postnatal diagnosis:
Antibody studies on cord blood and cerebrospinal fluid
CT scan of the brain
MRI scan of the brain
Neurological exams
Standard eye exam
TORCH screen
Treatment
Spiramycin can treat infection in the pregnant mother.
Pyrimethamine and sulfadiazine can treat fetal infection (diagnosed during the pregnancy).
Treatment of infants with congenital toxoplasmosis typically includes pyrimethamine, sulfadiazine, and leucovorin for one year. Infants are also sometimes given steroids if their vision is threatened or if the protein level in the spinal fluid is high.
Outlook (Prognosis)
The outcome depends on the severity of the congenital toxoplasmosis.
Possible Complications
Hydrocephalus
Blindness or severe visual disability
Severe mental retardation or other neurological problems
When to Contact a Medical Professional
Call for an appointment with your health care provider if you are pregnant and think you are at risk for toxoplasmosis (for example, if you have a cat and are the person who cleans the litter box).
Call for an appointment with your health care provider if you are pregnant and have not received any prenatal care.
Prevention
Prospective or expectant mothers can be tested to find out if they are at risk for toxoplasmosis.
Pregnant women who have cats as house pets may be at increased risk of developing toxoplasmosis. They should avoid contact with any materials that are potentially infected with cat feces, or that could be contaminated by insects exposed to cat feces (cockroaches, flies, etc.).
Cook meat until it is well done, and wash your hands after handling raw meat.
Congenital Toxoplasmosis
JEFFREY JONES, M.D., M.P.H., ADRIANA LOPEZ, M.H.S., and MARIANNA WILSON, M.S.
Centers for Disease Control and Prevention, Atlanta, Georgia
Approximately 85 percent of women of childbearing age in the United States are susceptible to acute infection with the protozoan parasite Toxoplasma gondii. Transmission of T. gondii to the fetus can result in serious health problems, including mental retardation, seizures, blindness, and death. Some health problems may not become apparent until the second or third decade of life. An estimated 400 to 4,000 cases of congenital toxoplasmosis occur in the United States each year. Serologic tests are used to diagnose acute T. gondii infection in pregnant women. Because false-positive tests occur frequently, serologic diagnosis must be confirmed at a Toxoplasma reference laboratory before treatment with potentially toxic drugs is considered. In many instances, congenital toxoplasmosis can be prevented by educating pregnant women and other women of childbearing age about not ingesting raw or undercooked meat, using measures to avoid cross-contamination of other foods with raw or undercooked meat, and protecting themselves against exposure to cat litter or contaminated soil. (Am Fam Physician 2003;67:2131-8,2145-6. Copyright? 2003 American Academy of Family Physicians.)
A patient information handout on toxoplasmosis, written by the authors of this article, is provided on page 2145.
A PDF version of this document is available. Download PDF now (8 pages /255 KB). More information on using PDF files.
Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. A recent serologic survey1 conducted as part of the Third National Health and Nutrition Survey found that 23 percent of adolescents and adults and 15 percent of women of childbearing age in the United States show laboratory evidence of T. gondii infection. Although T. gondii infection in adults is usually asymptomatic or associated with self-limited symptoms (e.g., fever, malaise, lymphadenopathy), infection in a pregnant woman may cause serious health problems if the parasite is transmitted to the fetus.
See page 2050 for definitions of strength-of-evidence levels.
Based on extrapolation of data from regional studies,2-4 400 to 4,000 cases of congenital toxoplasmosis occur in the United States each year. Congenital toxoplasmosis can have severe sequelae, including mental retardation, blindness, and epilepsy in infancy or much later in life.
Family physicians may be confronted with a number of issues regarding toxoplasmosis. Some of these issues are related to clinical presentation, laboratory testing, and prevention.
Toxoplasma gondii
LIFE CYCLE
The T. gondii life cycle has three stages: tachyzoite, bradyzoite, and sporozoite.5 During the acute stage of T. gondii infection, tachyzoites invade and replicate within cells and are responsible for congenital infection. The tachyzoites invade all organs, especially the muscles (including the heart), liver, spleen, lymph nodes, and central nervous system (CNS). During latent infection, bradyzoites are present in tissue cysts. Sporozoites are found in environmentally resistant oocysts formed after the sexual stage of the life cycle.
Members of the Felidae family, including domestic and feral cats, are the definitive hosts for the sexual stage of T. gondii, which takes place in their intestinal mucosa. During acute infection, cats excrete unsporulated (i.e., noninfectious) oocysts in their feces. Depending on environmental conditions, the oocysts sporulate and become infectious after one day to several weeks. Under favorable conditions (i.e., in warm, moist soil), oocysts remain infectious for a year or more.
TRANSMISSION
T. gondii is transmitted to humans by three principal routes (Figure 1).6 First, humans can acquire T. gondii by eating raw or inadequately cooked infected meat, especially pork, mutton, and wild game,7 or uncooked foods that have come in contact with infected meat. Second, humans can inadvertently ingest oocysts that cats have passed in their feces, either from a litter box or from soil (e.g., soil from gardening, on unwashed fruits or vegetables, or in unfiltered water). Third, women can transmit the infection transplacentally to their unborn fetus. In adults, the incubation period for T. gondii infection ranges from 10 to 23 days after the ingestion of undercooked meat and from five to 20 days after the ingestion of oocysts from cat feces.
FIGURE 1. Pathways for Toxoplasma gondii infection. The feline intestinal tract is the only source for the production of T. gondii oocysts. Transmission to humans usually occurs through the ingestion of oocysts from contaminated sources (e.g., soil, cat litter, garden vegetables, water) or the ingestion of tissue cysts in undercooked meat from infected animals. Although fetal infection most often occurs after acute T. gondii infection in a pregnant woman, it also can occur after the reactivation of latent infection in an immunocompromised pregnant woman.
Redrawn with permission from Lynfield R, Guerina NG. Toxoplasmosis. Pediatr Rev 1997;18(3):75-83.
A report8 from the Economic Research Service of the U.S. Department of Agriculture concluded that one half of toxoplasmosis cases in the United States are caused by eating contaminated meat. This conclusion is supported by the findings of a community-based epidemiologic study.9
Women infected with T. gondii before conception rarely transmit the parasite to their fetus, but those who become acutely infected or have reactivation of T. gondii during pregnancy (i.e., because of immunosuppression) can transmit the organism transplacentally. The risk of congenital disease is lowest (10 to 25 percent) when maternal infection occurs during the first trimester and highest (60 to 90 percent) when maternal infection occurs during the third trimester.10,11 However, congenital disease is more severe when infection is acquired in the first trimester.10 The overall risk of congenital infection from acute T. gondii infection during pregnancy ranges from approximately 20 to 50 percent.10
Immunosuppression resulting from human immunodeficiency virus (HIV) infection or therapies for malignancies, organ transplantation, and lymphoproliferative disorders can result in the reactivation of latent T. gondii infection. Reactivation most often involves the CNS, and symptoms may include those of meningoencephalitis or a mass lesion. Women with reactivated T. gondii infection can transmit the organism transplacentally.10
RISK FACTORS
Recent epidemiologic studies have identified the following risk factors for T. gondii infection: owning a cat,12 cleaning a cat litter box,13 eating raw or undercooked pork, mutton, lamb, beef, or minced-meat products,12-14 gardening,15 eating raw or unwashed vegetables or fruits,12 eating raw vegetables outside the home,12 having contact with soil,14 washing kitchen knives infrequently,13 having poor hand hygiene,12 travelling outside of Europe, Canada, or the United States,14 and drinking municipal water from a contaminated reservoir.16
It is important to note that recent epidemiologic studies have not shown cat ownership to be a consistent risk factor for T. gondii infection. The risk of infection is not related to owning a cat but to being exposed to feces from a cat that is shedding oocysts. When cats become infected with T. gondii, they generally shed oocysts only for a few weeks during their lifetime. Indoor cats that do not hunt and are not fed raw meat are unlikely to acquire T. gondii infection and therefore pose little risk. Furthermore, a study17 of cats induced to shed oocysts found no oocysts on the cats' fur after they shed the oocysts. Therefore, the possibility of T. gondii transmission through touching a cat is considered to be minimal or nonexistent.7
Because cats often do not develop antibodies to T. gondii during the oocyst-shedding period, serologic testing does not provide useful information about the ability of a particular cat to transmit toxoplasmosis.7 A cat that tests positive for T. gondii probably has shed oocysts previously and therefore may pose less of a risk than a serologically negative cat. Because cats can shed oocysts more than once, serologic testing is not helpful if a cat is seropositive to T. gondii antibody. Testing a cat's stool to determine human risk is also of little value, because cats shed oocysts for only a short period of time.
Toxoplasmosis in Pregnant Women
SCREENING
A practice bulletin from the American College of Obstetricians and Gynecologists on perinatal viral and parasitic infections recommends toxoplasmosis screening only in high-risk persons or those in whom routine ultrasound examination (or ultrasonography performed for other reasons) shows findings such as hydrocephalus, intracranial calcifications, microcephaly, fetal growth retardation, ascites, or hepatosplenomegaly.18 [Evidence level C, consensus/expert guidelines] Screening tests may have equivocal or false-positive results that could lead to inappropriate treatment or the termination of pregnancy.19,20
Because of the low incidence of toxoplasmosis in the United States, some investigators21 have determined that the risk to the fetus would be greater from routine screening than from no screening. However, women with HIV infection should be screened for toxoplasmosis because of the risk of T. gondii reactivation and toxoplasmic encephalitis.18
DIAGNOSTIC TESTS
When acute T. gondii infection is suspected in a pregnant woman, the diagnosis should be pursued. Toxoplasmosis usually is diagnosed on the basis of antibody detection. In acute infection, IgG and IgM antibody levels generally rise within one to two weeks of infection.22
The presence of elevated levels of T. gondii?specific IgG antibodies indicates that infection has occurred but does not distinguish between recent infection and infection acquired in the distant past. Detection of T. gondii?specific IgM antibodies has been used as an aid in determining the time of infection: a negative IgM test result with a positive IgG result usually indicates infection at least six months previously. However, the interpretation of T. gondii?specific IgM-positive results is complicated by the persistence of IgM antibodies up to 18 months after infection5 and by false-positive reactions in commercial tests.19 A guide for interpreting laboratory tests is provided in Table 1,5 and an algorithm for T. gondii serologic testing in patients older than one year is presented in Figure 2.5
TABLE 1
General Interpretation of Toxoplasma gondii Serologic Results Obtained with Commercial Assays
--------------------------------------------------------------------------------
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Serologic Testing for Toxoplasma gondii
The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.
FIGURE 2.
IgM-positive test results should be confirmed by a Toxoplasma reference laboratory.19 The laboratory may also be able to narrow the time of infection through the use of specific tests (e.g., IgG avidity test)23 or a serologic profile (e.g., Sabin-Feldman dye test, IgM enzyme-linked immunosorbent assay [ELISA], IgA ELISA, IgE ELISA, differential agglutination).24
When a pregnant woman is found to be infected with T. gondii, the next step is to determine whether the fetus is infected. Physicians most often use polymerase chain reaction (PCR) testing of amniotic fluid to diagnose congenital toxoplasmosis. PCR testing of amniotic fluid is safer and more sensitive than fetal blood sampling,25 and it allows earlier confirmation of fetal infection.26 However, false-positive and false-negative tests may occur with PCR tests.
Because of the high likelihood of fetal damage, abortion may be considered if T. gondii infection is confirmed and infection is thought to have occurred before the 16th week of pregnancy or if the fetus shows evidence of hydrocephalus.10
TREATMENT
If the presence of acute T. gondii infection in a pregnant woman is confirmed, treatment with spiramycin (Rovamycine) can be initiated in an effort to prevent transmission to the fetus. If fetal infection is confirmed through amniocentesis, the woman may be switched to pyrimethamine (Daraprim) and sulfadiazine after the first trimester27,28 or, according to some experts,10 after the 18th week of gestation. [Reference 27--Evidence level B, nonrandomized study] Folinic acid (leucovorin) is given with pyrimethamine and sulfadiazine to protect bone marrow from the suppressive effects of pyrimethamine.
Spiramycin is an investigational drug in the United States and can only be obtained through the manufacturer (Aventis Pharmaceuticals, Bridgewater, N.J.) with approval from the U.S. Food and Drug Administration.28 Pyrimethamine generally is not recommended for use in pregnant women because it is a folic acid antagonist (pregnancy category C drug) and can cause bone marrow suppression in both mother and infant.
The treatment of acute T. gondii infection in pregnancy has not been evaluated in randomized prospective studies. Questions have been raised about the effectiveness of treatment in preventing congenital infection29 or sequelae in infants.30 Nevertheless, historical observational studies suggest that treatment is beneficial, and a recent multicenter observational study31 found that treatment in pregnancy was associated with a reduction of sequelae in infants but not a reduction in maternal-fetal transmission.31
Congenital Toxoplasmosis
CLINCIAL MANIFESTATIONS
The classic triad of signs suggestive of congenital toxoplasmosis includes chorioretinitis, hydrocephalus, and intracranial calcifications. However, other clinical manifestations also are associated with the disease (Table 2).
TABLE 2
Possible Signs and Symptoms of Congenital Toxoplasmosis in Infancy and Later in Life*
--------------------------------------------------------------------------------
Abnormal spinal fluid
Hepatomegaly Mental retardation
Anemia Hydrocephalus? Microcephaly
Chorioretinitis? Intracranial calcifications? Spasticity and palsies
Convulsions Jaundice Splenomegaly
Deafness Learning disabilities Thrombocytopenia
Fever Lymphadenopathy Visual impairment
Growth retardation Maculopapular rash
--------------------------------------------------------------------------------
*--Most neonates with congenital toxoplasmosis are asymptomatic as determined by routine newborn examination.
?--Sign in the classic triad suggesting the presence of congenital toxoplasmosis.
Because clinical manifestations may be nonspecific, T. gondii infection must be considered in a large variety of presentations.22 Congenital toxoplasmosis can mimic disease caused by organisms such as herpes simplex virus, cytomegalovirus, and rubella virus.
Premature infants with toxoplasmosis may develop CNS and ocular disease in the first three months of life. In contrast, T. gondii? infected full-term infants more often have milder disease, with hepatosplenomegaly and lymphadenopathy in the first two months of life.22 Although most infants infected in utero are born with no obvious signs of toxoplasmosis on routine newborn examination, up to 80 percent develop learning or visual disabilities later in life.32,33 With congenital infection, reduction of visual acuity and new eye lesions may occur through the third decade of life or even later. Ocular problems require a complete ophthalmologic evaluation.
TREATMENT
Pyrimethamine and sulfadiazine generally are used to treat infants with congenital toxoplasmosis. Infants treated with these drugs have been shown to have improved outcomes compared with untreated infants and children from studies in the past.10,34 [Reference 34--Evidence level B, uncontrolled study] Drug therapy usually is continued for one year. Active and recurrent toxoplasmic eye disease also frequently responds to antiparasitic drugs, which may be given with steroids.
Prevention of Toxoplasmosis in Pregnant Women
Recommendations for the prevention of toxoplasmosis in pregnant women are presented in Table 3.35 In addition, pregnant women who travel abroad should avoid eating undercooked meat or drinking untreated water.
TABLE 3
Prevention of Toxoplasmosis in Pregnant Women
--------------------------------------------------------------------------------
To prevent toxoplasmosis and other food-borne illnesses, food should be cooked to a safe temperature (71.1?C [160?F]). A food thermometer should be used to ensure that meat is cooked all the way through.
Fruits and vegetables should be peeled or thoroughly washed before they are eaten.
Cutting boards, dishes, counters, utensils, and hands should be washed with hot soapy water after they have been in contact with raw meat, poultry, or seafood, or with unwashed fruits or vegetables.
Pregnant women should wear gloves when they are gardening or touching soil or sand, because of the possible presence of cat feces. Afterwards, they should wash their hands thoroughly.
If possible, pregnant women should avoid changing cat litter pans. If no one else is available to change the cat litter, pregnant women should wear gloves for this task and then wash their hands thoroughly. The litter box should be changed daily, because Toxoplasma gondii oocysts require more than 1 day to become infectious. Pregnant women should be encouraged to keep their cats inside and not to adopt or handle stray cats. Cats should be fed only canned or dried commercial cat food or well-cooked table food; they should not be given raw or undercooked meat.
Health education for women of childbearing age should include information about preventing T. gondii transmission from food and soil. At the first prenatal visit, health care providers should educate pregnant women about food hygiene and avoiding exposure to cat feces.
Health care providers who care for pregnant women should be educated about two potential problems associated with T. gondii serology tests: (1) no assay can determine precisely when initial T. gondii infection occurred; (2) in populations with a low incidence of T. gondii infection (e.g., U.S. population), a substantial proportion of positive IgM test results probably will be false positive.
The government and meat industry should continue efforts to reduce the presence of T. gondii in meat.
--------------------------------------------------------------------------------
Adapted from Preventing congenital toxoplasmosis. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2000;49(RR-2):57-75.
Programs that educate women of childbearing age about the prevention of toxoplasmosis have demonstrated some success in changing risk behaviors36 and have been associated with a decrease in T. gondii seroconversion over time.37 Finally, newborn screening for toxoplasmosis has been used in two states (Massachusetts and New Hampshire) in an attempt to identify and treat T. gondii?infected infants.4
Centers for Disease Control and Prevention, Atlanta, Georgia
Approximately 85 percent of women of childbearing age in the United States are susceptible to acute infection with the protozoan parasite Toxoplasma gondii. Transmission of T. gondii to the fetus can result in serious health problems, including mental retardation, seizures, blindness, and death. Some health problems may not become apparent until the second or third decade of life. An estimated 400 to 4,000 cases of congenital toxoplasmosis occur in the United States each year. Serologic tests are used to diagnose acute T. gondii infection in pregnant women. Because false-positive tests occur frequently, serologic diagnosis must be confirmed at a Toxoplasma reference laboratory before treatment with potentially toxic drugs is considered. In many instances, congenital toxoplasmosis can be prevented by educating pregnant women and other women of childbearing age about not ingesting raw or undercooked meat, using measures to avoid cross-contamination of other foods with raw or undercooked meat, and protecting themselves against exposure to cat litter or contaminated soil. (Am Fam Physician 2003;67:2131-8,2145-6. Copyright? 2003 American Academy of Family Physicians.)
A patient information handout on toxoplasmosis, written by the authors of this article, is provided on page 2145.
A PDF version of this document is available. Download PDF now (8 pages /255 KB). More information on using PDF files.
Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. A recent serologic survey1 conducted as part of the Third National Health and Nutrition Survey found that 23 percent of adolescents and adults and 15 percent of women of childbearing age in the United States show laboratory evidence of T. gondii infection. Although T. gondii infection in adults is usually asymptomatic or associated with self-limited symptoms (e.g., fever, malaise, lymphadenopathy), infection in a pregnant woman may cause serious health problems if the parasite is transmitted to the fetus.
See page 2050 for definitions of strength-of-evidence levels.
Based on extrapolation of data from regional studies,2-4 400 to 4,000 cases of congenital toxoplasmosis occur in the United States each year. Congenital toxoplasmosis can have severe sequelae, including mental retardation, blindness, and epilepsy in infancy or much later in life.
Family physicians may be confronted with a number of issues regarding toxoplasmosis. Some of these issues are related to clinical presentation, laboratory testing, and prevention.
Toxoplasma gondii
LIFE CYCLE
The T. gondii life cycle has three stages: tachyzoite, bradyzoite, and sporozoite.5 During the acute stage of T. gondii infection, tachyzoites invade and replicate within cells and are responsible for congenital infection. The tachyzoites invade all organs, especially the muscles (including the heart), liver, spleen, lymph nodes, and central nervous system (CNS). During latent infection, bradyzoites are present in tissue cysts. Sporozoites are found in environmentally resistant oocysts formed after the sexual stage of the life cycle.
Members of the Felidae family, including domestic and feral cats, are the definitive hosts for the sexual stage of T. gondii, which takes place in their intestinal mucosa. During acute infection, cats excrete unsporulated (i.e., noninfectious) oocysts in their feces. Depending on environmental conditions, the oocysts sporulate and become infectious after one day to several weeks. Under favorable conditions (i.e., in warm, moist soil), oocysts remain infectious for a year or more.
TRANSMISSION
T. gondii is transmitted to humans by three principal routes (Figure 1).6 First, humans can acquire T. gondii by eating raw or inadequately cooked infected meat, especially pork, mutton, and wild game,7 or uncooked foods that have come in contact with infected meat. Second, humans can inadvertently ingest oocysts that cats have passed in their feces, either from a litter box or from soil (e.g., soil from gardening, on unwashed fruits or vegetables, or in unfiltered water). Third, women can transmit the infection transplacentally to their unborn fetus. In adults, the incubation period for T. gondii infection ranges from 10 to 23 days after the ingestion of undercooked meat and from five to 20 days after the ingestion of oocysts from cat feces.
FIGURE 1. Pathways for Toxoplasma gondii infection. The feline intestinal tract is the only source for the production of T. gondii oocysts. Transmission to humans usually occurs through the ingestion of oocysts from contaminated sources (e.g., soil, cat litter, garden vegetables, water) or the ingestion of tissue cysts in undercooked meat from infected animals. Although fetal infection most often occurs after acute T. gondii infection in a pregnant woman, it also can occur after the reactivation of latent infection in an immunocompromised pregnant woman.
Redrawn with permission from Lynfield R, Guerina NG. Toxoplasmosis. Pediatr Rev 1997;18(3):75-83.
A report8 from the Economic Research Service of the U.S. Department of Agriculture concluded that one half of toxoplasmosis cases in the United States are caused by eating contaminated meat. This conclusion is supported by the findings of a community-based epidemiologic study.9
Women infected with T. gondii before conception rarely transmit the parasite to their fetus, but those who become acutely infected or have reactivation of T. gondii during pregnancy (i.e., because of immunosuppression) can transmit the organism transplacentally. The risk of congenital disease is lowest (10 to 25 percent) when maternal infection occurs during the first trimester and highest (60 to 90 percent) when maternal infection occurs during the third trimester.10,11 However, congenital disease is more severe when infection is acquired in the first trimester.10 The overall risk of congenital infection from acute T. gondii infection during pregnancy ranges from approximately 20 to 50 percent.10
Immunosuppression resulting from human immunodeficiency virus (HIV) infection or therapies for malignancies, organ transplantation, and lymphoproliferative disorders can result in the reactivation of latent T. gondii infection. Reactivation most often involves the CNS, and symptoms may include those of meningoencephalitis or a mass lesion. Women with reactivated T. gondii infection can transmit the organism transplacentally.10
RISK FACTORS
Recent epidemiologic studies have identified the following risk factors for T. gondii infection: owning a cat,12 cleaning a cat litter box,13 eating raw or undercooked pork, mutton, lamb, beef, or minced-meat products,12-14 gardening,15 eating raw or unwashed vegetables or fruits,12 eating raw vegetables outside the home,12 having contact with soil,14 washing kitchen knives infrequently,13 having poor hand hygiene,12 travelling outside of Europe, Canada, or the United States,14 and drinking municipal water from a contaminated reservoir.16
It is important to note that recent epidemiologic studies have not shown cat ownership to be a consistent risk factor for T. gondii infection. The risk of infection is not related to owning a cat but to being exposed to feces from a cat that is shedding oocysts. When cats become infected with T. gondii, they generally shed oocysts only for a few weeks during their lifetime. Indoor cats that do not hunt and are not fed raw meat are unlikely to acquire T. gondii infection and therefore pose little risk. Furthermore, a study17 of cats induced to shed oocysts found no oocysts on the cats' fur after they shed the oocysts. Therefore, the possibility of T. gondii transmission through touching a cat is considered to be minimal or nonexistent.7
Because cats often do not develop antibodies to T. gondii during the oocyst-shedding period, serologic testing does not provide useful information about the ability of a particular cat to transmit toxoplasmosis.7 A cat that tests positive for T. gondii probably has shed oocysts previously and therefore may pose less of a risk than a serologically negative cat. Because cats can shed oocysts more than once, serologic testing is not helpful if a cat is seropositive to T. gondii antibody. Testing a cat's stool to determine human risk is also of little value, because cats shed oocysts for only a short period of time.
Toxoplasmosis in Pregnant Women
SCREENING
A practice bulletin from the American College of Obstetricians and Gynecologists on perinatal viral and parasitic infections recommends toxoplasmosis screening only in high-risk persons or those in whom routine ultrasound examination (or ultrasonography performed for other reasons) shows findings such as hydrocephalus, intracranial calcifications, microcephaly, fetal growth retardation, ascites, or hepatosplenomegaly.18 [Evidence level C, consensus/expert guidelines] Screening tests may have equivocal or false-positive results that could lead to inappropriate treatment or the termination of pregnancy.19,20
Because of the low incidence of toxoplasmosis in the United States, some investigators21 have determined that the risk to the fetus would be greater from routine screening than from no screening. However, women with HIV infection should be screened for toxoplasmosis because of the risk of T. gondii reactivation and toxoplasmic encephalitis.18
DIAGNOSTIC TESTS
When acute T. gondii infection is suspected in a pregnant woman, the diagnosis should be pursued. Toxoplasmosis usually is diagnosed on the basis of antibody detection. In acute infection, IgG and IgM antibody levels generally rise within one to two weeks of infection.22
The presence of elevated levels of T. gondii?specific IgG antibodies indicates that infection has occurred but does not distinguish between recent infection and infection acquired in the distant past. Detection of T. gondii?specific IgM antibodies has been used as an aid in determining the time of infection: a negative IgM test result with a positive IgG result usually indicates infection at least six months previously. However, the interpretation of T. gondii?specific IgM-positive results is complicated by the persistence of IgM antibodies up to 18 months after infection5 and by false-positive reactions in commercial tests.19 A guide for interpreting laboratory tests is provided in Table 1,5 and an algorithm for T. gondii serologic testing in patients older than one year is presented in Figure 2.5
TABLE 1
General Interpretation of Toxoplasma gondii Serologic Results Obtained with Commercial Assays
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Serologic Testing for Toxoplasma gondii
The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.
FIGURE 2.
IgM-positive test results should be confirmed by a Toxoplasma reference laboratory.19 The laboratory may also be able to narrow the time of infection through the use of specific tests (e.g., IgG avidity test)23 or a serologic profile (e.g., Sabin-Feldman dye test, IgM enzyme-linked immunosorbent assay [ELISA], IgA ELISA, IgE ELISA, differential agglutination).24
When a pregnant woman is found to be infected with T. gondii, the next step is to determine whether the fetus is infected. Physicians most often use polymerase chain reaction (PCR) testing of amniotic fluid to diagnose congenital toxoplasmosis. PCR testing of amniotic fluid is safer and more sensitive than fetal blood sampling,25 and it allows earlier confirmation of fetal infection.26 However, false-positive and false-negative tests may occur with PCR tests.
Because of the high likelihood of fetal damage, abortion may be considered if T. gondii infection is confirmed and infection is thought to have occurred before the 16th week of pregnancy or if the fetus shows evidence of hydrocephalus.10
TREATMENT
If the presence of acute T. gondii infection in a pregnant woman is confirmed, treatment with spiramycin (Rovamycine) can be initiated in an effort to prevent transmission to the fetus. If fetal infection is confirmed through amniocentesis, the woman may be switched to pyrimethamine (Daraprim) and sulfadiazine after the first trimester27,28 or, according to some experts,10 after the 18th week of gestation. [Reference 27--Evidence level B, nonrandomized study] Folinic acid (leucovorin) is given with pyrimethamine and sulfadiazine to protect bone marrow from the suppressive effects of pyrimethamine.
Spiramycin is an investigational drug in the United States and can only be obtained through the manufacturer (Aventis Pharmaceuticals, Bridgewater, N.J.) with approval from the U.S. Food and Drug Administration.28 Pyrimethamine generally is not recommended for use in pregnant women because it is a folic acid antagonist (pregnancy category C drug) and can cause bone marrow suppression in both mother and infant.
The treatment of acute T. gondii infection in pregnancy has not been evaluated in randomized prospective studies. Questions have been raised about the effectiveness of treatment in preventing congenital infection29 or sequelae in infants.30 Nevertheless, historical observational studies suggest that treatment is beneficial, and a recent multicenter observational study31 found that treatment in pregnancy was associated with a reduction of sequelae in infants but not a reduction in maternal-fetal transmission.31
Congenital Toxoplasmosis
CLINCIAL MANIFESTATIONS
The classic triad of signs suggestive of congenital toxoplasmosis includes chorioretinitis, hydrocephalus, and intracranial calcifications. However, other clinical manifestations also are associated with the disease (Table 2).
TABLE 2
Possible Signs and Symptoms of Congenital Toxoplasmosis in Infancy and Later in Life*
--------------------------------------------------------------------------------
Abnormal spinal fluid
Hepatomegaly Mental retardation
Anemia Hydrocephalus? Microcephaly
Chorioretinitis? Intracranial calcifications? Spasticity and palsies
Convulsions Jaundice Splenomegaly
Deafness Learning disabilities Thrombocytopenia
Fever Lymphadenopathy Visual impairment
Growth retardation Maculopapular rash
--------------------------------------------------------------------------------
*--Most neonates with congenital toxoplasmosis are asymptomatic as determined by routine newborn examination.
?--Sign in the classic triad suggesting the presence of congenital toxoplasmosis.
Because clinical manifestations may be nonspecific, T. gondii infection must be considered in a large variety of presentations.22 Congenital toxoplasmosis can mimic disease caused by organisms such as herpes simplex virus, cytomegalovirus, and rubella virus.
Premature infants with toxoplasmosis may develop CNS and ocular disease in the first three months of life. In contrast, T. gondii? infected full-term infants more often have milder disease, with hepatosplenomegaly and lymphadenopathy in the first two months of life.22 Although most infants infected in utero are born with no obvious signs of toxoplasmosis on routine newborn examination, up to 80 percent develop learning or visual disabilities later in life.32,33 With congenital infection, reduction of visual acuity and new eye lesions may occur through the third decade of life or even later. Ocular problems require a complete ophthalmologic evaluation.
TREATMENT
Pyrimethamine and sulfadiazine generally are used to treat infants with congenital toxoplasmosis. Infants treated with these drugs have been shown to have improved outcomes compared with untreated infants and children from studies in the past.10,34 [Reference 34--Evidence level B, uncontrolled study] Drug therapy usually is continued for one year. Active and recurrent toxoplasmic eye disease also frequently responds to antiparasitic drugs, which may be given with steroids.
Prevention of Toxoplasmosis in Pregnant Women
Recommendations for the prevention of toxoplasmosis in pregnant women are presented in Table 3.35 In addition, pregnant women who travel abroad should avoid eating undercooked meat or drinking untreated water.
TABLE 3
Prevention of Toxoplasmosis in Pregnant Women
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To prevent toxoplasmosis and other food-borne illnesses, food should be cooked to a safe temperature (71.1?C [160?F]). A food thermometer should be used to ensure that meat is cooked all the way through.
Fruits and vegetables should be peeled or thoroughly washed before they are eaten.
Cutting boards, dishes, counters, utensils, and hands should be washed with hot soapy water after they have been in contact with raw meat, poultry, or seafood, or with unwashed fruits or vegetables.
Pregnant women should wear gloves when they are gardening or touching soil or sand, because of the possible presence of cat feces. Afterwards, they should wash their hands thoroughly.
If possible, pregnant women should avoid changing cat litter pans. If no one else is available to change the cat litter, pregnant women should wear gloves for this task and then wash their hands thoroughly. The litter box should be changed daily, because Toxoplasma gondii oocysts require more than 1 day to become infectious. Pregnant women should be encouraged to keep their cats inside and not to adopt or handle stray cats. Cats should be fed only canned or dried commercial cat food or well-cooked table food; they should not be given raw or undercooked meat.
Health education for women of childbearing age should include information about preventing T. gondii transmission from food and soil. At the first prenatal visit, health care providers should educate pregnant women about food hygiene and avoiding exposure to cat feces.
Health care providers who care for pregnant women should be educated about two potential problems associated with T. gondii serology tests: (1) no assay can determine precisely when initial T. gondii infection occurred; (2) in populations with a low incidence of T. gondii infection (e.g., U.S. population), a substantial proportion of positive IgM test results probably will be false positive.
The government and meat industry should continue efforts to reduce the presence of T. gondii in meat.
--------------------------------------------------------------------------------
Adapted from Preventing congenital toxoplasmosis. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2000;49(RR-2):57-75.
Programs that educate women of childbearing age about the prevention of toxoplasmosis have demonstrated some success in changing risk behaviors36 and have been associated with a decrease in T. gondii seroconversion over time.37 Finally, newborn screening for toxoplasmosis has been used in two states (Massachusetts and New Hampshire) in an attempt to identify and treat T. gondii?infected infants.4
Differential Diagnosis for Tonsil exudate
Electromagnetic, Physics, trauma, Radiation Causes
Radiation sickness/severe, acute
Infectious Disorders (Specific Agent)
Adenovirus infection
Streptococcus, beta hemolytic
Streptococcal pharyngitis, beta type A
Hemophilus Influenzae (HIB)infection
Pneumococcal (S. Pneumoniae) infection
Herpes simplex
Infectious mononucleosis
Scarlet fever
Vincent's infection/trench mouth
Diphtheria
Anthrax
Glanders (malleomyces mallei)
Kawasaki disease
Lassa fever
Measles (rubeola)
Monilia pharyngitis/thrush
Tularemia
Infected organ, Abscesses
Pharyngitis, acute septic
Pharyngitis
Tonsillitis/exudative, acute
Tonsillitis, chronic
Neoplastic Disorders
Leukemia
Hereditary, Familial, Genetic Disorders
Acatalasia
Reference to Organ System
Agranulocytic pharyngitis
Agranulocytosis
Radiation sickness/severe, acute
Infectious Disorders (Specific Agent)
Adenovirus infection
Streptococcus, beta hemolytic
Streptococcal pharyngitis, beta type A
Hemophilus Influenzae (HIB)infection
Pneumococcal (S. Pneumoniae) infection
Herpes simplex
Infectious mononucleosis
Scarlet fever
Vincent's infection/trench mouth
Diphtheria
Anthrax
Glanders (malleomyces mallei)
Kawasaki disease
Lassa fever
Measles (rubeola)
Monilia pharyngitis/thrush
Tularemia
Infected organ, Abscesses
Pharyngitis, acute septic
Pharyngitis
Tonsillitis/exudative, acute
Tonsillitis, chronic
Neoplastic Disorders
Leukemia
Hereditary, Familial, Genetic Disorders
Acatalasia
Reference to Organ System
Agranulocytic pharyngitis
Agranulocytosis
answer to the saudi medical council question examination
Leiner disease
What is Leiner disease?
Leiner disease occurs in infants and is characterised by severe generalised seborrhoeic dermatitis, recurrent diarrhoea, recurrent skin and internal infections, and failure to thrive. It is also known as ?erythroderma desquamativum?. Leiner disease may be present at birth but more commonly develops within the first few months of life. It appears to be more common in females than males and in breast-fed infants.
What causes Leiner disease?
The precise cause of Leiner disease remains unknown but it is known that a defect in the body's complement system has a major role to play in its development. The complement system is a vital part of the body's immune system, and in Leiner disease an inherited dysfunction or deficiency in the C5 component of complement alongside other factors have been implicated. Other immune deficiencies may present in an identical fashion in infancy.
What are the signs and symptoms?
The condition usually starts off as a scaly rash on the scalp, face or napkin area. Very rapidly it spreads to other parts of the body. The affected area is bright red and may look swollen. Infants appear uncomfortable but do not itch. Other symptoms include recurrent diarrhoea, infant not thriving or gaining weight, and local skin infections. There is also a risk of developing more severe infections that may lead to pneumonia, meningitis and septicaemia.
What treatment is available?
Initially affected babies may need to be hospitalised to manage fluid and heat loss. Bland emollients may be used to treat the rash. Providing adequate nutrition is also an essential part of treatment.
Biotin, a water-soluble vitamin that is found naturally in foods such as liver, kidney, meat, milk, egg yolks and vegetables, appears to be useful in treating Leiner disease.
What is Leiner disease?
Leiner disease occurs in infants and is characterised by severe generalised seborrhoeic dermatitis, recurrent diarrhoea, recurrent skin and internal infections, and failure to thrive. It is also known as ?erythroderma desquamativum?. Leiner disease may be present at birth but more commonly develops within the first few months of life. It appears to be more common in females than males and in breast-fed infants.
What causes Leiner disease?
The precise cause of Leiner disease remains unknown but it is known that a defect in the body's complement system has a major role to play in its development. The complement system is a vital part of the body's immune system, and in Leiner disease an inherited dysfunction or deficiency in the C5 component of complement alongside other factors have been implicated. Other immune deficiencies may present in an identical fashion in infancy.
What are the signs and symptoms?
The condition usually starts off as a scaly rash on the scalp, face or napkin area. Very rapidly it spreads to other parts of the body. The affected area is bright red and may look swollen. Infants appear uncomfortable but do not itch. Other symptoms include recurrent diarrhoea, infant not thriving or gaining weight, and local skin infections. There is also a risk of developing more severe infections that may lead to pneumonia, meningitis and septicaemia.
What treatment is available?
Initially affected babies may need to be hospitalised to manage fluid and heat loss. Bland emollients may be used to treat the rash. Providing adequate nutrition is also an essential part of treatment.
Biotin, a water-soluble vitamin that is found naturally in foods such as liver, kidney, meat, milk, egg yolks and vegetables, appears to be useful in treating Leiner disease.
answer to the saudi medical council question examination
high-output heart failure
Cardiology CHF due to an ? in circulating blood volume without functional myocardial abnormalities, resulting in a hyperkinetic state; the cardiac pump activity is a function of preload?ventricular end-diastolic fiber tension, myocardial contractility, afterload and heart rate; HOHF may be a physiologic response to such 'insults' as anemia, cor pulmonale, exercise, fever, high humidity, systemic HTN, obesity, pregnancy, emotional stress and temperature extremes, or non-physiologic in Albright's disease?polyostotic fibrous dysplasia, carcinoid syndrome?serotonin-producing usually hepatic metastases, arteriovenous fistulas?trauma, Paget's disease of bone, hemangiomatosis, glomerulonephritis, hemodialysis, hepatic disease?alcohol-related thiamine deficiency ? peripheral arterial resistance, hyperkinetic heart syndrome, P vera, thyrotoxicosis?T3 ? heart rate, cardiac sensitivity to epinephrine and peripheral vasodilation. Cf Low-output cardiac failure.
Cardiology CHF due to an ? in circulating blood volume without functional myocardial abnormalities, resulting in a hyperkinetic state; the cardiac pump activity is a function of preload?ventricular end-diastolic fiber tension, myocardial contractility, afterload and heart rate; HOHF may be a physiologic response to such 'insults' as anemia, cor pulmonale, exercise, fever, high humidity, systemic HTN, obesity, pregnancy, emotional stress and temperature extremes, or non-physiologic in Albright's disease?polyostotic fibrous dysplasia, carcinoid syndrome?serotonin-producing usually hepatic metastases, arteriovenous fistulas?trauma, Paget's disease of bone, hemangiomatosis, glomerulonephritis, hemodialysis, hepatic disease?alcohol-related thiamine deficiency ? peripheral arterial resistance, hyperkinetic heart syndrome, P vera, thyrotoxicosis?T3 ? heart rate, cardiac sensitivity to epinephrine and peripheral vasodilation. Cf Low-output cardiac failure.
answer to the saudi medical council question examination
High Output Cardiac Failure.
Anand IS, Florea VG.
Department of Cardiology, Veterans Administration Medical Center, One Veterans Drive 111-C, Minneapolis, MN 55417, USA. anand001@tc.umn.edu
Congestive heart failure describes a syndrome with complex and variable symptoms and signs, including dyspnea, increased fatigability, tachypnea, tachycardia, pulmonary rales, and peripheral edema. Although this syndrome usually is associated with low cardiac output, it may occur in a number of so-called high output states, when the cardiac output is normal or greater than normal. A high output state may occur in chronic severe anemia, large arteriovenous fistula or multiple small arteriovenous shunts as in Paget's bone disease, some forms of severe hepatic or renal disorders, and acutely in septic shock. The syndrome of systemic congestion in a high output state is traditionally referred to as high output heart failure. However, the term is a misnomer because the heart in these conditions is normal, capable of generating very high cardiac output. The underlying problem in high output failure is a decrease in the systemic vascular resistance that threatens the arterial blood pressure and causes activation of neurohormones, resulting in an increase in salt and water retention by the kidney. Many of the high output states are curable conditions, and because they are associated with decreased peripheral vascular resistance, the use of vasodilator therapy for treatment of congestion may aggravate the problem. There are other clinically important issues in high output failure that have received little attention in the current medical literature. This article reviews the available data on high output cardiac failure with particular emphasis on the underlying mechanisms and treatment.
Anand IS, Florea VG.
Department of Cardiology, Veterans Administration Medical Center, One Veterans Drive 111-C, Minneapolis, MN 55417, USA. anand001@tc.umn.edu
Congestive heart failure describes a syndrome with complex and variable symptoms and signs, including dyspnea, increased fatigability, tachypnea, tachycardia, pulmonary rales, and peripheral edema. Although this syndrome usually is associated with low cardiac output, it may occur in a number of so-called high output states, when the cardiac output is normal or greater than normal. A high output state may occur in chronic severe anemia, large arteriovenous fistula or multiple small arteriovenous shunts as in Paget's bone disease, some forms of severe hepatic or renal disorders, and acutely in septic shock. The syndrome of systemic congestion in a high output state is traditionally referred to as high output heart failure. However, the term is a misnomer because the heart in these conditions is normal, capable of generating very high cardiac output. The underlying problem in high output failure is a decrease in the systemic vascular resistance that threatens the arterial blood pressure and causes activation of neurohormones, resulting in an increase in salt and water retention by the kidney. Many of the high output states are curable conditions, and because they are associated with decreased peripheral vascular resistance, the use of vasodilator therapy for treatment of congestion may aggravate the problem. There are other clinically important issues in high output failure that have received little attention in the current medical literature. This article reviews the available data on high output cardiac failure with particular emphasis on the underlying mechanisms and treatment.
answer to the saudi medical council question examination
Dysphagia
Dysphagia is difficulty swallowing. It includes the feeling that food is stuck in the throat or somewhere between the throat and the stomach.
Difficulty swallowing is common among all age groups but is more common among older people. Between 5% and 10% of older people who live independently have difficulty swallowing.
Swallowing becomes difficult when food does not pass normally from the mouth to the stomach. This difficulty may be temporary and disappear on its own. Or it may be caused by a disorder. Swallowing is partly under a person's control (is voluntary) and occurs partly without conscious effort (is involuntary). Problems can affect either part of the action.
Causes
A problem as simple as eating too fast, taking bites that are too big, having poorly fitting dentures, or having missing or loose teeth can make swallowing difficult. Not drinking enough water when eating or eating while lying down makes swallowing more difficult.
People with dementia may not chew food adequately or may forget to swallow it.
Disorders that damage any part of the body that is involved in swallowing?muscles, nerves, or brain?may cause difficulty swallowing. A stroke is the most common example among older people. Almost 30% of people who have had a stroke have difficulty swallowing. Parkinson's disease, myasthenia gravis, pseudobulbar palsy, systemic sclerosis, and amyotrophic lateral sclerosis (Lou Gehrig's disease) can also cause difficulty swallowing. Some drugs, especially phenothiazines (a type of antipsychotic drug), can cause difficulty swallowing because they affect the throat muscles.
Some disorders interfere with normal contractions of the esophagus. Then food cannot move through the esophagus into the stomach as it normally does. The esophagus contracts, but the contractions do not move food. This abnormal contraction can cause esophageal spasm. In about one third of people with spasms, the lower esophageal sphincter does not open normally and does not contract in coordination with the rest of the esophagus. As a result, the movement of foods and fluids into the stomach may be delayed, causing a feeling that food is stuck.
Uncommonly, the nerves that control the lower esophageal sphincter and the esophagus are abnormal, resulting in achalasia. In achalasia, the esophagus does not contract, and the lower esophageal sphincter does not relax normally to allow food to pass into the stomach. The cause of achalasia is unknown. It usually begins, almost unnoticed, between the ages of 20 and 60, then progresses gradually over many months or years. At first, people have difficulty swallowing solid foods, but eventually they also have difficulty swallowing liquids.
Swallowing may become difficult because the esophagus is narrowed or completely blocked. Progressive damage to the esophagus can cause scar tissue to form. This inflexible scar tissue (called a stricture) narrows the esophagus and restricts the movement of food through it.
The esophagus is not easily damaged. However, it can be damaged gradually by the repeated backward flow of acid from the stomach (gastroesophageal reflux) over months to years. Taking certain drugs can damage the lining of the esophagus (causing erosion) or cause deeper sores (ulcers). These drugs include bisphosphonates (used to treat osteoporosis), aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), some antibiotics (such as doxycycline, tetracycline, and clindamycin), and potassium or iron supplements. Damage by drugs is more common among older people. Part of the reason may be that the esophagus does not contract normally or that older people do not drink enough water when they take the drug.
An abnormal ring of tissue may narrow the esophagus. The most common type is Schatzki's ring, which is located near the stomach. What causes these rings to form is unclear, but they may result from damage due to reflux, abnormal contractions of the esophagus, or the use of certain drugs. These rings intermittently cause difficulty swallowing. Usually, difficulty occurs when solid foods are eaten rapidly. The solid food most commonly caught in a ring is poorly chewed meat. The result is severe pain. Because this problem often occurs when dining out, it is sometimes called steakhouse syndrome.
Thin sheets of tissue (webs) may form across the interior of the esophagus, partially blocking it. Rarely, webs may result from severe iron deficiency that is not treated. Esophageal webs are more common among older people. A few people are born with esophageal rings or webs, which do not cause symptoms until later in life. Webs, like rings, cause difficulty swallowing solid foods, not liquids.
A pouch (diverticulum) that develops just above the upper esophageal sphincter or in the wall of the esophagus may make swallowing difficult. Food is caught in the pouch, causing discomfort. If the pouch is filled, it can block the passage of food. Sometimes pouches form in response to injury or irritation. They may form if the contractions of the throat and upper sphincter are not coordinated. Sometimes the cause is unknown. The most common type is Zenker's diverticulum, which forms just above the upper esophageal sphincter. Zenker's diverticulum usually develops after age 50.
Food and foreign bodies may block the esophagus. The esophagus can be partially or completely blocked by a noncancerous (benign) or cancerous (malignant) tumor in the esophagus. Esophageal cancer rarely causes difficulty swallowing, but many people still fear that possibility.
See the figure Pouches and Bulges in the Digestive Tract.
Several disorders can block the esophagus by putting pressure on it from outside. For example, a heart disorder may cause part of the aorta or heart to enlarge and press on the esophagus. Cancer (most commonly, lung cancer), an aortic aneurysm, enlargement of the thyroid gland, or excessive growth of bones in the spine (vertebrae) can also put pressure on the esophagus.
Symptoms
Most people who have difficulty swallowing have difficulty swallowing solids, particularly breads and meats. After eating, people may feel as if they have a lump in their throat or tightness in their chest. They may have to swallow several times before the food feels as if it has gone down. Much later, swallowing liquids may become difficult. Some people have difficulty swallowing solids and liquids from the beginning.
People with difficulty swallowing may regurgitate food through the mouth or nose. When they lie down at night, they may cough or spit up food swallowed many hours before. They may inhale (aspirate) food into the windpipe (trachea), then cough. Aspirating food can lead to lung disorders, including airway infections and a form of pneumonia called aspiration pneumonia.
Depending on the cause of dysphagia, people may have chest pain when they eat. Chest pain may be caused by spasms of the esophagus. This pain is often described as a squeezing pain under the breastbone (sternum). The pain resembles chest pain due to coronary artery disease (angina), so the two are sometimes confused. Some people feel pain in the throat when they swallow. This pain may be caused by an infection or, rarely, cancer.
People with Zenker's diverticulum may have bad breath because food collects in the pouch. The pouch can also interfere with taking pills. Pills can become stuck in the pouch and thus are not absorbed into the bloodstream. Occasionally, the pouch causes pressure or swelling in the neck.
If people continue to have difficulty swallowing, they may lose weight and become undernourished and dehydrated.
Diagnosis
If difficulty swallowing lasts more than a few days, the person should see a doctor promptly. The doctor tries to identify the cause. Symptoms provide some clues to the cause. So the doctor usually asks whether the person has difficulty swallowing both solids and liquids, whether pain is felt, and, if so, where and when. Whether the person has vomited blood or seen blood in stool is also a concern. The throat is examined, and the person is asked to swallow to see if the throat is working normally.
Usually, tests are needed to identify the cause. Most often, the esophagus is examined with a flexible viewing tube (endoscope) that is passed down the throat. To rule out cancer, doctors may take a sample of tissue with instruments threaded through the tube. Some disorders, such as esophageal rings or webs, can be treated at the same time.
A barium study may be done before endoscopy. Or it may be done afterward if endoscopy does not provide enough information. A barium study involves swallowing a barium solution or food coated with barium. Barium can be seen on x-rays. X-rays are taken continuously as the barium passes down the throat and esophagus to the stomach (in a procedure called fluoroscopy). This study is painless, and the barium passes through the digestive system and out of the body, causing no harm. A barium study can detect esophageal webs and rings, other blockages, and pouches. It can also detect tumors, ulcers, and evidence of spasm. This study helps doctors assess the function of the nerves and muscles involved in swallowing. Thus, doctors can determine whether a disorder that affects these muscles or nerves, such as a stroke, could be the cause.
Additional tests may be done, depending on the suspected cause. If the cause could be abnormal contractions of the esophagus (such as esophageal spasm), pressures in the esophagus may be measured with a tube placed in the esophagus. This test is called manometry. During the test, a person is asked to swallow water or a semisolid material or is given an injection of edrophonium, a drug that may trigger a spasm. This test helps doctors determine whether the pain is caused by spasms.
Treatment
Treatment focuses on helping the person swallow safely (including how to avoid aspiration) and on treating the disorder causing the problem if possible. Effective treatment enables a person to eat enough types of foods to get a well-balanced, adequate diet. Sometimes simple measures are the only treatment needed. For example, chewing food thoroughly and then sipping water can help prevent symptoms. Sitting upright while eating can help. Foods with certain textures, such as thick creamed soups or pureed fruits, may be easier to swallow. The best consistency is often found by trial and error. Using appropriate eating utensils may help. For example, using a small straw or small spoon can limit the amount of food put in the mouth. A smaller amount is easier to swallow.
If the cause is a disorder that impairs the muscles or nerves involved in swallowing, speech therapists may suggest exercises to strengthen the muscles or improve coordination and techniques to use when eating. If the cause is esophageal spasms or achalasia, drugs that relax the muscles of the esophagus may help relieve symptoms. Examples are nitroglycerin, long-acting nitrates, and calcium channel blockers (such as nifedipine). Some of these drugs?those with anticholinergic effects (such as dicyclomine)?are rarely used for older people because of side effects.
Usually, achalasia requires additional treatment. Doctors may inject botulinum toxin into the lower esophageal sphincter. Botulinum toxin paralyzes the sphincter, enabling it to relax and allow food to pass through. This treatment may provide more sustained symptom relief for older people than for younger people. The effects usually last 6 to 24 months, so injections need to be repeated. After two to three injections, they usually become ineffective. So injections cannot be used indefinitely. Alternatively, doctors may widen the passageway with a balloon dilator (called a bougie). This dilator is a tube with a deflated balloon attached to one end. It is passed down the throat to the lower esophageal sphincter, then inflated and deflated once. This procedure may provide long-lasting relief, sometimes permanently. If symptoms recur, the procedure can be repeated.
When these treatments are ineffective or symptoms are substantial, surgery may be done to correct achalasia. For this procedure (called myotomy), the muscular fibers in the lower esophageal sphincter are cut. As a result, the abnormal tightness of the sphincter is relieved. Myotomy can often be done with instruments threaded through a viewing tube called a laparoscope. The laparoscope is inserted through a small incision in the abdomen. This procedure is successful in most people. If needed, surgery to prevent reflux is usually done at the same time. Before surgery is done, a specialist is usually consulted.
If an esophageal web is due to iron deficiency, treating the deficiency usually results in disappearance of the web. For other esophageal webs and esophageal rings, an endoscope or dilators are used to clear or widen the esophagus.
If Zenker's diverticulum is large and causes symptoms, surgery to eliminate the pouch is usually recommended. Surgery may be done through an incision in the neck (open surgery) or through an endoscope inserted through the mouth. Using an endoscope may be preferred because it is faster, relieves symptoms equally well, and may not require an overnight stay in the hospital.
Dysphagia is difficulty swallowing. It includes the feeling that food is stuck in the throat or somewhere between the throat and the stomach.
Difficulty swallowing is common among all age groups but is more common among older people. Between 5% and 10% of older people who live independently have difficulty swallowing.
Swallowing becomes difficult when food does not pass normally from the mouth to the stomach. This difficulty may be temporary and disappear on its own. Or it may be caused by a disorder. Swallowing is partly under a person's control (is voluntary) and occurs partly without conscious effort (is involuntary). Problems can affect either part of the action.
Causes
A problem as simple as eating too fast, taking bites that are too big, having poorly fitting dentures, or having missing or loose teeth can make swallowing difficult. Not drinking enough water when eating or eating while lying down makes swallowing more difficult.
People with dementia may not chew food adequately or may forget to swallow it.
Disorders that damage any part of the body that is involved in swallowing?muscles, nerves, or brain?may cause difficulty swallowing. A stroke is the most common example among older people. Almost 30% of people who have had a stroke have difficulty swallowing. Parkinson's disease, myasthenia gravis, pseudobulbar palsy, systemic sclerosis, and amyotrophic lateral sclerosis (Lou Gehrig's disease) can also cause difficulty swallowing. Some drugs, especially phenothiazines (a type of antipsychotic drug), can cause difficulty swallowing because they affect the throat muscles.
Some disorders interfere with normal contractions of the esophagus. Then food cannot move through the esophagus into the stomach as it normally does. The esophagus contracts, but the contractions do not move food. This abnormal contraction can cause esophageal spasm. In about one third of people with spasms, the lower esophageal sphincter does not open normally and does not contract in coordination with the rest of the esophagus. As a result, the movement of foods and fluids into the stomach may be delayed, causing a feeling that food is stuck.
Uncommonly, the nerves that control the lower esophageal sphincter and the esophagus are abnormal, resulting in achalasia. In achalasia, the esophagus does not contract, and the lower esophageal sphincter does not relax normally to allow food to pass into the stomach. The cause of achalasia is unknown. It usually begins, almost unnoticed, between the ages of 20 and 60, then progresses gradually over many months or years. At first, people have difficulty swallowing solid foods, but eventually they also have difficulty swallowing liquids.
Swallowing may become difficult because the esophagus is narrowed or completely blocked. Progressive damage to the esophagus can cause scar tissue to form. This inflexible scar tissue (called a stricture) narrows the esophagus and restricts the movement of food through it.
The esophagus is not easily damaged. However, it can be damaged gradually by the repeated backward flow of acid from the stomach (gastroesophageal reflux) over months to years. Taking certain drugs can damage the lining of the esophagus (causing erosion) or cause deeper sores (ulcers). These drugs include bisphosphonates (used to treat osteoporosis), aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), some antibiotics (such as doxycycline, tetracycline, and clindamycin), and potassium or iron supplements. Damage by drugs is more common among older people. Part of the reason may be that the esophagus does not contract normally or that older people do not drink enough water when they take the drug.
An abnormal ring of tissue may narrow the esophagus. The most common type is Schatzki's ring, which is located near the stomach. What causes these rings to form is unclear, but they may result from damage due to reflux, abnormal contractions of the esophagus, or the use of certain drugs. These rings intermittently cause difficulty swallowing. Usually, difficulty occurs when solid foods are eaten rapidly. The solid food most commonly caught in a ring is poorly chewed meat. The result is severe pain. Because this problem often occurs when dining out, it is sometimes called steakhouse syndrome.
Thin sheets of tissue (webs) may form across the interior of the esophagus, partially blocking it. Rarely, webs may result from severe iron deficiency that is not treated. Esophageal webs are more common among older people. A few people are born with esophageal rings or webs, which do not cause symptoms until later in life. Webs, like rings, cause difficulty swallowing solid foods, not liquids.
A pouch (diverticulum) that develops just above the upper esophageal sphincter or in the wall of the esophagus may make swallowing difficult. Food is caught in the pouch, causing discomfort. If the pouch is filled, it can block the passage of food. Sometimes pouches form in response to injury or irritation. They may form if the contractions of the throat and upper sphincter are not coordinated. Sometimes the cause is unknown. The most common type is Zenker's diverticulum, which forms just above the upper esophageal sphincter. Zenker's diverticulum usually develops after age 50.
Food and foreign bodies may block the esophagus. The esophagus can be partially or completely blocked by a noncancerous (benign) or cancerous (malignant) tumor in the esophagus. Esophageal cancer rarely causes difficulty swallowing, but many people still fear that possibility.
See the figure Pouches and Bulges in the Digestive Tract.
Several disorders can block the esophagus by putting pressure on it from outside. For example, a heart disorder may cause part of the aorta or heart to enlarge and press on the esophagus. Cancer (most commonly, lung cancer), an aortic aneurysm, enlargement of the thyroid gland, or excessive growth of bones in the spine (vertebrae) can also put pressure on the esophagus.
Symptoms
Most people who have difficulty swallowing have difficulty swallowing solids, particularly breads and meats. After eating, people may feel as if they have a lump in their throat or tightness in their chest. They may have to swallow several times before the food feels as if it has gone down. Much later, swallowing liquids may become difficult. Some people have difficulty swallowing solids and liquids from the beginning.
People with difficulty swallowing may regurgitate food through the mouth or nose. When they lie down at night, they may cough or spit up food swallowed many hours before. They may inhale (aspirate) food into the windpipe (trachea), then cough. Aspirating food can lead to lung disorders, including airway infections and a form of pneumonia called aspiration pneumonia.
Depending on the cause of dysphagia, people may have chest pain when they eat. Chest pain may be caused by spasms of the esophagus. This pain is often described as a squeezing pain under the breastbone (sternum). The pain resembles chest pain due to coronary artery disease (angina), so the two are sometimes confused. Some people feel pain in the throat when they swallow. This pain may be caused by an infection or, rarely, cancer.
People with Zenker's diverticulum may have bad breath because food collects in the pouch. The pouch can also interfere with taking pills. Pills can become stuck in the pouch and thus are not absorbed into the bloodstream. Occasionally, the pouch causes pressure or swelling in the neck.
If people continue to have difficulty swallowing, they may lose weight and become undernourished and dehydrated.
Diagnosis
If difficulty swallowing lasts more than a few days, the person should see a doctor promptly. The doctor tries to identify the cause. Symptoms provide some clues to the cause. So the doctor usually asks whether the person has difficulty swallowing both solids and liquids, whether pain is felt, and, if so, where and when. Whether the person has vomited blood or seen blood in stool is also a concern. The throat is examined, and the person is asked to swallow to see if the throat is working normally.
Usually, tests are needed to identify the cause. Most often, the esophagus is examined with a flexible viewing tube (endoscope) that is passed down the throat. To rule out cancer, doctors may take a sample of tissue with instruments threaded through the tube. Some disorders, such as esophageal rings or webs, can be treated at the same time.
A barium study may be done before endoscopy. Or it may be done afterward if endoscopy does not provide enough information. A barium study involves swallowing a barium solution or food coated with barium. Barium can be seen on x-rays. X-rays are taken continuously as the barium passes down the throat and esophagus to the stomach (in a procedure called fluoroscopy). This study is painless, and the barium passes through the digestive system and out of the body, causing no harm. A barium study can detect esophageal webs and rings, other blockages, and pouches. It can also detect tumors, ulcers, and evidence of spasm. This study helps doctors assess the function of the nerves and muscles involved in swallowing. Thus, doctors can determine whether a disorder that affects these muscles or nerves, such as a stroke, could be the cause.
Additional tests may be done, depending on the suspected cause. If the cause could be abnormal contractions of the esophagus (such as esophageal spasm), pressures in the esophagus may be measured with a tube placed in the esophagus. This test is called manometry. During the test, a person is asked to swallow water or a semisolid material or is given an injection of edrophonium, a drug that may trigger a spasm. This test helps doctors determine whether the pain is caused by spasms.
Treatment
Treatment focuses on helping the person swallow safely (including how to avoid aspiration) and on treating the disorder causing the problem if possible. Effective treatment enables a person to eat enough types of foods to get a well-balanced, adequate diet. Sometimes simple measures are the only treatment needed. For example, chewing food thoroughly and then sipping water can help prevent symptoms. Sitting upright while eating can help. Foods with certain textures, such as thick creamed soups or pureed fruits, may be easier to swallow. The best consistency is often found by trial and error. Using appropriate eating utensils may help. For example, using a small straw or small spoon can limit the amount of food put in the mouth. A smaller amount is easier to swallow.
If the cause is a disorder that impairs the muscles or nerves involved in swallowing, speech therapists may suggest exercises to strengthen the muscles or improve coordination and techniques to use when eating. If the cause is esophageal spasms or achalasia, drugs that relax the muscles of the esophagus may help relieve symptoms. Examples are nitroglycerin, long-acting nitrates, and calcium channel blockers (such as nifedipine). Some of these drugs?those with anticholinergic effects (such as dicyclomine)?are rarely used for older people because of side effects.
Usually, achalasia requires additional treatment. Doctors may inject botulinum toxin into the lower esophageal sphincter. Botulinum toxin paralyzes the sphincter, enabling it to relax and allow food to pass through. This treatment may provide more sustained symptom relief for older people than for younger people. The effects usually last 6 to 24 months, so injections need to be repeated. After two to three injections, they usually become ineffective. So injections cannot be used indefinitely. Alternatively, doctors may widen the passageway with a balloon dilator (called a bougie). This dilator is a tube with a deflated balloon attached to one end. It is passed down the throat to the lower esophageal sphincter, then inflated and deflated once. This procedure may provide long-lasting relief, sometimes permanently. If symptoms recur, the procedure can be repeated.
When these treatments are ineffective or symptoms are substantial, surgery may be done to correct achalasia. For this procedure (called myotomy), the muscular fibers in the lower esophageal sphincter are cut. As a result, the abnormal tightness of the sphincter is relieved. Myotomy can often be done with instruments threaded through a viewing tube called a laparoscope. The laparoscope is inserted through a small incision in the abdomen. This procedure is successful in most people. If needed, surgery to prevent reflux is usually done at the same time. Before surgery is done, a specialist is usually consulted.
If an esophageal web is due to iron deficiency, treating the deficiency usually results in disappearance of the web. For other esophageal webs and esophageal rings, an endoscope or dilators are used to clear or widen the esophagus.
If Zenker's diverticulum is large and causes symptoms, surgery to eliminate the pouch is usually recommended. Surgery may be done through an incision in the neck (open surgery) or through an endoscope inserted through the mouth. Using an endoscope may be preferred because it is faster, relieves symptoms equally well, and may not require an overnight stay in the hospital.
answer to the saudi medical council question examination
Diffuse interstitial lung disease refers to a group of lung disorders in which the deep lung tissues become swollen and scarred.
Causes
Interstitial lung diseases (ILD) are caused by swelling and scarring of the air sacs (alveoli) and their supporting structures (the interstitium). This leads to reduced levels of oxygen in the blood.
The interstitial lung diseases can be broken down into two large groups:
Those that have no known cause (idiopathic ILD)
Those with an identifiable cause
One recent system further divides idiopathic ILD into the following three groups:
Idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP)
Nonspecific interstitial pneumonitis (NSIP)
Acute interstitial pneumonitis (AIP)
There are dozens of different causes of ILD. Many occupational substances can cause ILD, including:
Asbestos
Coal dust
Cotton dust
Sand (silica) dust
People who are heavily exposed to known causes of occupational lung disease in the workplace are usually routinely screened for lung disease. This can include coal miners, sand-blasters, ship workers, and others.
Occasionally, bird keeping or bathing in hot tubs may cause some forms of ILD.
The following diseases can cause ILD:
Lupus
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Certain medications (such as bleomycin, amiodarone, and methotrexate) may also cause ILD.
Cigarette smoking may increase the risk of developing some forms of ILD and may cause the disease to be more severe.
Symptoms
Abnormal enlargement of the base of the fingernails (clubbing)
Blue color of the lips, skin, or fingernails due to low blood oxygen levels (cyanosis)
Decreased tolerance for activity
Dry cough
Rapid breathing
Shortness of breath at rest or while active
Exams and Tests
The health care provider will perform a physical exam. Dry, crackling breath sounds may be heard when listening to the chest with a stethoscope. The health care provider may notice nasal flaring.
The following tests may be done:
Blood tests to check for connective tissue diseases
Bronchoscopy with biopsy
Chest x-ray
CT scan of the chest
Lung biopsy
Measurement of the blood oxygen level at rest or during exertion
Pulmonary function tests
Treatment
The treatment depends on the cause of the disease. Most often, anti-inflammatory drugs, such as corticosteroids or immunosuppressing drugs, are prescribed.
If there is no specific treatment for the condition, therapy is aimed at making the person more comfortable and supporting lung function. Those with low blood oxygen levels will receive oxygen. Lung rehabilitation can help people with advanced ILD.
Some patients with advanced ILD may need a lung transplant.
Support Groups
For additional information and resources, see lung disease support group.
Outlook (Prognosis)
Chances of recovery or the disease getting worse depend on the cause, and how severe the disease was when it was first diagnosed.
Possible Complications
Hypoxemia
Pulmonary hypertension
Respiratory failure
Right-sided heart failure (cor pulmonale)
When to Contact a Medical Professional
Call your health care provider if you have shortness of breath at rest that lasts for any period of time.
Prevention
Avoid exposure to substances known to cause lung disease.
Quitting smoking can prevent ILD from getting worse.
Alternative Names
Diffuse parenchymal lung disease; Alveolitis; Cryptogenic fibrosing alveolitis (CFA); Idiopathic pulmonary pneumonitis (IPP)
References
Goldman L, Ausiello D. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders; 2008.
Update Date: 1/18/2008
Updated by: Andrew Schriber, MD, FCCP, Specialist in Pulmonary, Critical Care, and Sleep Medicine, Virtua Memorial Hospital, Mount Holly, New Jersey. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.
Causes
Interstitial lung diseases (ILD) are caused by swelling and scarring of the air sacs (alveoli) and their supporting structures (the interstitium). This leads to reduced levels of oxygen in the blood.
The interstitial lung diseases can be broken down into two large groups:
Those that have no known cause (idiopathic ILD)
Those with an identifiable cause
One recent system further divides idiopathic ILD into the following three groups:
Idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP)
Nonspecific interstitial pneumonitis (NSIP)
Acute interstitial pneumonitis (AIP)
There are dozens of different causes of ILD. Many occupational substances can cause ILD, including:
Asbestos
Coal dust
Cotton dust
Sand (silica) dust
People who are heavily exposed to known causes of occupational lung disease in the workplace are usually routinely screened for lung disease. This can include coal miners, sand-blasters, ship workers, and others.
Occasionally, bird keeping or bathing in hot tubs may cause some forms of ILD.
The following diseases can cause ILD:
Lupus
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Certain medications (such as bleomycin, amiodarone, and methotrexate) may also cause ILD.
Cigarette smoking may increase the risk of developing some forms of ILD and may cause the disease to be more severe.
Symptoms
Abnormal enlargement of the base of the fingernails (clubbing)
Blue color of the lips, skin, or fingernails due to low blood oxygen levels (cyanosis)
Decreased tolerance for activity
Dry cough
Rapid breathing
Shortness of breath at rest or while active
Exams and Tests
The health care provider will perform a physical exam. Dry, crackling breath sounds may be heard when listening to the chest with a stethoscope. The health care provider may notice nasal flaring.
The following tests may be done:
Blood tests to check for connective tissue diseases
Bronchoscopy with biopsy
Chest x-ray
CT scan of the chest
Lung biopsy
Measurement of the blood oxygen level at rest or during exertion
Pulmonary function tests
Treatment
The treatment depends on the cause of the disease. Most often, anti-inflammatory drugs, such as corticosteroids or immunosuppressing drugs, are prescribed.
If there is no specific treatment for the condition, therapy is aimed at making the person more comfortable and supporting lung function. Those with low blood oxygen levels will receive oxygen. Lung rehabilitation can help people with advanced ILD.
Some patients with advanced ILD may need a lung transplant.
Support Groups
For additional information and resources, see lung disease support group.
Outlook (Prognosis)
Chances of recovery or the disease getting worse depend on the cause, and how severe the disease was when it was first diagnosed.
Possible Complications
Hypoxemia
Pulmonary hypertension
Respiratory failure
Right-sided heart failure (cor pulmonale)
When to Contact a Medical Professional
Call your health care provider if you have shortness of breath at rest that lasts for any period of time.
Prevention
Avoid exposure to substances known to cause lung disease.
Quitting smoking can prevent ILD from getting worse.
Alternative Names
Diffuse parenchymal lung disease; Alveolitis; Cryptogenic fibrosing alveolitis (CFA); Idiopathic pulmonary pneumonitis (IPP)
References
Goldman L, Ausiello D. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders; 2008.
Update Date: 1/18/2008
Updated by: Andrew Schriber, MD, FCCP, Specialist in Pulmonary, Critical Care, and Sleep Medicine, Virtua Memorial Hospital, Mount Holly, New Jersey. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.
13.11.09
Salpingo-oophorectomy
Definition
Unilateral salpingo-oophorectomy is the surgical removal of a fallopian tube and an ovary. If both sets of fallopian tubes and ovaries are removed, the procedure is called a bilateral salpingo-oophorectomy.
Purpose
This surgery is performed to treat ovarian or other gynecological cancers, or infections caused by pelvic inflammatory disease. Occasionally, removal of one or both ovaries may be done to treat endometriosis, a condition in which the lining of the uterus (the endometrium) grows outside of the uterus (usually on and around the pelvic organs). The procedure may also be performed if a woman has been diagnosed with an ectopic pregnancy in a fallopian tube and a salpingostomy (an incision into the fallopian tube to remove the pregnancy) cannot be done. If only one fallopian tube and ovary are removed, the woman may still be able to conceive and carry a pregnancy to term. If both are removed, however, the woman is rendered permanently infertile. This procedure is commonly combined with a hysterectomy (surgical removal of the uterus); the ovaries and fallopian tubes are removed in about one-third of hysterectomies.
Until the 1980s, women over age 40 having hysterectomies routinely had healthy ovaries and fallopian tubes removed at the same time. Many physicians reasoned that a woman over 40 was approaching menopause and soon her ovaries would stop secreting estrogen and releasing eggs. Removing the ovaries would eliminate the risk of ovarian cancer and only accelerate menopause by a few years.
In the 1990s, the thinking about routine salpingooophorectomy began to change. The risk of ovarian cancer in women who have no family history of the disease is less than 1%. Moreover, removing the ovaries increases the risk of cardiovascular disease and accelerates osteoporosis unless a woman takes prescribed hormone replacements.
Read more: http://www.surgeryencyclopedia.com/Pa-St/Salpingo-Oophorectomy.html#ixzz0Wo7QvcWU
Read more: http://www.surgeryencyclopedia.com/Pa-St/Salpingo-Oophorectomy.html#ixzz0Wo7QvcWU
Overall, ovarian cancer accounts for only 4% of all cancers in women. For women at increased risk, oophorectomy may be considered after the age of 35 if childbearing is complete. Factors that increase a woman's risk of developing ovarian cancer include age (most ovarian cancers occur after menopause), the presence of a mutation in the BRCA1 or BRCA2 gene, the number of menstrual periods a woman has had (affected by age of onset, pregnancy, breastfeeding, and oral contraceptive use), history of breast cancer, diet, and family history. The incidence of ovarian cancer is highest among American Indian (17.5 cases per 100,000 population), Caucasian (15.8 per 100,000), Vietnamese (13.8 per 100,000), Caucasian Hispanic (12.1 per 100,000), and Hawaiian (11.8 per 100,000) women; it is lowest among Korean (7.0 per 100,000) and Chinese (9.3 per 100,000) women. African American women have an ovarian cancer incidence of 10.2 per 100,000 population.
Endometriosis, another reason why salpingooophorectomy may be performed, has been estimated to affect up to 10% of women. Approximately four out of every 1,000 women are hospitalized as a result of endometriosis each year. Women 25?35 years of age are affected most, with 27 being the average age of diagnosis.
Description
General or regional anesthesia will be given to the patient before the procedure begins. If the procedure is
In a salpingo-oophorectomy, a woman's reproductive organs are accessed through an incision in the lower abdomen, or laparoscopically (A). Once the area is visualized, a diseased fallopian tube can be severed from the uterus and removed (B and C). The ovary can also be removed with the tube (D). The remaining structures are stitched (E), and the wound is closed. (
Illustration by GGS Inc.
)
performed through a laparoscope, the surgeon can avoid a large abdominal incision and can shorten recovery. With this technique, the surgeon makes a small cut through the abdominal wall just below the navel. A tube containing a tiny lens and light source (a laparoscope) is then inserted through the incision. A camera can be attached that allows the surgeon to see the abdominal cavity on a video monitor. When the ovaries and fallopian tubes are detached, they are removed though a small incision at the top of the vagina. The organs can also be cut into smaller sections and removed. When the laparoscope is used, the patient can be given either regional or general anesthesia; if there are no complications, the patient can leave the hospital in a day or two.
If a laparoscope is not used, the surgery involves an incision 4?6 in (10?15 cm) long into the abdomen extending either vertically up from the pubic bone toward the navel, or horizontally (the "bikini incision") across the pubic hairline. The scar from a bikini incision is less noticeable, but some surgeons prefer the vertical incision because it provides greater visibility while operating. A disadvantage to abdominal salpingo-oophorectomy is that bleeding is more likely to be a complication of this type of operation. The procedure is more painful than a laparoscopic operation and the recovery period is longer. A woman can expect to be in the hospital two to five days and will need three to six weeks to return to normal activities.
Diagnosis/Preparation
Before surgery, the doctor will order blood and urine tests, and any additional tests such as ultrasound or x rays to help the surgeon visualize the woman's condition. The woman may also meet with the anesthesiologist to evaluate any special conditions that might affect the administration of anesthesia. A colon preparation may be done, if extensive surgery is anticipated.
On the evening before the operation, the woman should eat a light dinner, then take nothing by mouth, including water or other liquids, after midnight.
Aftercare
If performed through an abdominal incision, salpingo-oophorectomy is major surgery that requires three to six weeks for full recovery. However, if performed laparoscopically, the recovery time can be much shorter. There may be some discomfort around the incision for the first few days after surgery, but most women are walking around by the third day. Within a month or so, patients can gradually resume normal activities such as driving, exercising, and working.
Immediately following the operation, the patient should avoid sharply flexing the thighs or the knees. Persistent back pain or bloody or scanty urine indicates that a ureter may have been injured during surgery.
If both ovaries are removed in a premenopausal woman as part of the operation, the sudden loss of estrogen will trigger an abrupt premature menopause that may involve severe symptoms of hot flashes, vaginal dryness, painful intercourse, and loss of sex drive. (This is also called "surgical menopause.") In addition to these symptoms, women who lose both ovaries also lose the protection these hormones provide against heart disease and osteoporosis many years earlier than if they had experienced natural menopause. Women who have had their ovaries removed are seven times more likely to develop coronary heart disease and much more likely to develop bone problems at an early age than are premenopausal women whose ovaries are intact. For these reasons, some form of hormone replacement therapy (HRT) may be prescribed to relieve the symptoms of surgical menopause and to help prevent heart and bone disease.
Reaction to the removal of fallopian tubes and ovaries depends on a wide variety of factors, including the woman's age, the condition that required the surgery, her reproductive history, how much social support she has, and any previous history of depression. Women who have had many gynecological surgeries or chronic pelvic pain seem to have a higher tendency to develop psychological problems after the surgery.
Risks
Major surgery always involves some risk, including infection, reactions to the anesthesia, hemorrhage, and scars at the incision site. Almost all pelvic surgery causes some internal scars, which in some cases can cause discomfort years after surgery.
Potential complications after a salpingo-oophorectomy include changes in sex drive, hot flashes, and other symptoms of menopause if both ovaries are removed. Women who have both ovaries removed and who do not take estrogen replacement therapy run an increased risk for cardiovascular disease and osteoporosis. Women with a history of psychological and emotional problems before an oophorectomy are more likely to experience psychological difficulties after the operation.
Normal results
If the surgery is successful, the fallopian tubes and ovaries will be removed without complication, and the underlying problem resolved. In the case of cancer, all the cancer will be removed. A woman will become infertile following a bilateral salpingo-oophorectomy.
Morbidity and mortality rates
Studies have shown that the complication rate following salpingo-oophorectomy is essentially the same as that following hysterectomy. The rate of complications differs by the type of hysterectomy performed. Abdominal hysterectomy is associated with a higher rate of complications (9.3%), while the overall complication rate for vaginal hysterectomy is 5.3%, and 3.6% for laparoscopic vaginal hysterectomy. The risk of death is about one in every 1,000 (1/1,000) women having a hysterectomy. The rates of some of the more commonly reported complications are:
excessive bleeding (hemorrhaging): 1.8?3.4%
fever or infection: 0.8?4.0%
accidental injury to another organ or structure: 1.5?1.8%
Because of the cessation of hormone production that occurs with a bilateral oophorectomy, women who lose both ovaries also prematurely lose the protection these hormones provide against heart disease and osteoporosis. Women who have undergone bilateral oophorectomy are seven times more likely to develop coronary heart disease and much more likely to develop bone problems at an early age than are premenopausal women whose ovaries are intact.
Read more: http://www.surgeryencyclopedia.com/Pa-St/Salpingo-Oophorectomy.html#ixzz0Wo7EdnOV
answer to the saudi medical council question examination
Oophorectomy (or ovariectomy) is the surgical removal of an ovary or ovaries. In the case of non-human animals, it is also called spaying and is a form of sterilization. Removal of the ovaries in women is the biological equivalent of castration in males, and the term is occasionally used in the medical literature instead of oophorectomy.
In the case of humans, oophorectomies are most often performed due to diseases such as ovarian cysts or cancer; prophylactically to reduce the chances of developing ovarian cancer or breast cancer; or in conjunction with removal of the uterus.
The removal of an ovary together with a Fallopian tube is called salpingo-oophorectomy or bilateral salpingo-oophorectomy if both ovaries and tubes are removed. Oophorectomy and salpingo-oophorectomy are not common forms of birth control in humans; more usual is tubal ligation, in which the Fallopian tubes are blocked but the ovaries remain intact. In many cases, surgical removal of the ovaries is performed concurrently with a hysterectomy. The surgery is then called "ovariohysterectomy" casually or "total abdominal hysterectomy with bilateral salpingo-oophorectomy" (sometimes abbreviated TAH-BSO), the more correct medical term. However, the term "hysterectomy" is often used colloquially yet incorrectly to refer to removal of any parts of the female reproductive system, including just the ovaries.
In the case of humans, oophorectomies are most often performed due to diseases such as ovarian cysts or cancer; prophylactically to reduce the chances of developing ovarian cancer or breast cancer; or in conjunction with removal of the uterus.
The removal of an ovary together with a Fallopian tube is called salpingo-oophorectomy or bilateral salpingo-oophorectomy if both ovaries and tubes are removed. Oophorectomy and salpingo-oophorectomy are not common forms of birth control in humans; more usual is tubal ligation, in which the Fallopian tubes are blocked but the ovaries remain intact. In many cases, surgical removal of the ovaries is performed concurrently with a hysterectomy. The surgery is then called "ovariohysterectomy" casually or "total abdominal hysterectomy with bilateral salpingo-oophorectomy" (sometimes abbreviated TAH-BSO), the more correct medical term. However, the term "hysterectomy" is often used colloquially yet incorrectly to refer to removal of any parts of the female reproductive system, including just the ovaries.
answer to the saudi medical council question examination
Culdocentesis is a procedure that checks for abnormal fluid in the space just behind the vagina (cul-de-sac).
How the Test is Performed
First, you will have a pelvic examination. Then, the health care provider will grasp the cervix with an instrument and lift it slightly.
A long, thin needle is inserted through the wall of the vagina (just below the uterus). A sample is taken of any fluid found in the space. The needle is pulled out.
How to Prepare for the Test
You may be asked to walk or sit for a short time before the test is done.
How the Test Will Feel
You may have an uncomfortable, cramping feeling when the cervix is grasped. There is a sharp, brief pain as the needle is inserted.
Why the Test is Performed
This procedure is done when you have pain in the lower abdomen and pelvis, and other tests suggest there is fluid in the cul-de-sac. This test may also be done when the doctor suspects a ruptured ectopic pregnancy or ovarian cyst.
The test is rarely done today because an ultrasound can usually detect fluid in the cul-de-sac.
Normal Results
No fluid in the cul-de-sac, or a very small amount of clear fluid, is normal.
What Abnormal Results Mean
Even when no fluid is found, it may be present, and you may need other tests. If fluid is drawn, it is cultured to see if you have an infection. If nonclotting blood is found in the cul-de-sac, you may need emergency surgery.
Risks
There is a slight risk of puncturing any growth, cyst, or ectopic pregnancy that exists. The needle should not be inserted too far or hard enough to go through the uterine wall.
Considerations
You may need someone to take you home if you were given a sedative.
How the Test is Performed
First, you will have a pelvic examination. Then, the health care provider will grasp the cervix with an instrument and lift it slightly.
A long, thin needle is inserted through the wall of the vagina (just below the uterus). A sample is taken of any fluid found in the space. The needle is pulled out.
How to Prepare for the Test
You may be asked to walk or sit for a short time before the test is done.
How the Test Will Feel
You may have an uncomfortable, cramping feeling when the cervix is grasped. There is a sharp, brief pain as the needle is inserted.
Why the Test is Performed
This procedure is done when you have pain in the lower abdomen and pelvis, and other tests suggest there is fluid in the cul-de-sac. This test may also be done when the doctor suspects a ruptured ectopic pregnancy or ovarian cyst.
The test is rarely done today because an ultrasound can usually detect fluid in the cul-de-sac.
Normal Results
No fluid in the cul-de-sac, or a very small amount of clear fluid, is normal.
What Abnormal Results Mean
Even when no fluid is found, it may be present, and you may need other tests. If fluid is drawn, it is cultured to see if you have an infection. If nonclotting blood is found in the cul-de-sac, you may need emergency surgery.
Risks
There is a slight risk of puncturing any growth, cyst, or ectopic pregnancy that exists. The needle should not be inserted too far or hard enough to go through the uterine wall.
Considerations
You may need someone to take you home if you were given a sedative.
answer to the saudi medical council question examination
What is Friedreich's ataxia?
Friedreich's ataxia is an inherited disease that causes progressive damage to the nervous system resulting in symptoms ranging from gait disturbance and speech problems to heart disease. It is named after the physician Nicholaus Friedreich, who first described the condition in the 1860s. "Ataxia," which refers to coordination problems such as clumsy or awkward movements and unsteadiness, occurs in many different diseases and conditions. The ataxia of Friedreich's ataxia results from the degeneration of nerve tissue in the spinal cord and of nerves that control muscle movement in the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath ? the insular covering on all nerve cells that helps conduct nerve impulses.
Friedreich's ataxia, although rare, is the most prevalent inherited ataxia, affecting about 1 in every 50,000 people in the United States. Males and females are affected equally.
top
What are the signs and symptoms?
Symptoms usually begin between the ages of 5 and 15 but can, on rare occasions, appear as early as 18 months or as late as 50 years of age. The first symptom to appear is usually difficulty in walking, or gait ataxia. The ataxia gradually worsens and slowly spreads to the arms and then the trunk. Foot deformities such as clubfoot, flexion (involuntary bending) of the toes, hammer toes, or foot inversion (turning inward) may be early signs. Over time, muscles begin to weaken and waste away, especially in the feet, lower legs, and hands, and deformities develop. Other symptoms include loss of tendon reflexes, especially in the knees and ankles. There is often a gradual loss of sensation in the extremities, which may spread to other parts of the body. Dysarthria (slowness and slurring of speech) develops, and the person is easily fatigued. Rapid, rhythmic, involuntary movements of the eye (nystagmus) are common. Most people with Friedreich's ataxia develop scoliosis (a curving of the spine to one side), which, if severe, may impair breathing.
Other symptoms that may occur include chest pain, shortness of breath, and heart palpitations. These symptoms are the result of various forms of heart disease that often accompany Friedreich's ataxia, such as cardiomyopathy (enlargement of the heart), myocardial fibrosis (formation of fiber-like material in the muscles of the heart), and cardiac failure. Heart rhythm abnormalities such as tachycardia (fast heart rate) and heart block (impaired conduction of cardiac impulses within the heart) are also common. About 20 percent of people with Friedreich's ataxia develop carbohydrate intolerance and 10 percent develop diabetes mellitus. Some people lose hearing or eyesight.
The rate of progression varies from person to person. Generally, within 10 to 20 years after the appearance of the first symptoms, the person is confined to a wheelchair, and in later stages of the disease individuals become completely incapacitated. Life expectancy may be affected, and many people with Friedreich's ataxia die in adulthood from the associated heart disease, the most common cause of death. However, some people with less severe symptoms of Friedreich's ataxia live much longer, sometimes into their sixties or seventies.
top
How is Friedreich's ataxia diagnosed?
Doctors diagnose Friedreich's ataxia by performing a careful clinical examination, which includes a medical history and a thorough physical examination. Tests that may be performed include:
electromyogram (EMG), which measures the electrical activity of muscle cells,
nerve conduction studies, which measure the speed with which nerves transmit impulses,
electrocardiogram (EKG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,
echocardiogram, which records the position and motion of the heart muscle,
magnetic resonance imaging (MRI) or computed tomography (CT) scan, which provides a picture of the brain and spinal cord,
spinal tap to evaluate the cerebrospinal fluid,
blood and urine tests to check for elevated glucose levels, and
genetic testing to identify the affected gene.
top
How is Friedreich's ataxia inherited?
Friedreich's ataxia is an autosomal recessive disease, which means the patient must inherit two affected genes, one from each parent, for the disease to develop. A person who has only one abnormal copy of a gene for a recessive genetic disease such as Friedreich's ataxia is called a carrier. A carrier will not develop the disease but could pass the affected gene on to his or her children. If both parents are carriers of the Friedreich's ataxia gene, their children will have a 1 in 4 chance of having the disease and a 1 in 2 chance of inheriting one abnormal gene that they, in turn, could pass on to their children. About one in 90 Americans of European ancestry carries one affected gene.
Humans have two copies of each gene ? one inherited from the mother and one from the father. Genes are located at a specific place on each of an individual's 46 chromosomes, which are tightly coiled chains of DNA containing millions of chemicals called bases. These bases ? adenine, thymine, cytosine, and guanine ? are abbreviated A, T, C, and G. Certain bases always "pair" together (A with T; C with G), and different combinations of base pairs join in sets of three to form coded messages.
These coded messages are "recipes" for making amino acids, the building blocks of proteins. By combining in long sequences, like long phone numbers, the paired bases tell each cell how to assemble different proteins. Proteins make up cells, tissues, and specialized enzymes that our bodies need to function normally. The protein that is altered in Friedreich's ataxia is called frataxin.
In 1996, an international group of scientists identified the cause of Friedreich's ataxia as a defect in a gene located on chromosome 9. Because of the inherited abnormal code, a particular sequence of bases (GAA) is repeated too many times. Normally, the GAA sequence is repeated 7 to 22 times, but in people with Friedreich's ataxia it can be repeated hundreds or even over a thousand times. This type of abnormality is called a triplet repeat expansion and has been implicated as the cause of several dominantly inherited diseases. Friedreich's ataxia is the first known recessive genetic disease that is caused by a triplet repeat expansion. Although about 98 percent of Friedreich's ataxia carriers have this particular genetic triplet repeat expansion, it is not found in all cases of the disease. A very small proportion of affected individuals have other gene coding defects responsible for causing disease.
The triplet repeat expansion apparently disrupts the normal assembly of amino acids into proteins, greatly reducing the amount of frataxin that is produced. Frataxin is found in the energy-producing parts of the cell called mitochondria. Research suggests that without a normal level of frataxin, certain cells in the body (especially brain, spinal cord, and muscle cells) cannot effectively produce energy and have a buildup of toxic byproducts leading to what is called "oxidative stress." This clue to the possible cause of Friedreich's ataxia came after scientists conducted studies using a yeast protein with a chemical structure similar to human frataxin. They found that the shortage of this protein in the yeast cell led to a toxic buildup of iron in the cell's mitochondria. When the excess iron reacted with oxygen, free radicals were produced. Although free radicals are essential molecules in the body's metabolism, they can also destroy cells and harm the body. Research continues on this subject (see section on "What research is being done?").
top
Can Friedreich's ataxia be cured or treated?
As with many degenerative diseases of the nervous system, there is currently no cure or effective treatment for Friedreich's ataxia. However, many of the symptoms and accompanying complications can be treated to help patients maintain optimal functioning as long as possible. Diabetes, if present, can be treated with diet and medications such as insulin, and some of the heart problems can be treated with medication as well. Orthopedic problems such as foot deformities and scoliosis can be treated with braces or surgery. Physical therapy may prolong use of the arms and legs. Scientists hope that recent advances in understanding the genetics of Friedreich's ataxia may lead to breakthroughs in treatment.
top
What services are useful to Friedreich's ataxia patients and their families?
Genetic testing is available at some specialized laboratories and can assist with clinical diagnosis, prenatal diagnosis, and carrier status determination. Genetic counselors can help explain how Friedreich's ataxia is inherited and its effect on the patient and the family. Psychological counseling and support groups for people with genetic diseases may also help patients and their families cope with the disease. A patient?s primary care physician can screen for complications like diabetes and scoliosis, and can refer patients to specialists such as cardiologists and physical therapists to help deal with some of the other associated problems.
top
What research is being done?
Within the Federal government the National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH), has primary responsibility for sponsoring research on neurological disorders. As part of this mission, the NINDS conducts research on Friedreich's ataxia and other forms of inherited ataxias at its facilities at the NIH and supports additional studies at medical centers throughout the United States.
Researchers are optimistic that they will soon be closer to understanding the causes of the disease, which eventually will help scientists develop effective treatments and prevention strategies for Friedreich's ataxia.
The studies using yeast proteins with a chemical structure similar to human frataxin (see section on "How is Friedreich's ataxia inherited?") led to further studies in mice and humans. These studies revealed that frataxin ? like the yeast protein ? is a mitochondrial protein that should normally be present in the nervous system, the heart, and the pancreas. Yet in patients with the disease, the amount of frataxin in affected cells of these tissues is severely reduced. Further evidence that frataxin may function similarly to the yeast protein was the finding of abnormally high levels of iron in the heart tissue of people with Friedreich's ataxia. It is believed that the nervous system, heart, and pancreas may be particularly susceptible to damage from free radicals (produced when the excess iron reacts with oxygen) because once certain cells in these tissues are destroyed by free radicals they cannot be replaced. Nerve and muscle cells also have metabolic needs that may make them particularly vulnerable to free radical damage. Free radicals have been implicated in other degenerative diseases such as Parkinson's and Alzheimer's diseases.
Based upon this information, scientists and physicians have tried to reduce the levels of free radicals, also called oxidants, using treatment with ?antioxidants.? Several clinical studies in Europe suggest that antioxidants like coenzyme Q10, vitamin E, and idebenone may offer patients some limited benefit. There are currently clinical trials in the United States and Europe to evaluate the effectiveness of idebenone in patients with Friedreich?s ataxia. There is also a clinical trial ongoing in France to examine the efficacy of selectively removing excess iron from the mitochondria. Several other compounds may be brought to clinical trials in the near future. To check for current trials, go to the following website: www.clinicaltrials.gov.
Since the disease is caused by a reduction in fraxatin levels, many scientists are exploring ways to increase those levels through drug treatments, genetic engineering, and protein delivery systems.
Armed with what they currently know about frataxin and Friedreich's ataxia, scientists are working to better define frataxin's role, clarify how defects in iron metabolism may be involved in the disease process, and explore new therapeutic approaches for the disease. The discovery by NINDS-supported researchers of the genetic mutation that causes Friedreich's ataxia has added new impetus to research efforts on this disease.
Friedreich's ataxia is an inherited disease that causes progressive damage to the nervous system resulting in symptoms ranging from gait disturbance and speech problems to heart disease. It is named after the physician Nicholaus Friedreich, who first described the condition in the 1860s. "Ataxia," which refers to coordination problems such as clumsy or awkward movements and unsteadiness, occurs in many different diseases and conditions. The ataxia of Friedreich's ataxia results from the degeneration of nerve tissue in the spinal cord and of nerves that control muscle movement in the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath ? the insular covering on all nerve cells that helps conduct nerve impulses.
Friedreich's ataxia, although rare, is the most prevalent inherited ataxia, affecting about 1 in every 50,000 people in the United States. Males and females are affected equally.
top
What are the signs and symptoms?
Symptoms usually begin between the ages of 5 and 15 but can, on rare occasions, appear as early as 18 months or as late as 50 years of age. The first symptom to appear is usually difficulty in walking, or gait ataxia. The ataxia gradually worsens and slowly spreads to the arms and then the trunk. Foot deformities such as clubfoot, flexion (involuntary bending) of the toes, hammer toes, or foot inversion (turning inward) may be early signs. Over time, muscles begin to weaken and waste away, especially in the feet, lower legs, and hands, and deformities develop. Other symptoms include loss of tendon reflexes, especially in the knees and ankles. There is often a gradual loss of sensation in the extremities, which may spread to other parts of the body. Dysarthria (slowness and slurring of speech) develops, and the person is easily fatigued. Rapid, rhythmic, involuntary movements of the eye (nystagmus) are common. Most people with Friedreich's ataxia develop scoliosis (a curving of the spine to one side), which, if severe, may impair breathing.
Other symptoms that may occur include chest pain, shortness of breath, and heart palpitations. These symptoms are the result of various forms of heart disease that often accompany Friedreich's ataxia, such as cardiomyopathy (enlargement of the heart), myocardial fibrosis (formation of fiber-like material in the muscles of the heart), and cardiac failure. Heart rhythm abnormalities such as tachycardia (fast heart rate) and heart block (impaired conduction of cardiac impulses within the heart) are also common. About 20 percent of people with Friedreich's ataxia develop carbohydrate intolerance and 10 percent develop diabetes mellitus. Some people lose hearing or eyesight.
The rate of progression varies from person to person. Generally, within 10 to 20 years after the appearance of the first symptoms, the person is confined to a wheelchair, and in later stages of the disease individuals become completely incapacitated. Life expectancy may be affected, and many people with Friedreich's ataxia die in adulthood from the associated heart disease, the most common cause of death. However, some people with less severe symptoms of Friedreich's ataxia live much longer, sometimes into their sixties or seventies.
top
How is Friedreich's ataxia diagnosed?
Doctors diagnose Friedreich's ataxia by performing a careful clinical examination, which includes a medical history and a thorough physical examination. Tests that may be performed include:
electromyogram (EMG), which measures the electrical activity of muscle cells,
nerve conduction studies, which measure the speed with which nerves transmit impulses,
electrocardiogram (EKG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,
echocardiogram, which records the position and motion of the heart muscle,
magnetic resonance imaging (MRI) or computed tomography (CT) scan, which provides a picture of the brain and spinal cord,
spinal tap to evaluate the cerebrospinal fluid,
blood and urine tests to check for elevated glucose levels, and
genetic testing to identify the affected gene.
top
How is Friedreich's ataxia inherited?
Friedreich's ataxia is an autosomal recessive disease, which means the patient must inherit two affected genes, one from each parent, for the disease to develop. A person who has only one abnormal copy of a gene for a recessive genetic disease such as Friedreich's ataxia is called a carrier. A carrier will not develop the disease but could pass the affected gene on to his or her children. If both parents are carriers of the Friedreich's ataxia gene, their children will have a 1 in 4 chance of having the disease and a 1 in 2 chance of inheriting one abnormal gene that they, in turn, could pass on to their children. About one in 90 Americans of European ancestry carries one affected gene.
Humans have two copies of each gene ? one inherited from the mother and one from the father. Genes are located at a specific place on each of an individual's 46 chromosomes, which are tightly coiled chains of DNA containing millions of chemicals called bases. These bases ? adenine, thymine, cytosine, and guanine ? are abbreviated A, T, C, and G. Certain bases always "pair" together (A with T; C with G), and different combinations of base pairs join in sets of three to form coded messages.
These coded messages are "recipes" for making amino acids, the building blocks of proteins. By combining in long sequences, like long phone numbers, the paired bases tell each cell how to assemble different proteins. Proteins make up cells, tissues, and specialized enzymes that our bodies need to function normally. The protein that is altered in Friedreich's ataxia is called frataxin.
In 1996, an international group of scientists identified the cause of Friedreich's ataxia as a defect in a gene located on chromosome 9. Because of the inherited abnormal code, a particular sequence of bases (GAA) is repeated too many times. Normally, the GAA sequence is repeated 7 to 22 times, but in people with Friedreich's ataxia it can be repeated hundreds or even over a thousand times. This type of abnormality is called a triplet repeat expansion and has been implicated as the cause of several dominantly inherited diseases. Friedreich's ataxia is the first known recessive genetic disease that is caused by a triplet repeat expansion. Although about 98 percent of Friedreich's ataxia carriers have this particular genetic triplet repeat expansion, it is not found in all cases of the disease. A very small proportion of affected individuals have other gene coding defects responsible for causing disease.
The triplet repeat expansion apparently disrupts the normal assembly of amino acids into proteins, greatly reducing the amount of frataxin that is produced. Frataxin is found in the energy-producing parts of the cell called mitochondria. Research suggests that without a normal level of frataxin, certain cells in the body (especially brain, spinal cord, and muscle cells) cannot effectively produce energy and have a buildup of toxic byproducts leading to what is called "oxidative stress." This clue to the possible cause of Friedreich's ataxia came after scientists conducted studies using a yeast protein with a chemical structure similar to human frataxin. They found that the shortage of this protein in the yeast cell led to a toxic buildup of iron in the cell's mitochondria. When the excess iron reacted with oxygen, free radicals were produced. Although free radicals are essential molecules in the body's metabolism, they can also destroy cells and harm the body. Research continues on this subject (see section on "What research is being done?").
top
Can Friedreich's ataxia be cured or treated?
As with many degenerative diseases of the nervous system, there is currently no cure or effective treatment for Friedreich's ataxia. However, many of the symptoms and accompanying complications can be treated to help patients maintain optimal functioning as long as possible. Diabetes, if present, can be treated with diet and medications such as insulin, and some of the heart problems can be treated with medication as well. Orthopedic problems such as foot deformities and scoliosis can be treated with braces or surgery. Physical therapy may prolong use of the arms and legs. Scientists hope that recent advances in understanding the genetics of Friedreich's ataxia may lead to breakthroughs in treatment.
top
What services are useful to Friedreich's ataxia patients and their families?
Genetic testing is available at some specialized laboratories and can assist with clinical diagnosis, prenatal diagnosis, and carrier status determination. Genetic counselors can help explain how Friedreich's ataxia is inherited and its effect on the patient and the family. Psychological counseling and support groups for people with genetic diseases may also help patients and their families cope with the disease. A patient?s primary care physician can screen for complications like diabetes and scoliosis, and can refer patients to specialists such as cardiologists and physical therapists to help deal with some of the other associated problems.
top
What research is being done?
Within the Federal government the National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH), has primary responsibility for sponsoring research on neurological disorders. As part of this mission, the NINDS conducts research on Friedreich's ataxia and other forms of inherited ataxias at its facilities at the NIH and supports additional studies at medical centers throughout the United States.
Researchers are optimistic that they will soon be closer to understanding the causes of the disease, which eventually will help scientists develop effective treatments and prevention strategies for Friedreich's ataxia.
The studies using yeast proteins with a chemical structure similar to human frataxin (see section on "How is Friedreich's ataxia inherited?") led to further studies in mice and humans. These studies revealed that frataxin ? like the yeast protein ? is a mitochondrial protein that should normally be present in the nervous system, the heart, and the pancreas. Yet in patients with the disease, the amount of frataxin in affected cells of these tissues is severely reduced. Further evidence that frataxin may function similarly to the yeast protein was the finding of abnormally high levels of iron in the heart tissue of people with Friedreich's ataxia. It is believed that the nervous system, heart, and pancreas may be particularly susceptible to damage from free radicals (produced when the excess iron reacts with oxygen) because once certain cells in these tissues are destroyed by free radicals they cannot be replaced. Nerve and muscle cells also have metabolic needs that may make them particularly vulnerable to free radical damage. Free radicals have been implicated in other degenerative diseases such as Parkinson's and Alzheimer's diseases.
Based upon this information, scientists and physicians have tried to reduce the levels of free radicals, also called oxidants, using treatment with ?antioxidants.? Several clinical studies in Europe suggest that antioxidants like coenzyme Q10, vitamin E, and idebenone may offer patients some limited benefit. There are currently clinical trials in the United States and Europe to evaluate the effectiveness of idebenone in patients with Friedreich?s ataxia. There is also a clinical trial ongoing in France to examine the efficacy of selectively removing excess iron from the mitochondria. Several other compounds may be brought to clinical trials in the near future. To check for current trials, go to the following website: www.clinicaltrials.gov.
Since the disease is caused by a reduction in fraxatin levels, many scientists are exploring ways to increase those levels through drug treatments, genetic engineering, and protein delivery systems.
Armed with what they currently know about frataxin and Friedreich's ataxia, scientists are working to better define frataxin's role, clarify how defects in iron metabolism may be involved in the disease process, and explore new therapeutic approaches for the disease. The discovery by NINDS-supported researchers of the genetic mutation that causes Friedreich's ataxia has added new impetus to research efforts on this disease.
9.11.09
answer to the saudi medical council question examination
Acid Base
Questions
1. What is the decision tree in acid base disorders?
2. Sampling: where are the following sampled
a. Osmolarity
b. pH, pCO2, and calculated standard bicarbonate
3. How is the acid base balance controlled in the
a. Lungs
b. Kidneys
c. How can pH be expressed to reflect this
4. What is the anion gap?
a. Give the formula, and the normal range
b. Increased anion gap acidosis would present when?
c. Normal anion gap acidosis would present when?
d. Decreased anion gap would present when?
5. How would the following present, clinically, and the primary change
a. Metabolic acidosis
b. Metabolic alkalosis
i. Hypokalemia
c. Respiratory acidosis
i. Acute:
ii. Chronic:
d. Respiratory alkalosis
i. Acute:
ii. Chronic:
Answers
1. Decision tree in acid base disorders
2. Sampling: where are the following sampled
a. Venous blood: Osmolarity, HCO3+,Na+, K+, Cl-
b. Arterial blood: pH, pCO2, and calculated standard bicarbonate
3. Acid base balance control
a. Lungs
i. Blow off CO2
b. Kidneys
i. Na+ + HCO3- reabsorbed for H+
ii. Acid phosphate excretion
iii. NH4 excretion
c. pH=
4. Anion gap: estimate unmeasured anions
a. positive ? negative = normal anion gap
i. Na+ ? (Cl- + HCO3-)= 12-18 mEq/L (other anions)
b. ? anion gap acidosis:
i. Normal chloride, low/normal HCO3-
1. Other metabolic acid: MUDPILES
a. Methanol & other Alcohols
b. Uremic
c. Diabetic Ketoacidosis
d. Paraldehyde, Phenformin
e. Isoniazid
f. Lactate
g. Ethylene glycol
h. Salicylate
i. Sulfates, phosphates, fixed acids
c. Normal anion gap acidosis
i. Hyperchloremic acidosis
1. Diarrhea
2. Renal tubular acidosis
a. Early renal failure
3. Hyperalimentation
d. ? anion gap: <6 mEq/L
i. Cationic myeloma proteins
ii. Hyperlipidemia with decreased plasma H2O & electrolytes
5. How would the following present, clinically, and the primary change
a. Metabolic acidosis ?HCO3-
i. Kussmaul breathing: respiratory compensation
ii. Hyperkalemia
1. Decreased consciousness
b. Metabolic alkalosis ?HCO3-
i. Hypokalemia
1. Paresthesia
2. Tetany
3. Weakness
c. Respiratory acidosis ?pCO2
i. Acute:
1. Air hunger
2. Disorientation
ii. Chronic:
1. Hypoventilation
2. Hypoxemia
3. Cyanosis
d. Respiratory alkalosis ?pCO2
i. Acute:
1. Hyperventilation
a. Paresthesia
b. Light headedness
ii. Chronic:
1. Hyperventilaton
2. Latent tetany
Questions
1. What is the decision tree in acid base disorders?
2. Sampling: where are the following sampled
a. Osmolarity
b. pH, pCO2, and calculated standard bicarbonate
3. How is the acid base balance controlled in the
a. Lungs
b. Kidneys
c. How can pH be expressed to reflect this
4. What is the anion gap?
a. Give the formula, and the normal range
b. Increased anion gap acidosis would present when?
c. Normal anion gap acidosis would present when?
d. Decreased anion gap would present when?
5. How would the following present, clinically, and the primary change
a. Metabolic acidosis
b. Metabolic alkalosis
i. Hypokalemia
c. Respiratory acidosis
i. Acute:
ii. Chronic:
d. Respiratory alkalosis
i. Acute:
ii. Chronic:
Answers
1. Decision tree in acid base disorders
2. Sampling: where are the following sampled
a. Venous blood: Osmolarity, HCO3+,Na+, K+, Cl-
b. Arterial blood: pH, pCO2, and calculated standard bicarbonate
3. Acid base balance control
a. Lungs
i. Blow off CO2
b. Kidneys
i. Na+ + HCO3- reabsorbed for H+
ii. Acid phosphate excretion
iii. NH4 excretion
c. pH=
4. Anion gap: estimate unmeasured anions
a. positive ? negative = normal anion gap
i. Na+ ? (Cl- + HCO3-)= 12-18 mEq/L (other anions)
b. ? anion gap acidosis:
i. Normal chloride, low/normal HCO3-
1. Other metabolic acid: MUDPILES
a. Methanol & other Alcohols
b. Uremic
c. Diabetic Ketoacidosis
d. Paraldehyde, Phenformin
e. Isoniazid
f. Lactate
g. Ethylene glycol
h. Salicylate
i. Sulfates, phosphates, fixed acids
c. Normal anion gap acidosis
i. Hyperchloremic acidosis
1. Diarrhea
2. Renal tubular acidosis
a. Early renal failure
3. Hyperalimentation
d. ? anion gap: <6 mEq/L
i. Cationic myeloma proteins
ii. Hyperlipidemia with decreased plasma H2O & electrolytes
5. How would the following present, clinically, and the primary change
a. Metabolic acidosis ?HCO3-
i. Kussmaul breathing: respiratory compensation
ii. Hyperkalemia
1. Decreased consciousness
b. Metabolic alkalosis ?HCO3-
i. Hypokalemia
1. Paresthesia
2. Tetany
3. Weakness
c. Respiratory acidosis ?pCO2
i. Acute:
1. Air hunger
2. Disorientation
ii. Chronic:
1. Hypoventilation
2. Hypoxemia
3. Cyanosis
d. Respiratory alkalosis ?pCO2
i. Acute:
1. Hyperventilation
a. Paresthesia
b. Light headedness
ii. Chronic:
1. Hyperventilaton
2. Latent tetany
Water, Electrolyte and Acid-Base Balance
Water, Electrolyte and Acid-Base Balance
I. Topics
A. Fluid balance
B. Electrolyte balance
C. Acid-base balance
II. Body systems involved
A. Urinary: water, electrolyte, pH
B. Respiratory: CO2, water loss
C. Digestive: water, electrolyte absorption
D. Integumentary: water, electrolyte loss
E. Endocrine: hormone control of electrolyte & water
F. Nervous: electrolyte & water
G. Cardiovascular: hormone control of electrolyte; bicarbonate buffer system in blood
H. Lymphatic: interstitial fluid return to cardiovascular
III. Fluid content
A. Baby: 75%; amniotic fluid consumption & absorption
B. Man: 55-60%; muscle tissue has lots of water; women less due to higher fat (low water tissue)
C. Elderly & obese: 45%
IV. Fluid compartments
A. Separated by selectively permeable membranes
B. Different chemical compositions
C. Intracellular fluid (ICF)
a. 65%
b. Major anions & buffers
i. Protein
ii. Phosphate
c. Major cations
i. K+
ii. Mg++
d. Low Ca++ usually
D. Extracellular fluid (ECF)
a. Total 35%
b. Major anions
i. Cl-
ii. HCO3-: buffer component
c. Major cations
i. Na+
ii. Some Ca++, K+, Mg++
d. Significant difference: plasma has more proteins than does any other in this group of
e. Interstitial: 25%
f. Blood plasma & lymph: 8%
g. Transcellular: 2%; cerebrospinal, bile, synovial, peritoneal, pleural, eye fluids, digestive, urinary, respiratory
E. Exchange among compartments
a. Across capillary walls
b. Across cell membranes
c. Water by osmosis: requires water channels in cell membrane
d. Water & small solutes by filtration: arterial ends of capillaries
e. Osmotic gradients between ICF & ECF do not last long (seconds) because of rapid water osmotic movement
f. Electrolytes (Na+, K+) most important in establishing osmotic gradients since so numerous
g. Proteins very important where osmotic gradient is ?manipulated? by filtration
F. Water flux possible among compartments (normal)
Digestive tract ? arteries ? interstitial fluid ?? intracellular fluid ??
interstitial fluid ? veins & lymph ? general circulation
G. Content of bloodstream will affect interstitial fluid that will affect intercellular fluid; site of regulation for balance in body = blood
V. Fluid balance
A. Normal gain/loss ? 2.5 L/day
B. Gains
a. Metabolic water: aerobic respiration & dehydration anabolic reactions
b. Preformed water: food (700 ml) & liquids (1600 ml)
C. Losses
a. Urine: 1.5 L; somewhat variable; minimal = 400ml
b. Feces: 0.2 L
c. Expired breath: 0.3 L, variable, more loss in cold (0.65 L)
d. Sweat: 0.1 L; extremely variable; up to 5L
e. Cutaneous transpiration: 0.4 L
D. Categories of losses
a. Insensible: breath & transpiration
b. Obligatory: breath, transpiration, sweat, feces, minimal urine output
c. Even in dehydration obligatory losses continue, so dehydration worsens if not treated
E. Water intake & output
a. Thirst center
i. Hypothalamus: responds to increased levels of angiotensin II, ADH & osmotic shrinkage of cells in thirst center
ii. Salivation inhibited
iii. Mouth is dry
iv. Other clues as well = ?; pharyngeal area
v. Increase of blood osmolarity by 2-3% or blood loss of 10-15% strongly stimulates hypothalamus
b. Quenching thirst
i. Immediate
1. Cooling & moistening mouth & pharynx
2. Distension of stomach & small intestine
3. Prevents overhydration
ii. Later: reduction of blood osmolarity
c. Regulation of water output
i. Vary urine volume
ii. Usually involves changes in Na+ urine content too (aldosterone/ANF)
iii. Hormones:
1. ADH: independent control of water output; aquaporins in collecting ducts
2. Present: more concentrated urine since Na+ is lost as usual; blood volume increases
3. Absent: less concentrated urine since more water is lost; blood volume decrease
4. Aldosterone /ANF and Na+
F. Disorders of water balance
a. Involve volume, concentration or distribution among compartments
b. Volume & concentration
i. Deficiency
1. Two types
a. Hypovolemia: volume depletion: loss of water and electrolytes
b. Dehydration: loss of water
2. Hypovolemia
a. Osmolarity of blood unchanged; volume decreased
b. Hemorrhage, severe burns, chronic v/d
3. Dehydration
a. Osmolarity if blood increased; volume decreased
b. Lack of access: young/old/exposure
c. The diabetes: mellitus & insipidus; 1st sign = PU; why?
d. Profuse sweating: sweat is hypotonic
e. Inappropriate diuretics
f. Secretory & osmotic diarrheas
4. Infants most vulnerable
a. High metabolic rate; more toxins need more water for excretion
b. Kidneys can?t concentrate urine very well
c. Greater body surface to volume ratio: loose more water to evaporation
d. Higher water content
5. Fluid recall with dehydration
a. Dehydration affects all fluid compartments
b. Blood osmolarity higher pulls more water from interstitial fluids
c. Higher osmolarity of interstitial fluids pulls water out of cells
d. Neurons susceptible: shrink & don?t function as well
e. Does this occur with hypovolemia?
6. Serious effects of fluid deficiency of any type
a. Circulatory shock due to volume: ischemia, etc, etc
b. What is source of neuron damage here?
ii. Excess
1. Volume excess:
a. ECF isotonic
b. Renal failure or excess aldosterone
2. Water intoxication:
a. ECF is hypotonic; cells swell
b. Psychogenic or intentional overhydration
c. Excess ADH
d. Hyponatremia = hallmark sign of water intoxication
3. Serious effects of overhydration
a. Pulmonary hypertension
b. With intoxication: cerebral edema; why?
c. Distribution
i. Fluid sequestration
ii. Edema: fluid retained in interstitial spaces
1. Local: inflammation
2. Generalized: CHF, liver failure, etc
3. Increased filtration pressure on arterial end: hypertension
4. Decreased osmotic pressure on venous end: low blood osmolarity
5. Blocked lymphatic return: surgery
iii. Third-spacing
1. Internal hemorrhage
2. Ascites in abdomen
3. Pleural effusion
4. Surgical ?dead space? & seromas
5. Intestinal sequestration of fluids
6. Period of development will govern effect on body?s fluid content
a. Peracute: hypovolemic hypotension
b. Chronic: total body water may increase; weight gain & fluid retention
VI. Electrolyte balance
A. Role of electrolytes
a. Chemical reactants
b. Generate electrical potential across cell membranes
c. Essential in creating osmotic gradients & causing water flux into fluid compartments
B. Cations: Na+. K+, Ca++, H+
C. Anions: Cl-, HCO3-, PO4 ---
D. Sodium
a. Functions
i. Responsible for 90% of osmolarity of ECF
ii. NaHCO3 buffer for ECF
iii. Na+ gradient for depolarization & cotransport (glucose)
b. Control
i. Retention: aldosterone (steroid) causes more Na+/K+ pumps to be installed in cell membranes of DCT & cortical portion of collecting duct
ii. Three effects: lowers blood K+, raises blood Na+ & water follows Na+ into blood (volume increases)
iii. Three stimuli for aldosterone release: hypovolemia (via rennin & angiotensin II), hyponatremia (low Na+) & hyperkalemia (high K+)
iv. No changes in Na+ concentration in blood although blood volume may increase
v. Atrial natriuretic factor ANF: opposite effects of aldosterone
vi. Estrogen & glucocorticoids both retain Na+; progesterone encourages it?s loss
c. Imbalances
i. Hypernatermia:
1. > 145 meq/L
2. Overzealous IV fluid administration (Nabicarboante, NaCl), aldosteronism
ii. Hyponatremia:
1. < 130 meq/L
2. Water intoxication, excess ADH
E. Potassium
a. Functions
i. Resting membrane potential: repolarization
ii. Intracellular osmolarity
b. Linked to Na+ homeostasis
c. Intracellular cation: blood levels don?t reflect total body K+
d. 90% reabsorbed in PCT of nephron
e. Adjustments made in DCT & cortical portion of collecting duct
i. Intercalated cells: reabsorb K+ when blood levels low
ii. Aldosterone increases K+ loss to urine
f. Levels out of range of normal hurt excitable tissues, especially the heart
i. Hypokalemia: < 3.5 meq/L
1. Excitable membranes: greater diffusion out of cell; hyperpolarized
2. Cells harder to excite: muscle weakness, loss of muscle tone & depressed reflexes, irregular electrical activity of heart (U waves, flattened T wave); heart may stop in diastole
3. Causes:
a. Aldosteronism
b. Diuretics
c. Intracellular shift: insulin, alkalosis
d. Diet contributing factor
ii. Hyperkalemia: > 5 meq/L
1. Excitable membranes: less diffusion out of cell; facilitated
2. Cells easier to depolarize but harder to repolarize; muscle cramping & cardiac standstill (heart may stop in systole); ECG has wide QRS & tall T waves
3. Causes
a. Decreased excretion: renal dz, Addison?s dz
b. Extracellular shift: crushing/destruction of cells, acidosis, insulin deficiency
g. Extracellular measurements of an intracellular cation; shifts in/out of cell important
F. Calcium
a. Functions
i. Essential for intracellular activity: muscle contraction,
neurotransmitter exocytosis, etc
ii. Blood clotting
iii. Ca++ levels in cytoplasm kept low to prevent precipitation of
calcium phosphate crystals
b. Homeostasis
i. Tightly regulated blood level
ii. PTH, calcitonin & metabolites of vitamin D
iii. Bone resoprtion/deposition, gut absorption & kidney
loss/retention
iv. Three forms in blood
1. Ionic: physiologically active form
2. Bound to albumin (for each change in 1g/dL of albumin = change of 1mg/dL Ca++ in blood)
3. With nonprotein anions
c. Imbalances affect mainly skeletal muscle tissue
a. Hypercalcemia (>5.8 mEq/L)
i. Inhibits depolarization of nerve & muscle cells
ii. Effect on RMP: greater; hyperpolarized (more + charges on outside of membrane)
iii. Heart: - chronotrope, + inotrope
iv. If occurs with normal [PO4], can cause precipitation of calcium phosphate
crystals in soft tissues
v. Causes can include cancer, primary hyperPTHism and secondary hyperPTHism in renal dz
b. Hypocalcemia (<4.5 mEq/L)
i. Facilitates excitable membranes because RMP is reduced (less + outside membrane)
ii. Convulsions & muscle tetany (role of SR with hypocalcemia ?)
iii. + Trousseau (carpal ischemic spasm) & Chvestock (facial nerve percussion & unilateral facial muscle spasm)
iv. Heart: + chronotrope, - inotrope
v. Causes can include: vitamin D deficiency, diarrhea, pregnancy & lactation,
vi. At very low levels laryngospasm & suffocation can occur
3. Other electrolytes that may also be of concern include PO4 and Mg.
a. Phosphate:
i. Intracellular anion
ii. Decreased levels affect RBC function: lowered AATP reduces 2,3,DPG
Which reduces myocardial oxygenation
which reduces CO
iii. Increased levels in renal failure: calcification of soft tissues
b. Magnesium
i. Intracellular cation
ii. Important coenzymes
VII. Acid-Base Balance
A. Stabilization of blood pH is critical: 7.35-7.45
B. Three systems help regulate the [H+]
a. Chemical buffers
i. Weak acid + weak base
ii. Each buffer system works best at an optimum pH
iii. Limited by the amounts of the components of the buffer system available for reaction
iv. Bicarbonate, phosphate (intracellular & urine) & protein (intracellular)
v. Works immediately
b. Lung
i. Regulates CO2 portion of bicarbonate buffer
ii. More is lost as [H+] rises; increased CO2 increases RR
iii. Less is lost as [H+] drops; decreased CO2 decreases RR
iv. Works in minutes
c. Kidney
i. Regulates HCO3- portion of bicarbonate buffer
ii. Regulates [H+] directly
iii. Works in days
C. Bicarbonate buffer
a. Balance of CO2:HCO3- should be 1:20
b. CO2 + H2O ?? H2CO3 ?? H+ and HCO3-
c. Main ECF buffer; unlimited amounts of reactants CO2 & H2O
d. Only buffer that can be adjusted by the kidney (HCO3- & H+)
i. Renal tubules excrete H+ onto series of bases in urine in exchange for Na+
1. NaHCO3 first ? CO2 + H2O
2. Na2HPO4 second ? NaH2PO4
3. Third, deamination of amino acids in tubules produce NH3 & NH3 combines with H+ & Cl- ? NH4Cl
4. 1 conserves and 2-3 creates more HCO3-: the alkaline reserve of the bicarbonate system
ii. At and above pH of 4.5, H+ excretion stops
D. Phosphate buffer
a. H2PO4- ?? HPO4-- and H+
b. Intracellular and urine buffer
c. Urine buffer helps ?keep? H+ in the urine
E. Protein buffer
a. 3/4ths of all buffering capacity of the body
b. Amphoteric molecules
i. R-COOH ?? R-COO- and H+
ii. R-NH2 and H+ ?? R-NH3+
iii. R = rest of protein
c. Intracellular and in blood plasma
i. Hemoglobin in RBCs
ii. Proteins found inside all cells
d. Amount of this buffer doesn?t change normally
F. Imbalances
a. Acidosis: pH < 7.35; pH below 6.8 incompatible with life
b. Alkalosis: pH > 7.45; pH above 8 incompatible with life
c. Basic cause of imbalance
i. Respiratory
1. CO2 retention = respiratory acidosis
2. CO2 low = respiratory alkalosis
ii. Metabolic
1. Excess H+ or low HCO3- = metabolic acidosis
2. Low H+ or high HCO3- = metabolic alkalosis
d. Compensation: non-causative system adjusts to bring pH closer to normal
i. Total compensation: pH normal; H+ and HCO3- values abnormal
ii. Partial compensation: pH, H+ and HCO3- values abnormal
e. Blood-gas analysis (ABGs)
i. Arterial sample: radial artery
ii. Measures: pH, pP of CO2/O2 & HCO3-
iii. Normal values
1. pH 4.35-7.45
2. pP CO2 35-45 mmHg; >45 = acid value
3. pP O2 80-95 mmHg or 95-99% saturation
4. HCO3- 22-26 mEq/L; >26 = alkaline value
iv. Use tic-tac-toe for ABG analysis
v. Finally, ask if compensated
G. Anion gap: cations should about equal anions; when don?t = a gap; gap indicates presence
of other unmeasured anions such as organic acids; with a gap there are more cations than anions.
VIII. Types of acid-base imbalances
A. Respiratory acidosis: acute; CO2 elevated with low pH and normal range HCO3-
a. Pulmonary/thoracic: ARDS, pneumothorax, hemothorax
b. Increased resistance to air flow: upper airway obstruction, aspiration, severe bronchospasm and/or swelling of mucosal lining of bronchial tree
c. CNS depression
d. Neuromuscular: Guillain-Barre syndrome, MG crisis, high-cervical cordotomy
e. Cardiovascular: cardiac arrest, pulmonary edema
f. Mechanical ventilation: excessive dead space & insufficient ventilation
B. Respiratory acidosis: chronic, CO2 elevated, pH near normal, HCO3- increased
a. Obstructive disease: COPD (emphysema, bronchitis), sleep apnea, cystic fibrosis
b. Restriction of ventilation: Pickwickian syndrome, kyphoscoliosis
c. Neuromuscular:
d. CNS depression: tumor, bulbarpoliomyelitis, chronic sedative overdose
e. Decompensation and pH drop likely with added problems
C. Respiratory alkalosis: acute, CO2 low, pH elevated and HCO3- normal
a. Hypoxemia: increased respiratory effort due to stimulation of secondary respiratory drive; pneumonia, high altitude, CHF, hypotension & anemia
b. Direct stimulation of CNS: fear, anxiety, CVA
D. Metabolic acidosis: acute, CO2 variable, HCO3- and pH (H+ high) low
a. Loss of HCO3-: diarrhea, drainage of pancreas, bile or gut contents
b. Renal: inability to excrete H+ due to tubular disease
c. Excess acid
1. Production: ketones; lactic acid
2. Ingestion: alcohols, salicylates
E. Metabolic acidosis: chronic: CO2 low, HCO3 and pH (H+ high) low
a. Renal failure
F. Metabolic alkalosis: acute; CO2 variable, HCO3 and pH (H+ low) high
a. H+ loss: gastric suction, vomiting, loop diuretics, excess mineralocorticoid
b. H+ shift into cells; hypokalemia
G. Metabolic alkalosis: chronic,
a. Same as above
IX Intravenous fluid administration
A. Crystalloids: electrolytes & glucose
a. Substances are not restricted to the intravascular space
b. Always expand entire ECF volume
c. Isotonic NaCl solutions: expands ECF only, not ICF, usually for intravascular volume replacement
d. Saline/electrolytes (Ringer?s & Lactated Ringer?s): similar to plasma, replace ECF losses & expand intravascular volume; lactate = buffer in mild acidosis (not lactiv acidosis)
e. Hypotonic NaCl solutions or those with dextrose & water expands ECF and ICF
i. Dextrose & water: treat total body water deficits; distributed equally in ECF & ICF
ii. Hypotonic NaCl solutions expand both ICF & ECF
B. Colloids
a. Contain cells, proteins or synthetic macromolecules
b. Expand intravascular volume only
c. Can cause fluid shifts from interstitial & ICF columes
I. Topics
A. Fluid balance
B. Electrolyte balance
C. Acid-base balance
II. Body systems involved
A. Urinary: water, electrolyte, pH
B. Respiratory: CO2, water loss
C. Digestive: water, electrolyte absorption
D. Integumentary: water, electrolyte loss
E. Endocrine: hormone control of electrolyte & water
F. Nervous: electrolyte & water
G. Cardiovascular: hormone control of electrolyte; bicarbonate buffer system in blood
H. Lymphatic: interstitial fluid return to cardiovascular
III. Fluid content
A. Baby: 75%; amniotic fluid consumption & absorption
B. Man: 55-60%; muscle tissue has lots of water; women less due to higher fat (low water tissue)
C. Elderly & obese: 45%
IV. Fluid compartments
A. Separated by selectively permeable membranes
B. Different chemical compositions
C. Intracellular fluid (ICF)
a. 65%
b. Major anions & buffers
i. Protein
ii. Phosphate
c. Major cations
i. K+
ii. Mg++
d. Low Ca++ usually
D. Extracellular fluid (ECF)
a. Total 35%
b. Major anions
i. Cl-
ii. HCO3-: buffer component
c. Major cations
i. Na+
ii. Some Ca++, K+, Mg++
d. Significant difference: plasma has more proteins than does any other in this group of
e. Interstitial: 25%
f. Blood plasma & lymph: 8%
g. Transcellular: 2%; cerebrospinal, bile, synovial, peritoneal, pleural, eye fluids, digestive, urinary, respiratory
E. Exchange among compartments
a. Across capillary walls
b. Across cell membranes
c. Water by osmosis: requires water channels in cell membrane
d. Water & small solutes by filtration: arterial ends of capillaries
e. Osmotic gradients between ICF & ECF do not last long (seconds) because of rapid water osmotic movement
f. Electrolytes (Na+, K+) most important in establishing osmotic gradients since so numerous
g. Proteins very important where osmotic gradient is ?manipulated? by filtration
F. Water flux possible among compartments (normal)
Digestive tract ? arteries ? interstitial fluid ?? intracellular fluid ??
interstitial fluid ? veins & lymph ? general circulation
G. Content of bloodstream will affect interstitial fluid that will affect intercellular fluid; site of regulation for balance in body = blood
V. Fluid balance
A. Normal gain/loss ? 2.5 L/day
B. Gains
a. Metabolic water: aerobic respiration & dehydration anabolic reactions
b. Preformed water: food (700 ml) & liquids (1600 ml)
C. Losses
a. Urine: 1.5 L; somewhat variable; minimal = 400ml
b. Feces: 0.2 L
c. Expired breath: 0.3 L, variable, more loss in cold (0.65 L)
d. Sweat: 0.1 L; extremely variable; up to 5L
e. Cutaneous transpiration: 0.4 L
D. Categories of losses
a. Insensible: breath & transpiration
b. Obligatory: breath, transpiration, sweat, feces, minimal urine output
c. Even in dehydration obligatory losses continue, so dehydration worsens if not treated
E. Water intake & output
a. Thirst center
i. Hypothalamus: responds to increased levels of angiotensin II, ADH & osmotic shrinkage of cells in thirst center
ii. Salivation inhibited
iii. Mouth is dry
iv. Other clues as well = ?; pharyngeal area
v. Increase of blood osmolarity by 2-3% or blood loss of 10-15% strongly stimulates hypothalamus
b. Quenching thirst
i. Immediate
1. Cooling & moistening mouth & pharynx
2. Distension of stomach & small intestine
3. Prevents overhydration
ii. Later: reduction of blood osmolarity
c. Regulation of water output
i. Vary urine volume
ii. Usually involves changes in Na+ urine content too (aldosterone/ANF)
iii. Hormones:
1. ADH: independent control of water output; aquaporins in collecting ducts
2. Present: more concentrated urine since Na+ is lost as usual; blood volume increases
3. Absent: less concentrated urine since more water is lost; blood volume decrease
4. Aldosterone /ANF and Na+
F. Disorders of water balance
a. Involve volume, concentration or distribution among compartments
b. Volume & concentration
i. Deficiency
1. Two types
a. Hypovolemia: volume depletion: loss of water and electrolytes
b. Dehydration: loss of water
2. Hypovolemia
a. Osmolarity of blood unchanged; volume decreased
b. Hemorrhage, severe burns, chronic v/d
3. Dehydration
a. Osmolarity if blood increased; volume decreased
b. Lack of access: young/old/exposure
c. The diabetes: mellitus & insipidus; 1st sign = PU; why?
d. Profuse sweating: sweat is hypotonic
e. Inappropriate diuretics
f. Secretory & osmotic diarrheas
4. Infants most vulnerable
a. High metabolic rate; more toxins need more water for excretion
b. Kidneys can?t concentrate urine very well
c. Greater body surface to volume ratio: loose more water to evaporation
d. Higher water content
5. Fluid recall with dehydration
a. Dehydration affects all fluid compartments
b. Blood osmolarity higher pulls more water from interstitial fluids
c. Higher osmolarity of interstitial fluids pulls water out of cells
d. Neurons susceptible: shrink & don?t function as well
e. Does this occur with hypovolemia?
6. Serious effects of fluid deficiency of any type
a. Circulatory shock due to volume: ischemia, etc, etc
b. What is source of neuron damage here?
ii. Excess
1. Volume excess:
a. ECF isotonic
b. Renal failure or excess aldosterone
2. Water intoxication:
a. ECF is hypotonic; cells swell
b. Psychogenic or intentional overhydration
c. Excess ADH
d. Hyponatremia = hallmark sign of water intoxication
3. Serious effects of overhydration
a. Pulmonary hypertension
b. With intoxication: cerebral edema; why?
c. Distribution
i. Fluid sequestration
ii. Edema: fluid retained in interstitial spaces
1. Local: inflammation
2. Generalized: CHF, liver failure, etc
3. Increased filtration pressure on arterial end: hypertension
4. Decreased osmotic pressure on venous end: low blood osmolarity
5. Blocked lymphatic return: surgery
iii. Third-spacing
1. Internal hemorrhage
2. Ascites in abdomen
3. Pleural effusion
4. Surgical ?dead space? & seromas
5. Intestinal sequestration of fluids
6. Period of development will govern effect on body?s fluid content
a. Peracute: hypovolemic hypotension
b. Chronic: total body water may increase; weight gain & fluid retention
VI. Electrolyte balance
A. Role of electrolytes
a. Chemical reactants
b. Generate electrical potential across cell membranes
c. Essential in creating osmotic gradients & causing water flux into fluid compartments
B. Cations: Na+. K+, Ca++, H+
C. Anions: Cl-, HCO3-, PO4 ---
D. Sodium
a. Functions
i. Responsible for 90% of osmolarity of ECF
ii. NaHCO3 buffer for ECF
iii. Na+ gradient for depolarization & cotransport (glucose)
b. Control
i. Retention: aldosterone (steroid) causes more Na+/K+ pumps to be installed in cell membranes of DCT & cortical portion of collecting duct
ii. Three effects: lowers blood K+, raises blood Na+ & water follows Na+ into blood (volume increases)
iii. Three stimuli for aldosterone release: hypovolemia (via rennin & angiotensin II), hyponatremia (low Na+) & hyperkalemia (high K+)
iv. No changes in Na+ concentration in blood although blood volume may increase
v. Atrial natriuretic factor ANF: opposite effects of aldosterone
vi. Estrogen & glucocorticoids both retain Na+; progesterone encourages it?s loss
c. Imbalances
i. Hypernatermia:
1. > 145 meq/L
2. Overzealous IV fluid administration (Nabicarboante, NaCl), aldosteronism
ii. Hyponatremia:
1. < 130 meq/L
2. Water intoxication, excess ADH
E. Potassium
a. Functions
i. Resting membrane potential: repolarization
ii. Intracellular osmolarity
b. Linked to Na+ homeostasis
c. Intracellular cation: blood levels don?t reflect total body K+
d. 90% reabsorbed in PCT of nephron
e. Adjustments made in DCT & cortical portion of collecting duct
i. Intercalated cells: reabsorb K+ when blood levels low
ii. Aldosterone increases K+ loss to urine
f. Levels out of range of normal hurt excitable tissues, especially the heart
i. Hypokalemia: < 3.5 meq/L
1. Excitable membranes: greater diffusion out of cell; hyperpolarized
2. Cells harder to excite: muscle weakness, loss of muscle tone & depressed reflexes, irregular electrical activity of heart (U waves, flattened T wave); heart may stop in diastole
3. Causes:
a. Aldosteronism
b. Diuretics
c. Intracellular shift: insulin, alkalosis
d. Diet contributing factor
ii. Hyperkalemia: > 5 meq/L
1. Excitable membranes: less diffusion out of cell; facilitated
2. Cells easier to depolarize but harder to repolarize; muscle cramping & cardiac standstill (heart may stop in systole); ECG has wide QRS & tall T waves
3. Causes
a. Decreased excretion: renal dz, Addison?s dz
b. Extracellular shift: crushing/destruction of cells, acidosis, insulin deficiency
g. Extracellular measurements of an intracellular cation; shifts in/out of cell important
F. Calcium
a. Functions
i. Essential for intracellular activity: muscle contraction,
neurotransmitter exocytosis, etc
ii. Blood clotting
iii. Ca++ levels in cytoplasm kept low to prevent precipitation of
calcium phosphate crystals
b. Homeostasis
i. Tightly regulated blood level
ii. PTH, calcitonin & metabolites of vitamin D
iii. Bone resoprtion/deposition, gut absorption & kidney
loss/retention
iv. Three forms in blood
1. Ionic: physiologically active form
2. Bound to albumin (for each change in 1g/dL of albumin = change of 1mg/dL Ca++ in blood)
3. With nonprotein anions
c. Imbalances affect mainly skeletal muscle tissue
a. Hypercalcemia (>5.8 mEq/L)
i. Inhibits depolarization of nerve & muscle cells
ii. Effect on RMP: greater; hyperpolarized (more + charges on outside of membrane)
iii. Heart: - chronotrope, + inotrope
iv. If occurs with normal [PO4], can cause precipitation of calcium phosphate
crystals in soft tissues
v. Causes can include cancer, primary hyperPTHism and secondary hyperPTHism in renal dz
b. Hypocalcemia (<4.5 mEq/L)
i. Facilitates excitable membranes because RMP is reduced (less + outside membrane)
ii. Convulsions & muscle tetany (role of SR with hypocalcemia ?)
iii. + Trousseau (carpal ischemic spasm) & Chvestock (facial nerve percussion & unilateral facial muscle spasm)
iv. Heart: + chronotrope, - inotrope
v. Causes can include: vitamin D deficiency, diarrhea, pregnancy & lactation,
vi. At very low levels laryngospasm & suffocation can occur
3. Other electrolytes that may also be of concern include PO4 and Mg.
a. Phosphate:
i. Intracellular anion
ii. Decreased levels affect RBC function: lowered AATP reduces 2,3,DPG
Which reduces myocardial oxygenation
which reduces CO
iii. Increased levels in renal failure: calcification of soft tissues
b. Magnesium
i. Intracellular cation
ii. Important coenzymes
VII. Acid-Base Balance
A. Stabilization of blood pH is critical: 7.35-7.45
B. Three systems help regulate the [H+]
a. Chemical buffers
i. Weak acid + weak base
ii. Each buffer system works best at an optimum pH
iii. Limited by the amounts of the components of the buffer system available for reaction
iv. Bicarbonate, phosphate (intracellular & urine) & protein (intracellular)
v. Works immediately
b. Lung
i. Regulates CO2 portion of bicarbonate buffer
ii. More is lost as [H+] rises; increased CO2 increases RR
iii. Less is lost as [H+] drops; decreased CO2 decreases RR
iv. Works in minutes
c. Kidney
i. Regulates HCO3- portion of bicarbonate buffer
ii. Regulates [H+] directly
iii. Works in days
C. Bicarbonate buffer
a. Balance of CO2:HCO3- should be 1:20
b. CO2 + H2O ?? H2CO3 ?? H+ and HCO3-
c. Main ECF buffer; unlimited amounts of reactants CO2 & H2O
d. Only buffer that can be adjusted by the kidney (HCO3- & H+)
i. Renal tubules excrete H+ onto series of bases in urine in exchange for Na+
1. NaHCO3 first ? CO2 + H2O
2. Na2HPO4 second ? NaH2PO4
3. Third, deamination of amino acids in tubules produce NH3 & NH3 combines with H+ & Cl- ? NH4Cl
4. 1 conserves and 2-3 creates more HCO3-: the alkaline reserve of the bicarbonate system
ii. At and above pH of 4.5, H+ excretion stops
D. Phosphate buffer
a. H2PO4- ?? HPO4-- and H+
b. Intracellular and urine buffer
c. Urine buffer helps ?keep? H+ in the urine
E. Protein buffer
a. 3/4ths of all buffering capacity of the body
b. Amphoteric molecules
i. R-COOH ?? R-COO- and H+
ii. R-NH2 and H+ ?? R-NH3+
iii. R = rest of protein
c. Intracellular and in blood plasma
i. Hemoglobin in RBCs
ii. Proteins found inside all cells
d. Amount of this buffer doesn?t change normally
F. Imbalances
a. Acidosis: pH < 7.35; pH below 6.8 incompatible with life
b. Alkalosis: pH > 7.45; pH above 8 incompatible with life
c. Basic cause of imbalance
i. Respiratory
1. CO2 retention = respiratory acidosis
2. CO2 low = respiratory alkalosis
ii. Metabolic
1. Excess H+ or low HCO3- = metabolic acidosis
2. Low H+ or high HCO3- = metabolic alkalosis
d. Compensation: non-causative system adjusts to bring pH closer to normal
i. Total compensation: pH normal; H+ and HCO3- values abnormal
ii. Partial compensation: pH, H+ and HCO3- values abnormal
e. Blood-gas analysis (ABGs)
i. Arterial sample: radial artery
ii. Measures: pH, pP of CO2/O2 & HCO3-
iii. Normal values
1. pH 4.35-7.45
2. pP CO2 35-45 mmHg; >45 = acid value
3. pP O2 80-95 mmHg or 95-99% saturation
4. HCO3- 22-26 mEq/L; >26 = alkaline value
iv. Use tic-tac-toe for ABG analysis
v. Finally, ask if compensated
G. Anion gap: cations should about equal anions; when don?t = a gap; gap indicates presence
of other unmeasured anions such as organic acids; with a gap there are more cations than anions.
VIII. Types of acid-base imbalances
A. Respiratory acidosis: acute; CO2 elevated with low pH and normal range HCO3-
a. Pulmonary/thoracic: ARDS, pneumothorax, hemothorax
b. Increased resistance to air flow: upper airway obstruction, aspiration, severe bronchospasm and/or swelling of mucosal lining of bronchial tree
c. CNS depression
d. Neuromuscular: Guillain-Barre syndrome, MG crisis, high-cervical cordotomy
e. Cardiovascular: cardiac arrest, pulmonary edema
f. Mechanical ventilation: excessive dead space & insufficient ventilation
B. Respiratory acidosis: chronic, CO2 elevated, pH near normal, HCO3- increased
a. Obstructive disease: COPD (emphysema, bronchitis), sleep apnea, cystic fibrosis
b. Restriction of ventilation: Pickwickian syndrome, kyphoscoliosis
c. Neuromuscular:
d. CNS depression: tumor, bulbarpoliomyelitis, chronic sedative overdose
e. Decompensation and pH drop likely with added problems
C. Respiratory alkalosis: acute, CO2 low, pH elevated and HCO3- normal
a. Hypoxemia: increased respiratory effort due to stimulation of secondary respiratory drive; pneumonia, high altitude, CHF, hypotension & anemia
b. Direct stimulation of CNS: fear, anxiety, CVA
D. Metabolic acidosis: acute, CO2 variable, HCO3- and pH (H+ high) low
a. Loss of HCO3-: diarrhea, drainage of pancreas, bile or gut contents
b. Renal: inability to excrete H+ due to tubular disease
c. Excess acid
1. Production: ketones; lactic acid
2. Ingestion: alcohols, salicylates
E. Metabolic acidosis: chronic: CO2 low, HCO3 and pH (H+ high) low
a. Renal failure
F. Metabolic alkalosis: acute; CO2 variable, HCO3 and pH (H+ low) high
a. H+ loss: gastric suction, vomiting, loop diuretics, excess mineralocorticoid
b. H+ shift into cells; hypokalemia
G. Metabolic alkalosis: chronic,
a. Same as above
IX Intravenous fluid administration
A. Crystalloids: electrolytes & glucose
a. Substances are not restricted to the intravascular space
b. Always expand entire ECF volume
c. Isotonic NaCl solutions: expands ECF only, not ICF, usually for intravascular volume replacement
d. Saline/electrolytes (Ringer?s & Lactated Ringer?s): similar to plasma, replace ECF losses & expand intravascular volume; lactate = buffer in mild acidosis (not lactiv acidosis)
e. Hypotonic NaCl solutions or those with dextrose & water expands ECF and ICF
i. Dextrose & water: treat total body water deficits; distributed equally in ECF & ICF
ii. Hypotonic NaCl solutions expand both ICF & ECF
B. Colloids
a. Contain cells, proteins or synthetic macromolecules
b. Expand intravascular volume only
c. Can cause fluid shifts from interstitial & ICF columes
8.11.09
Hypoxic-ischemic encephalopathy
Abstract
Hypoxic-ischemic encephalopathy (HIE) is one of the most important complications found in the newborn period. It is the result of a deprivation of oxygen and glucose to the neural tissue, which may be the result of either hypoxemia or ischemia. Experimental animal research and clinical observations in humans have noted that the pattern of injury occurs in 2 phases. The first phase is a primary energy failure related to the insult, and then a second energy failure occurs some hours later. The combined effects of cellular energy failure, acidosis, glutamate release, intracellular accumulation of calcium, lipid peroxidation, and nitric oxide neurotoxicity destroy essential components of the cell, culminating in cell death. The clinical presentation depends on the severity, timing, and duration of the insult, with symptoms typically evolving over approximately 72 hours. Hypothermia strategies are aimed at targeting this narrow window of opportunity to ameliorate the brain injury.
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Hypoxic-ischemic encephalopathy (HIE) is often one of the most devastating sequelae encountered in the newborn period. Although the predominant injury affects the brain, almost every organ system in the body is negatively impacted. Cerebral palsy (CP), seizure activity, and varying degrees of developmental delays are some of the chronic disabilities seen in survivors. Hypoxia and especially ischemia, in which there is decreased perfusion of the brain with oxygen and glucose, are usually the result of asphyxia. Experimental animal research and clinical observations in humans have noted that the pattern of injury occurs in 2 phases. The first is a primary energy failure related to the insult, and the second is an energy failure that occurs some hours later. Hypothermia strategies are aimed at targeting this narrow window of opportunity to ameliorate the brain injury. This article will review the etiology, biochemical and physiological events, clinical symptoms, treatment strategies, including those for hypothermia, and future avenues of research as they relate to HIE.
ETIOLOGY
Hypoxic-ischemic encephalopathy is the result of a deprivation of oxygen and glucose to the neural tissue, which may be the result of either hypoxemia or ischemia. Hypoxemia is a decrease in the amount of oxygen circulating in the blood. Ischemia is a decrease in the flow of blood available to perfuse the brain. Of the two, ischemia is the most problematic because less oxygen and glucose are delivered to the brain. Asphyxia is defined as an impairment to the exchange of oxygen and carbon dioxide (CO2). The increase in CO2 promotes an initial increase in cerebral blood flow and contributes to acidosis. Annually, asphyxia is responsible for approximately 23% of 4 million neonatal deaths globally.1 The rate of HIE is approximately 1 to 2 per 1000 term newborns in developed countries, with a mortality rate of 10% to 20%.2 There is a 10% risk of death in neonates who develop a moderate encephalopathy and a 30% risk of neurodevelopmental sequelae in those who survive.3 A severe encephalopathy is associated with a 60% risk of death and virtually guaranteed disabilities in survivors.3
According to Volpe, approximately 20% of neonatal HIE is primarily related to antepartum events that lead to hypoxic-ischemic fetal insults.4 Maternal conditions such as hypotension, placental vasculopathy, and insulin-dependent diabetes mellitus may predispose the fetus to intrapartum hypoxia-ischemia such that there is little reserve to compensate for the stresses of labor.5,6 Intrapartum events such as prolapsed cord, abruption placentae, and traumatic delivery have been linked to 35% of HIE cases.4 Sophisticated neuroimaging techniques, such as magnetic resonance imaging (MRI), have documented evidence of acute brain injury in neonates with clinical encephalopathy who were born with evidence of intrapartum asphyxia.7,8 It is thought that a combination of both antepartum and intrapartum untoward events is responsible for approximately 35% of HIE cases.4
Conditions in the neonatal period may be responsible for as much as 10% of HIE cases.4 These include congenital heart disease, severe pulmonary disease, severe recurrent apnea, and cardiac failure secondary to a large patent ductus arteriosus. The preterm infant is more affected than the term infant.
Because of the limitations in determining the actual timing of the insult, it may be difficult to identify/quantitate the antepartum contribution separately from the intrapartum. It is argued that other events besides intrapartum hypoxia may be responsible for HIE or CP, as less than 25% of these infants have symptoms of hypoxia-ischemia at birth.9 The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists have defined neonatal HIE as an encephalopathy associated with hypoxia that occurs in the intrapartum period with no evidence of other anomalies.9 They also identified 4 criteria that must be present to define an intrapartum event that is capable of resulting in HIE or CP (Box 1). Other criteria may suggest an intrapartum origin if they occur within approximately 48 hours of delivery.
Box 1. Criteria for defining an intrapartum hypoxic event
BIOCHEMICAL AND PHYSIOLOGICAL EVENTS
As mentioned above, glucose and oxygen play key roles in the pathogenesis of injury. Glucose is delivered to the brain via a carrier-mediated, facilitated diffusion, a much faster process than simple diffusion alone.10 In the brain, glucose is phosphorylated to glucose-6-phosphate, with the major end product being pyruvate under aerobic conditions. Pyruvate then enters the mitochondrion to be converted to acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is important in energy production via the citric acid cycle.10 Within the mitochondrion, the electron transport system, citric acid cycle, and acetyl-CoA generate adenosine triphosphate (ATP) from adenosine diphosphate.10 Under aerobic conditions, 38 molecules of ATP are generated for each molecule of glucose oxidized. The ATP is then transported from the mitochondrion to be used for transport or synthetic purposes. The transport processes involve impulse transmission and maintenance of calcium (Ca2+) within the neurons. The synthetic processes include neurotransmitters, membrane lipids, and structural and functional proteins.10
When a hypoxic-ischemic event occurs and an anaerobic state is induced, ATP is produced solely through glycolysis.10 Lactate results as the principal product, which gives off only 2 molecules of ATP. In response, glycolysis is increased as much as 10-fold.11 There is also a concomitant increase in the net uptake of glucose from the blood as well as an increase in glycogenolysis.11 Inefficient anaerobic metabolism continues to excessively consume glucose such that glucose delivery cannot meet the demand. As a result, ATP and brain glucose levels fall within minutes. Ischemia further compounds the hypoxia because the impaired circulation rapidly increases lactate and tissue acidosis. After approximately 6 minutes in a rat model, brain glucose levels were 70% lower, whereas blood glucose values were 100% higher.11 Thus, a ?normal? chemstrip or blood glucose reading may have little relationship to the brain glucose value under anaerobic conditions.
Asphyxia initially results in a redistribution of cardiac output, with as much as a 30% to 175% increase in cerebral blood flow.12 Continued asphyxia leads to a decrease in cardiac output and hypotension. Cerebral blood vessels lose the ability to respond to changes in blood flow, lactate, tissue acidosis, and increasing CO2. Loss of cerebral autoregulation and hypotension result in a decrease in cerebral blood flow. Cerebral edema, a result of damaged blood vessel walls becoming ?leaky,? sets into motion the cascade of biochemical events.
As the energy stores are failing, the transcellular ion pump (sodium-potassium-ATPase pump) begins to fail. Sodium, calcium, and water accumulate inside the glial cell, causing a cytotoxic edema. The cellular edema further decreases oxygen and glucose delivery to the neurons. Alteration of the charge on the cell's membrane causes it to become depolarized and opens calcium channels, facilitating cytosolic accumulation of calcium. The depolarization initiates a release of excitatory neurotransmitters, specifically glutamate from the axon terminals.
The increase in cytosolic calcium activates phospholipases, proteases, and endonucleases. Phospholipase A2 releases free fatty acids such as arachidonic acid by hydrolyzing membrane phospholipid. Arachidonic acid increases the release of glutamate and interferes with oxidative phosphorylation. Proteases destroy proteins within the cell. Activation of endonucleases, in combination with xanthine and prostaglandins, generates free radicals. Free radicals, molecules which contain an odd number of electrons, are chemically reactive and induce peroxidation of unsaturated fatty acids.13 The most commonly generated free radical is superoxide anion, which is converted to hydrogen peroxide by superoxide dismutase.4 Hydrogen peroxide is detoxified by catalase and glutathione peroxidase unless free iron is available.4 Asphyxia converts the nontoxic ?ferric? state of free ion to the dangerous ?ferrous? form, which is able to react with free radicals.12 In this environment, superoxide radicals react with hydrogen peroxide to produce deadly hydroxyl radicals.13
High levels of calcium ions accumulating within the cytoplasm induce production of nitric oxide (NO), a free radical. Neuronal nitric oxide synthase is initially increased and improves blood flow to the neurons.14 Neuronal nitric oxide synthase soon generates NO that diffuses to adjacent cells that are susceptible to NO toxicity. Nitric oxide quickly reacts with superoxide anions to form a highly toxic reactive nitrogen species and peroxynitrite.14 The peroxynitrite radical contributes to cell death by energy depletion, mitochondrial impairment, and future disruption of calcium homeostasis.14 It also stimulates cyclooxygenase activity and reenters the presynaptic neuron to further increase the release of glutamate.12 In addition, free fatty acids accumulate within the cell and undergo peroxidation by oxygen free radicals.
Within 1 to 4 hours following an asphyxia insult, inflammatory mediators are found. Interleukin-1[beta], tumor necrosis factor [alpha] (TNF [alpha]), and [alpha] and [beta] chemokines are produced, followed by neutrophil invasion of the site of injury. Inflammatory mediators have an indirect toxic effect in that they induce glial cells to produce neurotoxic factors such as excitatory amino acids. The influx of Ca2+ into the presynaptic nerve ending releases glutamate.14 Glutamate accumulates because ATP depletion leads to failure in the major reuptake and removal mechanisms such that glutamate excess produces excitotoxicity.14 Most important, the release of inflammatory mediators perpetuates the excitotoxic injury. The combined effects of cellular energy failure, acidosis, glutamate release, intracellular accumulation of calcium, lipid peroxidation, and NO neurotoxicity destroy essential components of the cell, culminating in cell death.
Immediately when cerebral circulation and oxygenation is restored, the acute cellular hypoxic depolarization is resolved and cellular energy metabolism is restored.12 During this phase of reperfusion, high energy phosphate levels return to baseline levels, lactate levels improve, and glutamate is cleared.14 A secondary or delayed brain injury becomes apparent by 8 to 16 hours that reaches a nadir at 24 to 48 hours that is evidenced by a second decline in high energy phosphate levels.14 There is a decrease in the ratio of phosphocreatine/inorganic phosphate and an unchanged intracellular pH. Nitric oxide initially vasodilates the cerebral circulation and later inhibits activity within the mitochondria. An exaggerated calcium influx, further injury to the sodium-potassium-ATPase pump, and enhanced release of glutamate by NO occur. Free fatty acids generate arachidonic acids and prostaglandins, while xanthine oxidase converts hypoxanthine to uric acid. In the microvascular system, free radicals activate adhesion molecules in platelets and leukocytes. The vessels become occluded, with decreased blood flow and delivery of oxygen and glucose, and the injury is perpetuated. Despite an upregulation of the main antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase, their increased levels are inadequate to scavenge the free radicals.13
Clinical deterioration, seizure activity, cytotoxic edema, and a release of excitatory neurotransmitters occur. The mitochondria are dysfunctional, secondary to extended reactions from the primary insult due to the influx of calcium influx, ongoing generation of oxygen free radicals, and NO formation. Studies from a rat model demonstrate that neuronal protein loss (total creatine and adenine nucleotides) is seen at 6 hours and is very apparent by 18 hours.15 The findings indicate that the secondary energy depletion is a consequence of the events that cause cellular destruction rather than the cause.14,15 The time until the occurrence of the secondary energy failure provides a window of opportunity for possible interventions that may ameliorate the injury.
Depending on the severity of the asphyxial event, 3 distinct patterns of brain injury have been noted in the term neonate. A mild to moderate insult, such as prolonged partial hypoxia-ischemia, has been correlated to a cortical and subcortical injury in a watershed parasagittal distribution.16 Acute profound asphyxia results in damage to the thalami, basal ganglia, hippocampi, mesencephalic structures, and perirolandic cortex while leaving the cortex relatively intact.16,17 A diffuse, destructive anoxic-ischemic injury causes extensive injury to the cortex and the white matter as depicted by multicystic encephalopathy.14,16 The mode of cell death may be necrosis and/or apoptosis, dependent on the severity of the insult and the maturational state of the cell.
Necrosis of the cell occurs within minutes to hours as a result of a severe insult. It is characterized by cell swelling, disintegration of the cellular membrane leading to cell rupture. Release of the intracellular components activates phagocytosis and the inflammatory process. Apoptosis occurs over hours to days as a result of a less severe insult. It is an active process of cell shrinkage, nuclear pyknosis (the nucleus loses density), chromatin condensation, and genomic fragmentation. Because the inflammatory process is not involved, it is difficult to discern. Necrotic cells are found more commonly in the central area of the severe, acute injury or core of the insult. Apoptosis is found in the penumbra, an area of evolving cell injury that surrounds the core. Cells in the penumbra are initially sustained by anaerobic glycolysis. However, within hours, the injury becomes irreversible, the area of infarction enlarges such that the cells within penumbra become more damaged.
CLINICAL SYMPTOMS OF HIE
The clinical presentation depends on the severity, timing, and duration of the insult, with symptoms typically evolving over approximately 72 hours.4 Symptoms that appear during the first 12 hours are presumed to be secondary to cerebral hemisphere depression.4 The neonate is not easily arousable, with minimal to absent response to sensory input. Respiratory patterns may range from a type of periodic breathing to respiratory failure. Generalized hypotonia is present with minimal spontaneous movements. If there is involvement of the basal ganglia, tone may be increased. There are spontaneous eye movements with intact papillary responses to light. The size of the pupils vary, with dilated reactive pupils found in neonates less affected and constricted reactive pupils in those with more severe insults.4 Approximately 50% to 60% of those severely affected will demonstrate seizures, with onset within the first 6 to 12 hours of life. Virtually all asphyxiated neonates express subtle seizures such as rowing or bicycling, blinking, tongue or lip smacking, sucking movements, and apnea. Full-term neonates demonstrate clonic movements that move in a random pattern known as multifocal clonic seizures. As many as 80% of neonates with focal cerebral infarcts will demonstrate focal seizures.4
During the next 12 to 24 hours, there may be an apparent increase in the neonate's level of awareness, although those severely affected typically remain unresponsive. The improvement in consciousness is not associated with any other signs of improvement in neurological function. Indeed, 15% to 20% of neonates first show seizure activity at this time that requires immediate intervention.4 Apneic episodes are found in 50% of neonates and 35% to 50% exhibit moderate to severe jitteriness. Full-term neonates may show weakness in the hip-shoulder distribution.4 If the basal ganglia were involved, there may be an increase in hypertonia. Deep tendon reflexes and the Moro reflex may be exaggerated.
In the 24 to 72 hours postinjury, the neonate with severe HIE often deteriorates and succumbs. Decreased level of consciousness, deep stupor, fixed pupils, and respiratory failure may be seen. The less severely affected neonate may exhibit constricted pupils that remain reactive to light. Brain-stem oculomotor disturbances are apparent as seen by loss of responsiveness of the eyes to the doll's eyes maneuver and to cold caloric stimulation.4 Delayed cell death has been postulated to be responsible for the slow progression to brain death, given the evidence for a delayed deterioration of the brain's energy state as discussed above.4
For those neonates who survive the first 72 hours, there is typically a slow improvement. They continue to demonstrate a mild to moderate stupor although the level of consciousness increases. Because of damage to cranial nerves V, VII, IX, X, and XII, the suck, swallow, and gag reflexes are disturbed. Feeding difficulties are commonly extreme enough that tube feedings or gastrostomy tubes are required for weeks to months. Generalized hypotonia is common in those neonates with selective neuronal necrosis that involves the basal ganglia and thalamus.4
CLINICAL MANAGEMENT
The diagnosis is made through a careful history to note the presence of maternal factors that may have resulted in uteroplacental insufficiency antenatally. Events surrounding labor and delivery should be explored to determine whether there was decreased placental blood flow, nonreassuring fetal heart rate variability, and the presence of meconium, for example. The immediate transition to extrauterine life should also be evaluated in light of Apgar scores, the need and response to resuscitative measures, and overall clinical condition of the neonate. Although the Apgar score is not a predictor of outcome, neonates with a continued low score of less than 6 have been shown to develop neurologic abnormalities.18
Once in the neonatal intensive care unit (NICU), a thorough physical and neurological examination should be done. The nurse should note the presence of jitteriness, seizures, pattern of breathing, tone, and other clinical sequelae as discussed above (routine nursing NICU care will not be discussed here). Diagnostic tests should rule out liver, renal, or cardiopulmonary dysfunction in addition to the usual complete blood cell count with differential and blood chemistry panels. Given the clinical condition of the neonate, it is important to monitor for hypoglycemia, hypocalcemia, hyponatremia, hypoxia, and acidosis. Hypoglycemia may be due to the enhanced anaerobic glycolysis in an attempt to preserve cellular energy levels.4,14 Fifteen percent of neonates diagnosed with intrauterine asphyxia had blood glucose values less than 40 mg/dL in the first 30 minutes of life.19
Perinatal asphyxia has also been associated with increased levels of lactate in blood and cerebrospinal fluid (CSF) and an elevated lactate/creatinine ratio in urine.14,20 Elevations in levels of excitatory amino acids, especially glutamate, aspartate, and glycine, found in the CSF within the first day of life have been correlated with severity of injury.21 Increased levels of free radicals, indicators of lipid peroxidation, and antioxidant enzymes have also been noted.22,23 Creatine kinase-BB is a brain-specific protein that when found in the CSF may provide information regarding brain injury.24 S100[beta] protein is found in neural glial and Schwann cells and may serve as a biochemical marker for HIE.25
A lumbar puncture should be done in the symptomatic neonate in which a diagnosis cannot be made with certainly to rule out infectious etiologies and hemorrhage. An electroencephalogram (EEG) may provide information regarding the type and severity of brain injury suffered.4,26 Amplitude-integrated EEG and sequential EEGs have been valuable in estimating neurodevelopmental outcomes.4,27 Brain ultrasound is typically a part of the initial diagnostic workup; however, the scan may be negative in almost 50% of neonates.4 Ultrasound, however, is very good at evaluating the extent of periventricular leukomalacia, as well as locating hemorrhagic complications.28 Computed tomography is very helpful in identifying focal and multifocal ischemic brain injuries several weeks after the insult.4
Magnetic resonance imaging is the tool of choice for evaluating hypoxic-ischemic injuries, both in the immediate period and also for long-term follow-up.29 Magnetic resonance imaging is not only able to document brain injury patterns but also may be predictive of the severity of the neurodevelopmental outcome. Diffusion-weighted MRI, based on the molecular diffusion of water, is more sensitive than the conventional MRI and is capable of detecting abnormalities within the first 24 to 48 hours of birth.4 Other diagnostic modalities may include magnetic resonance (MR) spectroscopy, phosphorus MR spectroscopy, and proton MR spectroscopy.4
TREATMENT STRATEGIES
Supportive strategies include adequate perfusion, ventilation, and oxygenation. Maintaining perfusion pressure within normal limits is necessary to avoid hemorrhagic complications due to systemic hypertension and ischemic injury due to systemic hypotension. Prevention of hypoxemia is essential to prevent additional neuronal and white matter injury. On the other hand, hyperoxia also must be avoided as it is thought that it may result in decreased cerebral blood flow and further any injury.30 As with oxygen, attention must be paid to CO2. Hypercarbia not only adds to acidosis but also more importantly promotes a pressure-passive cerebral circulation. Hypocarbia, especially values less than 20 mm Hg, is associated with impaired cerebral blood flow due to vasoconstriction and has been correlated with adverse neurological outcomes.30
Volpe suggests that the blood glucose level be maintained between 75 and 100 mg/d, although more research is needed on what constitutes an optimal range for the neonate with HIE.4 Seizures also need to be controlled, as they accelerate the brain's metabolic rate. Seizures are also associated with hypoxemia and hypercarbia. Observation for the development of inappropriate antidiuretic hormone syndrome should be done to prevent fluid overload, cerebral edema, and secondary brain swelling.4
NEUROPROTECTIVE INTERVENTIONS
As discussed above, there appears to be a therapeutic window prior to the secondary energy failure. A Cochrane review of 8 randomized controlled trials found that therapeutic hypothermia was beneficial to term neonates with HIE and that cooling decreased mortality without increasing morbidity.31 The exact mechanism by which hypothermia is neuroprotective has not yet been fully elucidated. It is thought that cells programmed for apoptosis are modified such that they survive.32 The brain's metabolic rate may be decreased, weakening the response of excitatory amino acids such as glutamate, slowing the uptake of glutamate, and decreasing production of NO and free radicals.4
Four pilot studies of hypothermia in human newborns reported no serious adverse effects.33?36 Sinus bradycardia and increased blood pressure and oxygen requirements were reversible with rewarming.35 From results obtained in animal studies, it was concluded that cooling should be initiated as early as possible after the brain injury and not later than 6 hours; body temperature should be cooled to 32?C to 34?C for whole-body cooling and 34?C to 35?C for head cooling; and hypothermia should be maintained for 48 to 72 hours.37 It is currently recommended that therapeutic hypothermia be considered as an evolving therapy, and in general, that it should be used only in NICUs with the expertise who strictly follow the guidelines of the protocols utilized in the CoolCap and NICHD trials.1,37 Selective head cooling did not show a statistically significant reduction in mortality although there was a significant decrease in major neurodevelopmental disability.31 Total body cooling demonstrated a significant decrease in mortality and major neurodevelopmental disability.31 A systematic review of hypothermia for the treatment of HIE found that systemic or selective head cooling reduced the combined outcome of death or neurodevelopmental disability, as well as death and moderate to severe neurodevelopmental disability when analyzed separately.1 Although potentially very promising for the treatment of HIE, and the lack of serious adverse effects, long-term efficacy and safety have not yet been established.37
HYPOTHERMIA PROTOCOL
Cooling must be initiated within 6 hours of birth as research has demonstrated this period as an optimal time for hypothermia to decrease the extent of the brain injury.38?40 Thus, the NICU must be prepared and well organized given the time constraint. The first step is to screen the infant for eligibility before accepting him for the therapy (Box 2). When the infant meets the criteria, the equipment is quickly assembled to the bedside and the blanket is precooled, but hung behind the radiant warmer. Because a thorough physical and neurological examination is required to determine eligibility for the protocol, the infant is admitted to a prewarmed radiant warmer on servo control. In addition to an amplified EEG, head ultrasound, and an echocardiogram, the physician will note the infant's level of consciousness, posture, tone, presence of any spontaneous activity, and quality of primitive reflexes (suck, Moro) and evaluate the autonomic nervous system (quality of respiration, heart rate, and pupils).
Box 2. Criteria for whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy
Immediately after establishing eligibility, the infant is placed on the precooled blanket with 1 regular hospital baby blanket under him. An esophageal temperature probe is inserted through a nare to a level of T 6?9, which corresponds to approximately 2 cm above the diaphragm. Placement is confirmed radiographically. The esophageal temperature probe is connected to the temperature cable and the radiant warmer is turned to manual control with the heater in the off position (Fig 1).
Figure 1. Infant on cooling blanket with esophageal temperature probe connected to the temperature cable in the foreground.
The radiant warmer temperature probe is left on the abdomen. The Blanketrol II is turned to auto control to keep the esophageal temperature 33.5?C (92.3?F) for 72 hours. An acceptable range is 32.5? to 34.5?C (90.5?F?94.1?F) and although some fluctuation is to be expected, it should be no more than 1?C higher or lower than the acceptable range. To better stabilize the temperature of the water flowing through the blanket, 2 blankets may be connected together, with one blanket under the infant and one hung behind the radiant warmer (Fig 2).
Figure 2. Infant on cooling blanket with Blanketrol II system in background and the second blanket hanging behind the radiant warmer. Note the cyanotic extremities associated with cold stress.
A specific hypothermia flow sheet is used to record the set point, patient esophageal temperature, skin temperature, and blanket (water) temperature every 15 minutes for the first 4 hours of cooling and every hour thereafter. On the standard nursing flow sheet, axillary temperature, blood pressure, and heart rate are recorded every hour, with axillary temperature being recorded every 4 hours after 12 hours of cooling. The axillary temperature will again be taken hourly once the rewarming period begins at 72 hours. In addition to noting the vital signs, it is also important that attention be given to skin integrity. Skin condition is documented every 4 hours, and the patient is gently repositioned using the rolls that were placed for nesting (Figs 1 and 2).
Nursing care of the infant includes developmental positioning with hands to midline and knees aligned with shoulders if possible. Typical NICU supportive care is also provided as for example, mechanical ventilation, pressors, fluids, and hematological conditions. A low resting heart rate is expected given the body temperature. Blood pressure fluctuations are also anticipated given the critical status of the neonate. It is also imperative that the bedside nurse ensure that the radiant warmer heater is not turned on during the 72 hours of cooling. Because of the effect of cold stress, blood flow to the extremities is typically decreased. Thus, values obtained from pulse oximetry should be interpreted with caution. The nurse must also adjust the temperature on the blood gas analyzer to the infant's actual temperature when processing blood gases.
Exactly at 72 hours of hypothermia, the gradual rewarming period begins. The cooling machine is turned to the warming mode and the auto control is increased by 0.5?C every hour for 6 hours until the set temper is 36.5?C. The esophageal probe is removed and the cooling blanket is turned off. At that point, the radiant warmer heater is turned on with the servo control set to 0.5?C greater than the infant's skin temperature. The servo control set point is increased 0.5?C every hour until the skin or axillary temperature reaches 36.5?C. The nursing/medical plan of care anticipates what supportive care the neonate needs as the temperature returns to normal.
In addition to the standard discharge protocol (automatic brainstem response, discharge medications, hepatitis B vaccine, and state screen), a Whole Body Hypothermia Discharge checklist must be completed prior to the neonate leaving the NICU. It documents that a brain MRI test and developmental evaluation have been completed, as well as the appointments at the follow-up high-risk clinic and the neurologist and pediatrician offices. Early Childhood Intervention and Home Health nursing referrals are also made as warranted.
Other neuroprotective strategies under investigation include oxygen free radical inhibitors and scavengers and excitatory amino acid antagonists. Allopurinol is a xanthine oxidase inhibitor and free radical scavenger. Studies using allopurinol in term neonates with asphyxia found beneficial effects on free radical formation and cerebral hemodynamics.41,42 Glutamate receptor antagonists such as N-methyl-d-aspartate (NMDA) have been extensively studied. Available N-methyl-d-aspartate agonists include magnesium sulfate, a medication widely used as a tocolytic agent and to treat preeclampsia. Magnesium blocks the neuronal influx of calcium within the ion channel, a major variable in the cascade of injury. Although studies show conflicting results, retrospective observations in premature neonates who were exposed to antenatal magnesium sulfate show a decreased incidence of CP at 3 years of age.43
CONCLUSION
Hypoxic-ischemic encephalopathy is associated with high mortality and severe morbidity in term neonates who have suffered a hypoxic-ischemic or asphyxia injury. An overview of the pathophysiology underlying HIE reveals the knowledge at the molecular and cellular levels that has been learned over the past 10 years. Although our understanding of the processes is enhanced, there remain considerable gaps yet to be elucidated. Hypothermia currently appears to be the best treatment modality, although there are many questions yet to be answered regarding its optimal use, timing, what level of hypothermia should be used, and which strategy (head vs total body cooling) ultimately will produce the best outcome. There is the prospect of exciting novel therapies ahead that specifically target the various levels of the cascade that may ultimately interfere with sequences to prevent or ameliorate cell death. It is likely that a combination of hypothermia, excitatory amino acid antagonists, and oxygen free radical inhibitors/scavengers will provide the best chance for recovery for the neonate affected by HIE.
Hypoxic-ischemic encephalopathy (HIE) is one of the most important complications found in the newborn period. It is the result of a deprivation of oxygen and glucose to the neural tissue, which may be the result of either hypoxemia or ischemia. Experimental animal research and clinical observations in humans have noted that the pattern of injury occurs in 2 phases. The first phase is a primary energy failure related to the insult, and then a second energy failure occurs some hours later. The combined effects of cellular energy failure, acidosis, glutamate release, intracellular accumulation of calcium, lipid peroxidation, and nitric oxide neurotoxicity destroy essential components of the cell, culminating in cell death. The clinical presentation depends on the severity, timing, and duration of the insult, with symptoms typically evolving over approximately 72 hours. Hypothermia strategies are aimed at targeting this narrow window of opportunity to ameliorate the brain injury.
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Hypoxic-ischemic encephalopathy (HIE) is often one of the most devastating sequelae encountered in the newborn period. Although the predominant injury affects the brain, almost every organ system in the body is negatively impacted. Cerebral palsy (CP), seizure activity, and varying degrees of developmental delays are some of the chronic disabilities seen in survivors. Hypoxia and especially ischemia, in which there is decreased perfusion of the brain with oxygen and glucose, are usually the result of asphyxia. Experimental animal research and clinical observations in humans have noted that the pattern of injury occurs in 2 phases. The first is a primary energy failure related to the insult, and the second is an energy failure that occurs some hours later. Hypothermia strategies are aimed at targeting this narrow window of opportunity to ameliorate the brain injury. This article will review the etiology, biochemical and physiological events, clinical symptoms, treatment strategies, including those for hypothermia, and future avenues of research as they relate to HIE.
ETIOLOGY
Hypoxic-ischemic encephalopathy is the result of a deprivation of oxygen and glucose to the neural tissue, which may be the result of either hypoxemia or ischemia. Hypoxemia is a decrease in the amount of oxygen circulating in the blood. Ischemia is a decrease in the flow of blood available to perfuse the brain. Of the two, ischemia is the most problematic because less oxygen and glucose are delivered to the brain. Asphyxia is defined as an impairment to the exchange of oxygen and carbon dioxide (CO2). The increase in CO2 promotes an initial increase in cerebral blood flow and contributes to acidosis. Annually, asphyxia is responsible for approximately 23% of 4 million neonatal deaths globally.1 The rate of HIE is approximately 1 to 2 per 1000 term newborns in developed countries, with a mortality rate of 10% to 20%.2 There is a 10% risk of death in neonates who develop a moderate encephalopathy and a 30% risk of neurodevelopmental sequelae in those who survive.3 A severe encephalopathy is associated with a 60% risk of death and virtually guaranteed disabilities in survivors.3
According to Volpe, approximately 20% of neonatal HIE is primarily related to antepartum events that lead to hypoxic-ischemic fetal insults.4 Maternal conditions such as hypotension, placental vasculopathy, and insulin-dependent diabetes mellitus may predispose the fetus to intrapartum hypoxia-ischemia such that there is little reserve to compensate for the stresses of labor.5,6 Intrapartum events such as prolapsed cord, abruption placentae, and traumatic delivery have been linked to 35% of HIE cases.4 Sophisticated neuroimaging techniques, such as magnetic resonance imaging (MRI), have documented evidence of acute brain injury in neonates with clinical encephalopathy who were born with evidence of intrapartum asphyxia.7,8 It is thought that a combination of both antepartum and intrapartum untoward events is responsible for approximately 35% of HIE cases.4
Conditions in the neonatal period may be responsible for as much as 10% of HIE cases.4 These include congenital heart disease, severe pulmonary disease, severe recurrent apnea, and cardiac failure secondary to a large patent ductus arteriosus. The preterm infant is more affected than the term infant.
Because of the limitations in determining the actual timing of the insult, it may be difficult to identify/quantitate the antepartum contribution separately from the intrapartum. It is argued that other events besides intrapartum hypoxia may be responsible for HIE or CP, as less than 25% of these infants have symptoms of hypoxia-ischemia at birth.9 The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists have defined neonatal HIE as an encephalopathy associated with hypoxia that occurs in the intrapartum period with no evidence of other anomalies.9 They also identified 4 criteria that must be present to define an intrapartum event that is capable of resulting in HIE or CP (Box 1). Other criteria may suggest an intrapartum origin if they occur within approximately 48 hours of delivery.
Box 1. Criteria for defining an intrapartum hypoxic event
BIOCHEMICAL AND PHYSIOLOGICAL EVENTS
As mentioned above, glucose and oxygen play key roles in the pathogenesis of injury. Glucose is delivered to the brain via a carrier-mediated, facilitated diffusion, a much faster process than simple diffusion alone.10 In the brain, glucose is phosphorylated to glucose-6-phosphate, with the major end product being pyruvate under aerobic conditions. Pyruvate then enters the mitochondrion to be converted to acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is important in energy production via the citric acid cycle.10 Within the mitochondrion, the electron transport system, citric acid cycle, and acetyl-CoA generate adenosine triphosphate (ATP) from adenosine diphosphate.10 Under aerobic conditions, 38 molecules of ATP are generated for each molecule of glucose oxidized. The ATP is then transported from the mitochondrion to be used for transport or synthetic purposes. The transport processes involve impulse transmission and maintenance of calcium (Ca2+) within the neurons. The synthetic processes include neurotransmitters, membrane lipids, and structural and functional proteins.10
When a hypoxic-ischemic event occurs and an anaerobic state is induced, ATP is produced solely through glycolysis.10 Lactate results as the principal product, which gives off only 2 molecules of ATP. In response, glycolysis is increased as much as 10-fold.11 There is also a concomitant increase in the net uptake of glucose from the blood as well as an increase in glycogenolysis.11 Inefficient anaerobic metabolism continues to excessively consume glucose such that glucose delivery cannot meet the demand. As a result, ATP and brain glucose levels fall within minutes. Ischemia further compounds the hypoxia because the impaired circulation rapidly increases lactate and tissue acidosis. After approximately 6 minutes in a rat model, brain glucose levels were 70% lower, whereas blood glucose values were 100% higher.11 Thus, a ?normal? chemstrip or blood glucose reading may have little relationship to the brain glucose value under anaerobic conditions.
Asphyxia initially results in a redistribution of cardiac output, with as much as a 30% to 175% increase in cerebral blood flow.12 Continued asphyxia leads to a decrease in cardiac output and hypotension. Cerebral blood vessels lose the ability to respond to changes in blood flow, lactate, tissue acidosis, and increasing CO2. Loss of cerebral autoregulation and hypotension result in a decrease in cerebral blood flow. Cerebral edema, a result of damaged blood vessel walls becoming ?leaky,? sets into motion the cascade of biochemical events.
As the energy stores are failing, the transcellular ion pump (sodium-potassium-ATPase pump) begins to fail. Sodium, calcium, and water accumulate inside the glial cell, causing a cytotoxic edema. The cellular edema further decreases oxygen and glucose delivery to the neurons. Alteration of the charge on the cell's membrane causes it to become depolarized and opens calcium channels, facilitating cytosolic accumulation of calcium. The depolarization initiates a release of excitatory neurotransmitters, specifically glutamate from the axon terminals.
The increase in cytosolic calcium activates phospholipases, proteases, and endonucleases. Phospholipase A2 releases free fatty acids such as arachidonic acid by hydrolyzing membrane phospholipid. Arachidonic acid increases the release of glutamate and interferes with oxidative phosphorylation. Proteases destroy proteins within the cell. Activation of endonucleases, in combination with xanthine and prostaglandins, generates free radicals. Free radicals, molecules which contain an odd number of electrons, are chemically reactive and induce peroxidation of unsaturated fatty acids.13 The most commonly generated free radical is superoxide anion, which is converted to hydrogen peroxide by superoxide dismutase.4 Hydrogen peroxide is detoxified by catalase and glutathione peroxidase unless free iron is available.4 Asphyxia converts the nontoxic ?ferric? state of free ion to the dangerous ?ferrous? form, which is able to react with free radicals.12 In this environment, superoxide radicals react with hydrogen peroxide to produce deadly hydroxyl radicals.13
High levels of calcium ions accumulating within the cytoplasm induce production of nitric oxide (NO), a free radical. Neuronal nitric oxide synthase is initially increased and improves blood flow to the neurons.14 Neuronal nitric oxide synthase soon generates NO that diffuses to adjacent cells that are susceptible to NO toxicity. Nitric oxide quickly reacts with superoxide anions to form a highly toxic reactive nitrogen species and peroxynitrite.14 The peroxynitrite radical contributes to cell death by energy depletion, mitochondrial impairment, and future disruption of calcium homeostasis.14 It also stimulates cyclooxygenase activity and reenters the presynaptic neuron to further increase the release of glutamate.12 In addition, free fatty acids accumulate within the cell and undergo peroxidation by oxygen free radicals.
Within 1 to 4 hours following an asphyxia insult, inflammatory mediators are found. Interleukin-1[beta], tumor necrosis factor [alpha] (TNF [alpha]), and [alpha] and [beta] chemokines are produced, followed by neutrophil invasion of the site of injury. Inflammatory mediators have an indirect toxic effect in that they induce glial cells to produce neurotoxic factors such as excitatory amino acids. The influx of Ca2+ into the presynaptic nerve ending releases glutamate.14 Glutamate accumulates because ATP depletion leads to failure in the major reuptake and removal mechanisms such that glutamate excess produces excitotoxicity.14 Most important, the release of inflammatory mediators perpetuates the excitotoxic injury. The combined effects of cellular energy failure, acidosis, glutamate release, intracellular accumulation of calcium, lipid peroxidation, and NO neurotoxicity destroy essential components of the cell, culminating in cell death.
Immediately when cerebral circulation and oxygenation is restored, the acute cellular hypoxic depolarization is resolved and cellular energy metabolism is restored.12 During this phase of reperfusion, high energy phosphate levels return to baseline levels, lactate levels improve, and glutamate is cleared.14 A secondary or delayed brain injury becomes apparent by 8 to 16 hours that reaches a nadir at 24 to 48 hours that is evidenced by a second decline in high energy phosphate levels.14 There is a decrease in the ratio of phosphocreatine/inorganic phosphate and an unchanged intracellular pH. Nitric oxide initially vasodilates the cerebral circulation and later inhibits activity within the mitochondria. An exaggerated calcium influx, further injury to the sodium-potassium-ATPase pump, and enhanced release of glutamate by NO occur. Free fatty acids generate arachidonic acids and prostaglandins, while xanthine oxidase converts hypoxanthine to uric acid. In the microvascular system, free radicals activate adhesion molecules in platelets and leukocytes. The vessels become occluded, with decreased blood flow and delivery of oxygen and glucose, and the injury is perpetuated. Despite an upregulation of the main antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase, their increased levels are inadequate to scavenge the free radicals.13
Clinical deterioration, seizure activity, cytotoxic edema, and a release of excitatory neurotransmitters occur. The mitochondria are dysfunctional, secondary to extended reactions from the primary insult due to the influx of calcium influx, ongoing generation of oxygen free radicals, and NO formation. Studies from a rat model demonstrate that neuronal protein loss (total creatine and adenine nucleotides) is seen at 6 hours and is very apparent by 18 hours.15 The findings indicate that the secondary energy depletion is a consequence of the events that cause cellular destruction rather than the cause.14,15 The time until the occurrence of the secondary energy failure provides a window of opportunity for possible interventions that may ameliorate the injury.
Depending on the severity of the asphyxial event, 3 distinct patterns of brain injury have been noted in the term neonate. A mild to moderate insult, such as prolonged partial hypoxia-ischemia, has been correlated to a cortical and subcortical injury in a watershed parasagittal distribution.16 Acute profound asphyxia results in damage to the thalami, basal ganglia, hippocampi, mesencephalic structures, and perirolandic cortex while leaving the cortex relatively intact.16,17 A diffuse, destructive anoxic-ischemic injury causes extensive injury to the cortex and the white matter as depicted by multicystic encephalopathy.14,16 The mode of cell death may be necrosis and/or apoptosis, dependent on the severity of the insult and the maturational state of the cell.
Necrosis of the cell occurs within minutes to hours as a result of a severe insult. It is characterized by cell swelling, disintegration of the cellular membrane leading to cell rupture. Release of the intracellular components activates phagocytosis and the inflammatory process. Apoptosis occurs over hours to days as a result of a less severe insult. It is an active process of cell shrinkage, nuclear pyknosis (the nucleus loses density), chromatin condensation, and genomic fragmentation. Because the inflammatory process is not involved, it is difficult to discern. Necrotic cells are found more commonly in the central area of the severe, acute injury or core of the insult. Apoptosis is found in the penumbra, an area of evolving cell injury that surrounds the core. Cells in the penumbra are initially sustained by anaerobic glycolysis. However, within hours, the injury becomes irreversible, the area of infarction enlarges such that the cells within penumbra become more damaged.
CLINICAL SYMPTOMS OF HIE
The clinical presentation depends on the severity, timing, and duration of the insult, with symptoms typically evolving over approximately 72 hours.4 Symptoms that appear during the first 12 hours are presumed to be secondary to cerebral hemisphere depression.4 The neonate is not easily arousable, with minimal to absent response to sensory input. Respiratory patterns may range from a type of periodic breathing to respiratory failure. Generalized hypotonia is present with minimal spontaneous movements. If there is involvement of the basal ganglia, tone may be increased. There are spontaneous eye movements with intact papillary responses to light. The size of the pupils vary, with dilated reactive pupils found in neonates less affected and constricted reactive pupils in those with more severe insults.4 Approximately 50% to 60% of those severely affected will demonstrate seizures, with onset within the first 6 to 12 hours of life. Virtually all asphyxiated neonates express subtle seizures such as rowing or bicycling, blinking, tongue or lip smacking, sucking movements, and apnea. Full-term neonates demonstrate clonic movements that move in a random pattern known as multifocal clonic seizures. As many as 80% of neonates with focal cerebral infarcts will demonstrate focal seizures.4
During the next 12 to 24 hours, there may be an apparent increase in the neonate's level of awareness, although those severely affected typically remain unresponsive. The improvement in consciousness is not associated with any other signs of improvement in neurological function. Indeed, 15% to 20% of neonates first show seizure activity at this time that requires immediate intervention.4 Apneic episodes are found in 50% of neonates and 35% to 50% exhibit moderate to severe jitteriness. Full-term neonates may show weakness in the hip-shoulder distribution.4 If the basal ganglia were involved, there may be an increase in hypertonia. Deep tendon reflexes and the Moro reflex may be exaggerated.
In the 24 to 72 hours postinjury, the neonate with severe HIE often deteriorates and succumbs. Decreased level of consciousness, deep stupor, fixed pupils, and respiratory failure may be seen. The less severely affected neonate may exhibit constricted pupils that remain reactive to light. Brain-stem oculomotor disturbances are apparent as seen by loss of responsiveness of the eyes to the doll's eyes maneuver and to cold caloric stimulation.4 Delayed cell death has been postulated to be responsible for the slow progression to brain death, given the evidence for a delayed deterioration of the brain's energy state as discussed above.4
For those neonates who survive the first 72 hours, there is typically a slow improvement. They continue to demonstrate a mild to moderate stupor although the level of consciousness increases. Because of damage to cranial nerves V, VII, IX, X, and XII, the suck, swallow, and gag reflexes are disturbed. Feeding difficulties are commonly extreme enough that tube feedings or gastrostomy tubes are required for weeks to months. Generalized hypotonia is common in those neonates with selective neuronal necrosis that involves the basal ganglia and thalamus.4
CLINICAL MANAGEMENT
The diagnosis is made through a careful history to note the presence of maternal factors that may have resulted in uteroplacental insufficiency antenatally. Events surrounding labor and delivery should be explored to determine whether there was decreased placental blood flow, nonreassuring fetal heart rate variability, and the presence of meconium, for example. The immediate transition to extrauterine life should also be evaluated in light of Apgar scores, the need and response to resuscitative measures, and overall clinical condition of the neonate. Although the Apgar score is not a predictor of outcome, neonates with a continued low score of less than 6 have been shown to develop neurologic abnormalities.18
Once in the neonatal intensive care unit (NICU), a thorough physical and neurological examination should be done. The nurse should note the presence of jitteriness, seizures, pattern of breathing, tone, and other clinical sequelae as discussed above (routine nursing NICU care will not be discussed here). Diagnostic tests should rule out liver, renal, or cardiopulmonary dysfunction in addition to the usual complete blood cell count with differential and blood chemistry panels. Given the clinical condition of the neonate, it is important to monitor for hypoglycemia, hypocalcemia, hyponatremia, hypoxia, and acidosis. Hypoglycemia may be due to the enhanced anaerobic glycolysis in an attempt to preserve cellular energy levels.4,14 Fifteen percent of neonates diagnosed with intrauterine asphyxia had blood glucose values less than 40 mg/dL in the first 30 minutes of life.19
Perinatal asphyxia has also been associated with increased levels of lactate in blood and cerebrospinal fluid (CSF) and an elevated lactate/creatinine ratio in urine.14,20 Elevations in levels of excitatory amino acids, especially glutamate, aspartate, and glycine, found in the CSF within the first day of life have been correlated with severity of injury.21 Increased levels of free radicals, indicators of lipid peroxidation, and antioxidant enzymes have also been noted.22,23 Creatine kinase-BB is a brain-specific protein that when found in the CSF may provide information regarding brain injury.24 S100[beta] protein is found in neural glial and Schwann cells and may serve as a biochemical marker for HIE.25
A lumbar puncture should be done in the symptomatic neonate in which a diagnosis cannot be made with certainly to rule out infectious etiologies and hemorrhage. An electroencephalogram (EEG) may provide information regarding the type and severity of brain injury suffered.4,26 Amplitude-integrated EEG and sequential EEGs have been valuable in estimating neurodevelopmental outcomes.4,27 Brain ultrasound is typically a part of the initial diagnostic workup; however, the scan may be negative in almost 50% of neonates.4 Ultrasound, however, is very good at evaluating the extent of periventricular leukomalacia, as well as locating hemorrhagic complications.28 Computed tomography is very helpful in identifying focal and multifocal ischemic brain injuries several weeks after the insult.4
Magnetic resonance imaging is the tool of choice for evaluating hypoxic-ischemic injuries, both in the immediate period and also for long-term follow-up.29 Magnetic resonance imaging is not only able to document brain injury patterns but also may be predictive of the severity of the neurodevelopmental outcome. Diffusion-weighted MRI, based on the molecular diffusion of water, is more sensitive than the conventional MRI and is capable of detecting abnormalities within the first 24 to 48 hours of birth.4 Other diagnostic modalities may include magnetic resonance (MR) spectroscopy, phosphorus MR spectroscopy, and proton MR spectroscopy.4
TREATMENT STRATEGIES
Supportive strategies include adequate perfusion, ventilation, and oxygenation. Maintaining perfusion pressure within normal limits is necessary to avoid hemorrhagic complications due to systemic hypertension and ischemic injury due to systemic hypotension. Prevention of hypoxemia is essential to prevent additional neuronal and white matter injury. On the other hand, hyperoxia also must be avoided as it is thought that it may result in decreased cerebral blood flow and further any injury.30 As with oxygen, attention must be paid to CO2. Hypercarbia not only adds to acidosis but also more importantly promotes a pressure-passive cerebral circulation. Hypocarbia, especially values less than 20 mm Hg, is associated with impaired cerebral blood flow due to vasoconstriction and has been correlated with adverse neurological outcomes.30
Volpe suggests that the blood glucose level be maintained between 75 and 100 mg/d, although more research is needed on what constitutes an optimal range for the neonate with HIE.4 Seizures also need to be controlled, as they accelerate the brain's metabolic rate. Seizures are also associated with hypoxemia and hypercarbia. Observation for the development of inappropriate antidiuretic hormone syndrome should be done to prevent fluid overload, cerebral edema, and secondary brain swelling.4
NEUROPROTECTIVE INTERVENTIONS
As discussed above, there appears to be a therapeutic window prior to the secondary energy failure. A Cochrane review of 8 randomized controlled trials found that therapeutic hypothermia was beneficial to term neonates with HIE and that cooling decreased mortality without increasing morbidity.31 The exact mechanism by which hypothermia is neuroprotective has not yet been fully elucidated. It is thought that cells programmed for apoptosis are modified such that they survive.32 The brain's metabolic rate may be decreased, weakening the response of excitatory amino acids such as glutamate, slowing the uptake of glutamate, and decreasing production of NO and free radicals.4
Four pilot studies of hypothermia in human newborns reported no serious adverse effects.33?36 Sinus bradycardia and increased blood pressure and oxygen requirements were reversible with rewarming.35 From results obtained in animal studies, it was concluded that cooling should be initiated as early as possible after the brain injury and not later than 6 hours; body temperature should be cooled to 32?C to 34?C for whole-body cooling and 34?C to 35?C for head cooling; and hypothermia should be maintained for 48 to 72 hours.37 It is currently recommended that therapeutic hypothermia be considered as an evolving therapy, and in general, that it should be used only in NICUs with the expertise who strictly follow the guidelines of the protocols utilized in the CoolCap and NICHD trials.1,37 Selective head cooling did not show a statistically significant reduction in mortality although there was a significant decrease in major neurodevelopmental disability.31 Total body cooling demonstrated a significant decrease in mortality and major neurodevelopmental disability.31 A systematic review of hypothermia for the treatment of HIE found that systemic or selective head cooling reduced the combined outcome of death or neurodevelopmental disability, as well as death and moderate to severe neurodevelopmental disability when analyzed separately.1 Although potentially very promising for the treatment of HIE, and the lack of serious adverse effects, long-term efficacy and safety have not yet been established.37
HYPOTHERMIA PROTOCOL
Cooling must be initiated within 6 hours of birth as research has demonstrated this period as an optimal time for hypothermia to decrease the extent of the brain injury.38?40 Thus, the NICU must be prepared and well organized given the time constraint. The first step is to screen the infant for eligibility before accepting him for the therapy (Box 2). When the infant meets the criteria, the equipment is quickly assembled to the bedside and the blanket is precooled, but hung behind the radiant warmer. Because a thorough physical and neurological examination is required to determine eligibility for the protocol, the infant is admitted to a prewarmed radiant warmer on servo control. In addition to an amplified EEG, head ultrasound, and an echocardiogram, the physician will note the infant's level of consciousness, posture, tone, presence of any spontaneous activity, and quality of primitive reflexes (suck, Moro) and evaluate the autonomic nervous system (quality of respiration, heart rate, and pupils).
Box 2. Criteria for whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy
Immediately after establishing eligibility, the infant is placed on the precooled blanket with 1 regular hospital baby blanket under him. An esophageal temperature probe is inserted through a nare to a level of T 6?9, which corresponds to approximately 2 cm above the diaphragm. Placement is confirmed radiographically. The esophageal temperature probe is connected to the temperature cable and the radiant warmer is turned to manual control with the heater in the off position (Fig 1).
Figure 1. Infant on cooling blanket with esophageal temperature probe connected to the temperature cable in the foreground.
The radiant warmer temperature probe is left on the abdomen. The Blanketrol II is turned to auto control to keep the esophageal temperature 33.5?C (92.3?F) for 72 hours. An acceptable range is 32.5? to 34.5?C (90.5?F?94.1?F) and although some fluctuation is to be expected, it should be no more than 1?C higher or lower than the acceptable range. To better stabilize the temperature of the water flowing through the blanket, 2 blankets may be connected together, with one blanket under the infant and one hung behind the radiant warmer (Fig 2).
Figure 2. Infant on cooling blanket with Blanketrol II system in background and the second blanket hanging behind the radiant warmer. Note the cyanotic extremities associated with cold stress.
A specific hypothermia flow sheet is used to record the set point, patient esophageal temperature, skin temperature, and blanket (water) temperature every 15 minutes for the first 4 hours of cooling and every hour thereafter. On the standard nursing flow sheet, axillary temperature, blood pressure, and heart rate are recorded every hour, with axillary temperature being recorded every 4 hours after 12 hours of cooling. The axillary temperature will again be taken hourly once the rewarming period begins at 72 hours. In addition to noting the vital signs, it is also important that attention be given to skin integrity. Skin condition is documented every 4 hours, and the patient is gently repositioned using the rolls that were placed for nesting (Figs 1 and 2).
Nursing care of the infant includes developmental positioning with hands to midline and knees aligned with shoulders if possible. Typical NICU supportive care is also provided as for example, mechanical ventilation, pressors, fluids, and hematological conditions. A low resting heart rate is expected given the body temperature. Blood pressure fluctuations are also anticipated given the critical status of the neonate. It is also imperative that the bedside nurse ensure that the radiant warmer heater is not turned on during the 72 hours of cooling. Because of the effect of cold stress, blood flow to the extremities is typically decreased. Thus, values obtained from pulse oximetry should be interpreted with caution. The nurse must also adjust the temperature on the blood gas analyzer to the infant's actual temperature when processing blood gases.
Exactly at 72 hours of hypothermia, the gradual rewarming period begins. The cooling machine is turned to the warming mode and the auto control is increased by 0.5?C every hour for 6 hours until the set temper is 36.5?C. The esophageal probe is removed and the cooling blanket is turned off. At that point, the radiant warmer heater is turned on with the servo control set to 0.5?C greater than the infant's skin temperature. The servo control set point is increased 0.5?C every hour until the skin or axillary temperature reaches 36.5?C. The nursing/medical plan of care anticipates what supportive care the neonate needs as the temperature returns to normal.
In addition to the standard discharge protocol (automatic brainstem response, discharge medications, hepatitis B vaccine, and state screen), a Whole Body Hypothermia Discharge checklist must be completed prior to the neonate leaving the NICU. It documents that a brain MRI test and developmental evaluation have been completed, as well as the appointments at the follow-up high-risk clinic and the neurologist and pediatrician offices. Early Childhood Intervention and Home Health nursing referrals are also made as warranted.
Other neuroprotective strategies under investigation include oxygen free radical inhibitors and scavengers and excitatory amino acid antagonists. Allopurinol is a xanthine oxidase inhibitor and free radical scavenger. Studies using allopurinol in term neonates with asphyxia found beneficial effects on free radical formation and cerebral hemodynamics.41,42 Glutamate receptor antagonists such as N-methyl-d-aspartate (NMDA) have been extensively studied. Available N-methyl-d-aspartate agonists include magnesium sulfate, a medication widely used as a tocolytic agent and to treat preeclampsia. Magnesium blocks the neuronal influx of calcium within the ion channel, a major variable in the cascade of injury. Although studies show conflicting results, retrospective observations in premature neonates who were exposed to antenatal magnesium sulfate show a decreased incidence of CP at 3 years of age.43
CONCLUSION
Hypoxic-ischemic encephalopathy is associated with high mortality and severe morbidity in term neonates who have suffered a hypoxic-ischemic or asphyxia injury. An overview of the pathophysiology underlying HIE reveals the knowledge at the molecular and cellular levels that has been learned over the past 10 years. Although our understanding of the processes is enhanced, there remain considerable gaps yet to be elucidated. Hypothermia currently appears to be the best treatment modality, although there are many questions yet to be answered regarding its optimal use, timing, what level of hypothermia should be used, and which strategy (head vs total body cooling) ultimately will produce the best outcome. There is the prospect of exciting novel therapies ahead that specifically target the various levels of the cascade that may ultimately interfere with sequences to prevent or ameliorate cell death. It is likely that a combination of hypothermia, excitatory amino acid antagonists, and oxygen free radical inhibitors/scavengers will provide the best chance for recovery for the neonate affected by HIE.
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