Archive for February 1st, 2007
Diabetes Mellitus and Pregnancy
Synonyms and related keywords: gestational diabetes mellitus, gestational diabetes, GDM, infants of diabetic mothers, IDMs, infant of diabetic mother, IDM, maternal hyperglycemia, fetal hyperglycemia, diabetes in pregnancy, diabetes-associated birth defects, diabetic birth defects, gestational DM, macrosomia, macrosomic infant, macrosomic fetus, diabetic pregnancy, fetal macrosomia
INTRODUCTION Depending on the specific population, abnormal maternal glucose regulation occurs in 3-10% of pregnancies. Recent studies suggest that the prevalence of diabetes among women of childbearing age is increasing in the United States. This increase is believed to be attributable to (1) more sedentary lifestyles, (2) changes in diet, (3) continued immigration from high-risk populations, and (4) the virtual epidemic of childhood and adolescent obesity presently evolving in United States. Although 80% or more of this glucose intolerance during pregnancy occurs in women with gestational diabetes mellitus (GDM), the associated fetal and newborn morbidity rates are disproportionate. Infants of mothers with preexisting diabetes experience double the risk of serious injury at birth, triple the likelihood of cesarean delivery, and quadruple the incidence of newborn intensive care unit admission. Recent studies indicate that the risk of these morbidities in individual cases is proportional to the degree of maternalhyperglycemia. For this reason, the excessive fetal and neonatal morbidity attributable to diabetes in pregnancy should be considered preventable. Maternal-fetal metabolism in normal pregnancy With each feeding, the pregnant woman undergoes a complex series of maternal hormonal actions, including a rise in blood glucose and the secondary secretion of pancreatic insulin, glucagon, somatomedins, and adrenal catecholamines. These adjustments ensure that an ample, but not excessive, supply of glucose is available to the mother and fetus. The key features of this complex interaction include the following:
Background
Pathophysiology
During a healthy pregnancy, mean fasting blood sugar levels decline progressively to a remarkably low value of 74 ± 2.7 (standard deviation) mg/dL. On the other hand, peak postprandial blood sugar values rarely exceed 120 mg/dL. Meticulous replication of the normal glycemic profile during pregnancy has been demonstrated to reduce the rate of macrosomia. Specifically, when 2-hour postprandial glucose levels are maintained at less than 120 mg/dL, approximately 20% of fetuses demonstrate macrosomia. Conversely, if postprandial levels range up to 160 mg/dL, macrosomia rates rise to 35%.
Frequency
United States
In the United States today, 17 million people (6.2% of the population) have some form of diagnosed diabetes. Another 6 million people may be undiagnosed. Approximately 4-6% of pregnancies in the United States are complicated by diabetes, of which 90% is gestational diabetes and 3% is type 2 diabetes (ie, preexisting, insulin-resistant, or adult-onset diabetes). The prevalence of type 2 diabetes is increasing markedly in the United States, probably related to rising population obesity and shifts in ethnicity.
Race
The prevalence of gestational diabetes is strongly related to the patient’s race and culture.
- Typically, only 1.5-2% of white persons from the midwestern United States develop GDM, while American Indians from the southwestern United States may have rates as high as 15%.
- In Hispanic, African American, and Asian populations, the rate is 5-8%.
CLINICAL
History
- Current data suggest a strong association between the degree of glycemic control prior to pregnancy and the miscarriage rate. Relaxed glycemic control has been shown to double the miscarriage rate. In addition, more advanced diabetes and miscarriage rates are correlated.
- Patients with long-standing diabetes (glycohemoglobin exceeding 11%) have been shown to have miscarriage rates of up to 44%. Conversely, recent reports demonstrate a normalization of the miscarriage rate with excellent glycemic control.
- Among the general population, major birth defects occur in 1-2% of the population. In women with overt diabetes and suboptimal glycemic control prior to conception, the likelihood of a structural anomaly is increased 4- to 8-fold.
- Most lesions involve the central nervous and cardiovascular systems.
- The fact that no increase in birth defects occurs among the offspring of fathers who are diabetic, women who are prediabetic, and women who develop gestational diabetes after the first trimester is notable. This suggests that periconceptional glycemic control is the main factor in the genesis of diabetes-associated birth defects.
- When the frequency of congenital anomalies in patients with normal or high first-trimester maternal glycohemoglobin values was compared to the frequency in healthy patients, the rate of anomalies was only 3.4% with glycosylated hemoglobin (HbA1C) values of less than 8.5%, whereas patients with poorer glycemic control in the periconceptional period (HbA1C >8.5%) had a 22.4% rate of malformations. An overall malformation rate of 13.3% was reported in 105 patients with diabetes, but the risk of delivering an infant who is malformed was comparable to a normal population when the HbA1C value was less than 7%.
- Because birth defects occur during the critical time 3-6 weeks after conception, preconceptionally institute nutritional and metabolic intervention. Clinical trials of metabolic care have demonstrated that normal malformation rates can be achieved with meticulous periconceptional glycemic control (Fuhrmann, 1983). Subsequent trials comparing a preconceptional intensive metabolic program to standard treatment over 15 years’ duration have demonstrated lower perinatal mortality (0% vs 7%) and congenital anomaly rates (14% to 2%). In addition, when the preconceptional counseling program was discontinued, the congenital anomaly rate increased by more than 50%.
- Although most fetuses of diabetic mothers exhibit growth acceleration, growth restriction occurs with significant frequency in pregnancies complicated by preexisting type 1 diabetes.
- The most import predictor of fetal growth restriction is underlying maternal vascular disease. Specifically, pregnant patients with diabetes-associated retinal or renal vasculopathies and/or chronic hypertension are most at risk for growth restriction.
- Excessive body fat stores, stimulated by excessive glucose delivery during diabetic pregnancy, often extend into childhood and adult life.
- The adverse downstream effects of deranged maternal metabolism have been documented well into puberty. Glucose intolerance and higher serum insulin levels are more frequent in offspring of diabetic mothers compared with normal controls. By age 10-16 years, offspring of diabetic mothers have a 19.3% rate of impaired glucose intolerance.
- Macrosomia is typically defined as a birthweight above the 90th percentile for gestational age or greater than 4000 g. In pregnant diabetic women, macrosomia occurs in 15-45% of cases, a 3-fold increase from normoglycemic controls.
- Newborns with macrosomia experience excessive rates of neonatal morbidity, as illustrated by a study by Hunter et al in 1993, which compared the neonatal morbidity among infants of 230 women with type 1 diabetes mellitus and infants of 460 women without diabetes. The infants of diabetic mothers (IDMs) had 5-fold higher rates of severe hypoglycemia, a 4-fold increase in macrosomia, and a doubled increase in neonatal jaundice.
- Birth injury, including shoulder dystocia and brachial plexus trauma, is more common among IDMs, and macrosomic fetuses are at the highest risk.
- The macrosomic fetus develops a unique pattern of overgrowth, involving central deposition of subcutaneous fat in the abdominal and interscapular areas. Skeletal growth is largely unaffected. Neonates of diabetic mothers have a larger shoulder and extremity circumference, a decreased head-to-shoulder ratio, significantly higher body fat, and thicker upper extremity skin folds compared with nondiabetic control infants of similar weights.
- When serial ultrasound examination findings from diabetic fetuses are plotted, the growth velocity of the abdominal circumference is well above the growth velocity seen in nondiabetic fetuses and is higher than the growth pattern for the fetal head and femur of diabetic fetuses. The abdominal circumference growth begins to rise significantly above normal after 24 weeks.
- Excess nutrient delivery to the fetus causes macrosomia, but whether fasting or peak glucose values are more correlated with fetal overgrowth is less clear.
- Data from the Diabetes in Early Pregnancy (DIEP) study indicate that fetal birthweight correlates best with second- and third-trimester postprandial blood sugar levels and not with fasting or mean glucose levels.
- When postprandial glucose values average 120 mg/dL or less, approximately 20% of infants can be expected to be macrosomic. When postprandial levels range as high as 160 mg/dL, macrosomia rates can reach 35%.
- In addition, excessive fetal insulin levels appear to play some role in mediating excessive fetal growth, as shown in the 1995 study by Simmons, who compared umbilical cord sera in newborn IDMs and normal newborns. Simmons found that the heavier, fatter babies from diabetic pregnancies were also hyperinsulinemic.
- Maternal obesity has a strong and independent effect on fetal macrosomia. Birthweight is largely determined by maternal factors other than hyperglycemia, with the most significant influences being gestational age at delivery, prepregnancy body mass index (BMI), maternal height, pregnancy weight gain, the presence of hypertension, and cigarette smoking.
- When women who are very obese (weight >300 lb) were compared with women of normal weight, the former had more than double the risk of macrosomia compared with the women who were of normal weight. This may explain the failure of glycemic control to completely prevent fetal macrosomia in several series.
- Perinatal mortality
- In diabetic pregnancy, perinatal mortality has decreased 30-fold since the discovery of insulin in 1922 and intensive obstetrical and infant care in the 1970s. Nevertheless, the current perinatal mortality rates among diabetic women remain approximately twice those observed in the nondiabetic population.
- Congenital malformations, respiratory distress syndrome (RDS), and extreme prematurity account for most perinatal deaths in contemporary diabetic pregnancies.
Table 1. Perinatal Morbidity Rates in Diabetic Pregnancy
Morbidity Gestational Diabetes Type 1 Diabetes Type 2 Diabetes Hyperbilirubinemia 29% 55% 44% Hypoglycemia 9% 29% 24% Respiratory distress 3% 8% 4% Transienttachypnea 2% 3% 4% Hypocalcemia 1% 4% 1% Cardiomyopathy 1% 2% 1% Polycythemia 1% 3% 3% Adapted from California Department of Health Services, 1991
- Birth injury
- Injuries of birth, including shoulder dystocia and brachial plexus trauma, are more common among IDMs, and macrosomic fetuses are at the highest risk.
- Most of the birth injuries occurring to IDMs are associated with difficult vaginal delivery and shoulder dystocia. While shoulder dystocia occurs in 0.3-0.5% of vaginal deliveries among healthy pregnant women, the rate is 2- to 4-fold higher in women with diabetes. With strict glycemic control, the birth injury rate has been shown to be only slightly higher than controls (3.2% vs 2.5%).
- Currently, the ability to predict shoulder dystocia clinically is poor. Warning signs during labor (eg, labor protraction, suspected fetal macrosomia, need for forceps delivery) successfully predict only 30% of these events.
- Common birth injuries associated with diabetes are brachial plexus trauma, facial nerve injury, and cephalohematoma.
- Polycythemia
- A central venous hemoglobin concentration greater than 20 g/dL or a hematocrit value greater than 65% (polycythemia) is not uncommon in IDMs and is related to glycemic control.
- Hyperglycemia is a powerful stimulus to fetal erythropoietin production mediated by decreased fetal oxygen tension.
- Untreated neonatal polycythemia may promote vascular sludging, ischemia, and infarction of vital tissues, including the kidneys and central nervous system.
- Hypoglycemia
- Hyperinsulinemic IDMs are at increased risk for hypoglycemia after birth, especially those born from mothers with poor glycemic control. The strongest predictor for neonatal hypoglycemia is the mean maternal glucose level during labor. This complication is usually much milder and less common in infants who have mothers who are diabetic; insulin-dependent; and well controlled throughout the entire pregnancy, labor, and delivery.
- Unrecognized postnatal hypoglycemia may lead to neonatal seizures, coma, and brain damage.
- Neonatal hypocalcemia
- Up to 50% of IDMs have low levels of serum calcium (less than 7 mg/100 mL). With improved management of diabetes in pregnancy, this rate has been reduced to 5% or less.
- These changes in calcium appear to be attributable to a functional hypoparathyroidism, although the exact pathophysiology is not well understood.
- Postnatal hyperbilirubinemia
- Hyperbilirubinemia occurs in approximately 25% of IDMs, a rate approximately double that in a normal population. The causes of hyperbilirubinemia in IDMs are multiple, but prematurity and polycythemia are the primary contributing factors. Increased destruction of red blood cells contributes to the risk of jaundice and kernicterus.
- The treatment of this complication is usually phototherapy, but exchange transfusions may be necessary if bilirubin levels are markedly elevated.
- Respiratory problems
- Until recently, neonatal RDS was the most common and serious morbidity in IDMs. In the 1970s, improved prenatal maternal management for diabetes and new techniques in obstetrics for timing and mode of delivery resulted in a dramatic decline in its incidence from 31% to 3% (Taeusch, 1979). Nevertheless, RDS continues to be a relatively preventable complication.
- The nondiabetic fetus achieves pulmonary maturity at a mean gestational age of 34-35 weeks. By 37 weeks’ gestation, more than 99% of healthy newborn infants have mature lung profiles as assessed by phospholipid assays. However, in a diabetic pregnancy, presuming that the risk of respiratory distress has passed is unwise until after 38.5 gestational weeks have been completed.
- Prior to contemplating any delivery before 38.5 weeks’ gestation for other than the most urgent fetal and maternal indications, perform an amniocentesis to document pulmonary maturity.
- Diabetic retinopathy
- This is the leading cause of blindness in women aged 24-64 years. Some form of retinopathy is present in virtually 100% of women who have had type 1 diabetes for 25 years or more; of these women, approximately 1 in 5 is legally blind.
- A prospective study showed that while half the patients with preexisting retinopathy experienced deterioration during pregnancy, all the patients had partial regression following delivery and returned to their prepregnant state by 6 months postpartum.
- Other studies, such as the 1995 study by Hopp et al, have suggested that rapid induction of glycemic control in early pregnancy stimulates retinal vascular proliferation. However, when the total effect of pregnancy on ophthalmologic status was considered, pregnant women had a slower progression of retinopathy than nonpregnant women, probably because the modest deterioration in retinal status during rapid improvement in control is offset by the excellent control during the remainder of the pregnancy.
- Current management recommendations include referral to an ophthalmologist for baseline studies for pregnant patients with diabetes, with follow-up according to the degree of retinopathy.
- Renal function
- In general, patients with underlying nephropathy can expect varying degrees of deterioration of renal function during a pregnancy. As renal blood flow and the glomerular filtration rate increase 30-50% during pregnancy, the degree of proteinuria also increases.
- The most recent studies indicate that pregnancy does not measurably alter the time course of diabetic renal disease and it does not increase the likelihood of progression to end-stage renal disease. The progression to renal disease in diabetic patients appears to be related to the duration of diabetes and degree of glycemic control.
- Patients using the subcutaneous insulin pump have lower mean glucose levels than those using intermittent injections. The effect on nephropathy progression with 2 years of strict metabolic control showed that none of the patients using the insulin pump progressed to clinical nephropathy, while 5 patients using conventional treatment did.
- Perinatal complications are greatly increased in patients with diabetic nephropathy. Preterm birth, intrauterine growth restriction, and preeclampsia are all significantly more common in women with diabetic nephropathy during pregnancy.
- Chronic hypertension
- This complicates approximately 1 in 10 diabetic pregnancies overall. Patients with underlying renal or retinal vascular disease are at a substantially higher risk, with 40% having chronic hypertension.
- Patients with chronic hypertension and diabetes are at increased risk of intrauterine growth restriction, superimposed preeclampsia, abruptio placentae, and maternal stroke.
- Baseline renal function determination is recommended in all patients with preexisting diabetes. Renal function assessments in each trimester should be performed in patients with overt vascular disease or those who have had diabetes for more than 10 years.
- Preeclampsia
- Patient symptomology includes abrupt elevation in blood pressure, significant proteinuria, plasma uric acid levels greater than 6 mg/dL, or evidence of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome.
- Preeclampsia is more frequent among women with diabetes, occurring in approximately 12%, compared with 8% in the nondiabetic population. The risk of preeclampsia is also related to maternal age and the duration of preexisting diabetes. In patients who have chronic hypertension coexisting with diabetes, preeclampsia may be difficult to distinguish from near-term blood pressure elevations.
- The onset typically is insidious and not confidently recognized until it is severe.
Physical
- Diagnosing diabetes
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- Patients with type 1 diabetes are typically diagnosed during an episode of hyperglycemia, ketosis, and dehydration; this occurs most commonly in childhood or adolescence, before pregnancy. Type 1 diabetes is diagnosed only rarely during pregnancy and is most often accompanied by unexpected coma because early pregnancy may provoke diet and glycemic control instability in patients with occult diabetes. A pregnancy test should be ordered in all reproductive-aged women admitted to the hospital for blood sugar management.
- Diagnosing type 2 diabetes mellitus is very difficult during pregnancy because severe forms of GDM have similar clinical characteristics. On the other hand, it is not unusual for women tentatively diagnosed with GDM in early pregnancy to be found to have overt diabetes after delivery. Although a first-trimester HbA1C value of 8% is highly suggestive of preexisting type 2 diabetes, definitive diagnosis of type 2 diabetes must be made after pregnancy using the 75-g, 2-hour glucose tolerance test.
- The American Diabetes Association 2002 diagnostic criteria for diabetes mellitus, of which only one of the following must be met, are as follows:
- Symptoms of diabetes and a casual plasma glucose level of greater than 200 mg/dL (11.1 mmol/L): Casual is defined as any time of the day without regard to time since the patient’s last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.
- Fasting plasma glucose level of greater than 126 mg/dL (7 mmol/L): Fasting is defined as no energy (caloric) intake for at least 8 hours.
- Two-hour plasma glucose level greater than 200 mg/dL (11.1 mmol/L) during a 75-g, 2-hour oral glucose tolerance test (OGTT)
- In the absence of unequivocal hyperglycemia with acute metabolic decompensation, the diagnosis should be confirmed by repeat testing on a different day.
- Prediabetes is a term used to distinguish people who are at increased risk of developing diabetes. People with prediabetes have impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Some people may have both IFG and IGT.
- IFG is a condition in which the fasting blood sugar level is elevated (100-125 mg/dL) after an overnight fast but is not high enough to be classified as diabetes.
- IGT is a condition in which the blood sugar level is elevated (140-199 mg/dL) after a 2-h OGTT but is not high enough to be classified as diabetes.
- Patients with prediabetes identified prior to pregnancy should be considered at extremely high risk of developing GDM during pregnancy. As such, they should receive early (first trimester) diabetic screening. Prediabetes, IFG, and IGT are not meaningful terms in treating patients during pregnancy unless they exceed the plasma glucose limits for the diagnosis of GDM.
- Screening for gestational diabetes
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- GDM only occurs during pregnancy. The diagnosis is established by glucose tolerance testing. Risk factors for gestational diabetes include advanced maternal age, ethnicity, obesity, obstetrical history of diabetes or macrosomia, and strong family history of diabetes. The best method for diagnosing GDM continues to be controversial. The 2-step system is currently recommended in the United States. A 50-g, 1-hour screening test is administered to all pregnant women at 26-28 weeks’, followed by a 100-g, 3-hour OGTT for those with an abnormal screening result. Alternatively, a 1-step, 75-g, 2-hour test can be administered. Other measurements (eg, maternal HbA1C, random postprandial or fasting blood sugar level, fructosamine level) are not recommended because of low sensitivity.
- OGTT prerequisites for gestational diabetes are as follows:
- One-hour, 50-g glucose challenge result greater than 135 mg/dL
- Overnight fast of 8-14 hours
- Carbohydrate loading for 3 days (>150 g carbohydrates)
- Seated and not smoking during the test
- Two or more values met or exceeded
- Either a 2-hour (75 g of glucose) or 3-hour (100 g of glucose) test
- Plasma glucose criteria for gestational diabetes are as follows:
- Fasting test
- With glucose load of 100 g, result of 95 mg/dL (5.3 mmol/L)
- With glucose load of 75 g, result of 95 mg/dL (5.3 mmol/L)
- One-hour test
- With glucose load of 100 g, result of 180 mg/dL (10 mmol/L)
- With glucose load of 75 g, result of 180 mg/dL (10 mmol/L)
- Two-hour test
- With glucose load of 100 g, result of 155 mg/dL (8.6 mmol/L)
- With glucose load of 75 g, result of 155 mg/dL (8.6 mmol/L)
- Three-hour test – With glucose load of 100 g, result of 140 mg/dL (7.8 mmol/L)
- Fasting test
- Screening for GDM during pregnancy is recommended because less than 20% of women with significant glucose intolerance during pregnancy exhibit glucosuria or other symptoms during pregnancy. However, whether universal screening of all pregnant women or targeted screening of patients with risk factors is most efficacious continues to be controversial. At present, both methods (universal and selective screening) are used in reputable centers. In areas in which the prevalence of insulin resistance is 5% or higher (eg, the southwestern and southeastern United States), universal screening is recommended.
- First-trimester screening should be performed on patients with the risk factors noted above during the first trimester in order to identify those with occult type 2 diabetes. In 1995 when Moses et al assessed the prevalence of GDM in patients with various risk factors, GDM was diagnosed in 6.7% of the women overall, in 8.5% of the women aged 30 years, in 12.3% of the women with a preconception BMI of 30, and in 11.6% of women with a family history of diabetes in a first-degree relative. A combination of one or all of these risk factors predicted GDM in 61% cases. GDM was present in 4.8% of the women without risk factors. Screen patients with any of the following risk factors for GDM at the first prenatal visit.
- Maternal age older than 35 years
- Previous infant weighing less than 4000 g
- Previous unexplained fetal demise
- Previous pregnancy with GDM
- Strong immediate family history of type 2 diabetes mellitus or GDM
- Obesity (>90 kg)
- Fasting glucose value greater than 140 mg/dL (7.8 mmol/L) or random glucose value greater than 200 mg/dL (11.1 mmol/L)
- For third-trimester screening, patients with risk factors who have negative test results in the first trimester should be retested at 26-28 weeks’ gestation. Because the insulin resistance that causes hyperglycemia becomes increasingly prevalent as the third trimester progresses, the condition may be missed during early testing on patients who will become glucose intolerant later. However, performing the test too late in the third trimester abbreviates the time in which metabolic intervention can be instituted. For this reason, glucose tolerance testing in all patients is typically performed at 26-28 weeks’ gestation.
- Patients with a single abnormal value on a 3-hour glucose tolerance test are likely to exhibit some degree of glucose intolerance. When left untreated, these patients are at higher risk for macrosomia and neonatal morbidity. Consequently, patients with a single abnormal value should be followed appropriately with a second screening.
- Whether administered at 12 or 26 weeks’ gestation, the glucose challenge test can be performed without regard to recent food intake (ie, nonfasting state). Indeed, according to Coustan et al in 1986, results from tests performed in fasting subjects are more likely to be falsely elevated than results from tests conducted between meals.
DIFFERENTIALS
Acute Abdomen and Pregnancy
Acute Renal Failure
Acute Respiratory Distress Syndrome
Acute Tubular Necrosis
Appendicitis
Autoimmune Thyroid Disease and Pregnancy
Cholecystitis
Cholelithiasis
Chronic Renal Failure
Diabetes Mellitus, Type 1
Diabetes Mellitus, Type 2
Diabetic Foot Infections
Diabetic Ketoacidosis
Diabetic Nephropathy
Diabetic Ulcers
Early Pregnancy Loss
Fetal Growth Restriction
Hypertension
Hypoglycemia
Pulmonary Edema, Cardiogenic
WORKUP
Lab Studies
- Repeat 24-hour urine studies in women with elevated creatinine value in first trimester or 24-hour protein or creatinine clearance less than 100 mL/min
- Repeat HbA1C
- Blood sugar levels from capillary device 4-7 times daily in all women with diabetes
- Repeat 24-hour urine studies
- Blood urea nitrogen and creatinine
- Liver function tests
- Uric acid
- CBC count with platelets
- Assessment of fetal well-being with nonstress test, amniotic fluid index, fetal growth, and Doppler examination of the umbilical cord and middle cerebral artery
Imaging Studies
- First trimester – Ultrasonogram (crown-rump length) for dating and viability
- Second trimester
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- Detailed anatomy ultrasonogram at 18-20 weeks’ gestation
- Fetal echocardiogram if HbA1C value was elevated in first trimester
- Third trimester
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- Growth ultrasonogram to assess fetal size every 4-6 weeks from 26-36 weeks’ gestation in women with overt preexisting diabetes
- Growth ultrasonogram for fetal size at least once at 36-37 weeks’ gestation for women with GDM (Consider performing this study more frequently if macrosomia is suggested.)
Other Tests
- First trimester – Ophthalmologic evaluation
Procedures
- Third trimester – Amniocentesis for fetal lung profile if delivery is contemplated prior to 39 weeks’ gestation
TREATMENT
Medical Care
- Perform a thorough assessment of cardiovascular, renal, and ophthalmologic status.
- Institute a regimen of frequent and regular monitoring of both preprandial and postprandial capillary glucose levels.
- Whether the target glucose levels to be maintained before and during a diabetic pregnancy should be designed to limit macrosomia or to closely mimic nondiabetic pregnancy profiles remains controversial. As reported by Jovanovic-Peterson et al in 1991, the American Diabetes Association currently recommends the following, based on evidence from the DIEP study, to limit fetal macrosomia:
- Fasting whole blood glucose level less than 95 mg/dL (5.3 mmol/L)
- Fasting plasma glucose level less than 105 mg/dL (5.8 mmol/L)
- One-hour postprandial whole blood glucose level of less than 140 mg/dL (7.8 mmol/L)
- One-hour postprandial plasma glucose less than 155 mg/dL (8.6 mmol/L)
- Alternatively, the American Diabetes Association (also based on the DIEP study) recommends the following:
- Fasting whole blood glucose level less than 95 mg/dL (5.3 mmol/L)
- Fasting plasma glucose level less than 105 mg/dL (5.8 mmol/L)
- Two-hour postprandial whole blood glucose level less than 120 mg/dL (6.7 mmol/L)
- Two-hour postprandial plasma glucose level less than 130 mg/dL (7.2 mmol/L)
- The insulin regimen should result in a smooth glucose profile throughout the day, with no hypoglycemic reactions between meals or at night. Initiate the regimen early enough before pregnancy so that the glycohemoglobin level is lowered into the reference range for at least 3 months before conception.
- Patients should take a prenatal vitamin containing at least 1 mg/d folic acid for at least 3 months prior to conception to minimize the risk of neural tube defects in the fetus.
- The development of family, financial, and personal resources necessary to achieve successful pregnancy is important. Pay particular attention to support systems that permit extended bed rest in the third trimester if necessary.
- In many perinatal centers, diabetes-in-pregnancy programs focus on outreach to nonpregnant reproductive-aged women with diabetes in order to minimize the morbidity attendant to poor periconceptional control.
- Urge nonpregnant patients to continue avoidance of pregnancy until their HbA1C value is in within the reference range (less than 6.5%).
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Dietary therapy
- The goal of dietary therapy is to avoid single large meals and foods with a large percentage of simple carbohydrates. A total of 6 feedings per day is preferred, with 3 major meals and 3 snacks to limit the amount of energy intake presented to the bloodstream at any interval. Examples include foods with complex carbohydrates and cellulose, such as whole grain breads and legumes.
- According to the American Diabetes Association report from 2002, carbohydrates should account for no more than 50% of the diet, with protein and fats equally accounting for the remainder. However, Major et al reported in 1998 that moderate restriction of carbohydrates to 35-40% has been shown to decrease maternal glucose levels and improve maternal and fetal outcomes.
- Nutritional therapy should be supervised by a trained professional, ideally a registered dietitian, with formal dietary assessment and counseling provided at several points. For women who are obese (BMI >30 kg/m2), a 30-33% energy restriction (to £105 kJ/kg/d [25 kcal/kg/d] actual weight) has been shown to reduce hyperglycemia and plasma triglyceride levels with no increase in ketonuria.
- Glucose monitoring
- The availability of capillary, glucose, and chemical test strips has revolutionized the management of diabetes, and these should now be considered the standard of care for pregnancy monitoring. The discipline of measuring and recording blood glucose levels prior to and after meals clearly has a positive effect on improving glycemic control.
- Individualize the frequency and timing of home glucose monitoring. A typical schedule involves capillary glucose checks upon awakening in the morning, 1 hour after breakfast, before and after lunch, before dinner, and at bedtime. Place emphasis on gaining and sustaining compliance with the target glucose levels mentioned above. Meticulous glycemic control requires attention to both preprandial and postprandial glucose levels.
- Insulin therapy
- The goal of insulin therapy during pregnancy is to achieve glucose profiles similar to those of nondiabetic pregnant women. Given that healthy pregnant women maintain their postprandial blood sugar excursions within a relatively narrow range (70-120 mg/dL), the task of reproducing this profile requires meticulous daily attention by both the patient and physician.
- As pregnancy progresses, the increasing fetal demand for glucose fasting and the progressive lowering of fasting and between-meal blood sugar levels increases the risk of symptomatic hypoglycemia. Upward adjustment of short-acting insulin to control postprandial glucose surges within the target band only exacerbates the tendency to interprandial hypoglycemia. Thus, any insulin regimen for pregnant women requires combinations and timing of insulin injections quite different from those that are effective in the nonpregnant state. Further, the regimens must be continually modified as the patient progresses from the first to the third trimester and insulin resistance rises. Strive to stay ahead of the rising need for insulin, and increase insulin dosages preemptively.
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Unique pathophysiological features
- Women with GDM present particular challenges to the clinician because they have their metabolic disorder for a limited time and may not appreciate the potential risks to their fetus (ie, macrosomia, hypoglycemia, poor neonatal transition). For this reason, early and thorough education about the effects of their disordered metabolism on fetal growth and oxygenation is necessary.
- Once the patient understands the benefits of maintaining excellent glucose control for approximately 10 weeks, compliance markedly improves.
- Dietary therapy
- Metabolic management of a patient with GDM is focused on dietary control, regular home glucose monitoring, and judicious use of insulin therapy.
- Most patients with GDM diagnosed in the third trimester can maintain 1-hour postprandial blood glucose levels less than 130 mg/dL via diet manipulation alone (ie, multiple, small, nonglycemic meals and increased exercise).
- Glucose monitoring
- A home glucose monitor is essential to assist the patient in choosing the types and timing of food ingestion. For the first 1-2 weeks, the patient should perform capillary glucose checks upon awakening (fasting) and 1 hour after each major meal. Midmorning, midafternoon, and bedtime snacks are essential to blunt the glucose surge occurring after meals.
- Once the patient has demonstrated success in controlling postprandial glucose with diet, the occurrence of abnormal fasting levels is exceedingly rare and the morning checks can be discontinued. Fasting checks are reinstituted if any postprandial glucose levels are abnormal.
- Insulin therapy
- Clinicians and GDM patients may be reluctant to start insulin therapy, but this intervention may be key in achieving a good outcome.
- Recent research from a study in which randomized subjects with GDM whose fetuses had abdominal circumferences above the 75th percentile either dieted or took twice-daily insulin therapy suggests that the earlier insulin therapy is started, the better the outcome. Although the gestational age at delivery was similar in insulin- and diet-treated groups, birth weights (3647 ± 67 g vs 3878 ± 84 g; P less than .02), the prevalence of infants who were large for gestational age (13% vs 45%, P less than .02), and neonatal skin-fold measurements at 3 sites (P less than .005) were reduced in the insulin-treated group.
- In a historical control study of early aggressive insulin treatment of patients with GDM, fasting or postprandial glucose values exceeded 120 mg/dL when the patient exceeded 90 mg/dL. In 1992, the prevalence of macrosomia decreased from 18% to 7% and the cesarean delivery rate dropped from 30% to 20%. A policy of insulin treatment was estimated to save more than $800,000 yearly in one county.
- Determine the insulin regimen based on the patient’s individual glucose profile. Typically, one to several postprandial glucose levels become consistently above target because the patient’s ability to compensate for rising insulin resistance with diet becomes inadequate. When more than 20% of postprandial blood sugar values exceed 130 mg/dL, administering rapid-acting lispro or aspart insulin injections (4-8 U to start) before meals is usually successful in controlling glucose overshoots. If more than 10 U of short-acting insulin is needed prior to the noon meal, adding an 6-12 U dose of neutral protamine Hagedorn (NPH) insulin prior to breakfast helps achieve smoother control. When more than 10% of fasting glucose levels rise above 95 mg/dL, a starting dose of 6-8 U of NPH insulin at bedtime can be used.
- The doses are scaled up as necessary once or twice weekly to keep glucose levels on target.
- Insulin pump
- In a select group of patients, use of an insulin pump may improve glycemic control while enhancing patient convenience. These devices can be programmed to infuse varying basal and bolus levels of insulin that change smoothly even while the patient sleeps or is otherwise preoccupied.
- Although an early study cited improved control, it also noted at least one major complication (eg, diabetic ketoacidosis, infection, hypoglycemic coma) in 42% of patients. Subsequent studies have been more optimistic, reporting more uniformly successful outcomes.
- Oral hypoglycemic agents
- Interest in the second-generation oral sulfonylurea, glyburide, has been rekindled following recent reports of its effectiveness and safety.
- Glyburide minimally transports across the human placenta. This is probably largely due to the high plasma protein binding coupled with a short half-life.
- The results of a randomized trial comparing glyburide with insulin were published in 2000, studying 404 pregnancies. At the conclusion of this trial, no difference was noted in the mean maternal blood glucose level, the percentage of infants who were large for gestational age, the birthweight, or neonatal complications between the groups. Only 4% of the glyburide study arm required the addition of insulin to achieve glucose control.
- Glyburide should not be used in the first trimester because its effects on the embryo, if any, are unknown.
-
Prenatal obstetric management
- The goals of management of third-trimester pregnancies in women with diabetes are to prevent stillbirth and asphyxia while minimizing maternal and fetal morbidity associated with delivery.
- Monitoring fetal growth is essential to select the proper timing and route of delivery. This is accomplished by frequent testing for fetal well-being and serial ultrasound examinations for trending of fetal size.
- Periodic fetal biophysical testing
- Various fetal biophysical tests are available to the clinician to ensure that the fetus is well oxygenated, including fetal heart rate testing, fetal movement assessment, ultrasound biophysical scoring, and fetal umbilical Doppler studies.
- If applied properly, most of these can be used with confidence to provide assurance of fetal well-being while awaiting fetal maturity.
Table 2. Biophysical Tests of Fetal Well-Being for Diabetic Pregnancy
Test Frequency Reassuring Result Comment Fetal movement counting Every night from 28 wk 10 movements in less than 60 min Performed in all patients Nonstress test Twice weekly 2 heart rate accelerations in 20 min Begin at 28-34 wk with type 1 diabetes, and begin at 36 wk in diet-controlled GDM. Contraction stress test Weekly No heart rate decelerations in response to 3 contractions in 10 min Same as for nonstress test Ultrasound biophysical profile Weekly Score of 8 in 30 min 3 movements = 2 1 flexion = 2
30 seconds of breathing = 2
2 cm of amniotic fluid = 2
- Initiate testing early enough to avoid significant stillbirth but not so early that a high rate of false-positive test results is encountered. In patients with poor glycemic control or significant hypertension, begin formal biophysical testing as early as 28 weeks’ gestation. In patients who are at lower risk, most centers begin formal fetal testing by 34 weeks’ gestation. Fetal movement counting is performed in all pregnancies from 28 weeks onward.
- Assessing fetal growth
- Monitoring fetal growth continues to be a challenging and imprecise process. Although the tools available now (eg, serial plotting of fetal growth parameters) are superior to those used previously for clinical estimations, accuracy is still only plus or minus 15%.
- In 1994, Tongsong et al reported on several polynomial formulas using combinations of head, abdominal, and limb measurements that were developed to predict the weight of a macrosomic fetus from ultrasound parameters. Unfortunately, in these formulas, small errors in individual measurements of the head, abdomen, and femur are typically compounded.
- In obese fetuses, the inaccuracies are further magnified. In 1992, Bernstein and Catalano reported significant correlation between the degree of error in the ultrasound-based estimation of fetal weight and the percent of body fat on the fetus (r = 0.28, P less than .05). Perhaps this is why no single formula has proven to be adequate in identifying a macrosomic fetus with certainty.
- Despite problems with accuracy, ultrasound-based estimations of fetal size have become the standard of care. Estimate fetal size once or twice at least 3 weeks apart in order to establish a trend. Time the last examination to be at 36-37 weeks’ gestation or as close to the planned delivery date as possible.
- Select the timing of delivery to minimize morbidity for the mother and fetus. Delaying delivery to as near as possible to the expected date of confinement helps maximize cervical maturity and improves the chances of spontaneous labor and vaginal delivery. However, the risks of advancing fetal macrosomia, birth injury, and in utero demise increase as the due date approaches
- Although delivery as early as 37 weeks’ gestation might reduce the risk of shoulder dystocia, a coinciding increase in the incidence of failed labor inductions and poor neonatal pulmonary status would also occur. Because fetal growth from 37 weeks’ gestation onward may be 100-150 g/wk, the reduction in net fetal weight and the risk of shoulder dystocia by inducing labor 2 weeks early may theoretically improve outcome
- In 1993, when Kjos et al compared the outcomes associated with labor induction in patients with gestational diabetes at 38 weeks’ gestation versus expectant management with fetal testing, they found that expectant management increased the gestational age at delivery by 1 week, but the cesarean delivery rate was not significantly different. However, the prevalence of infants who were macrosomic in the expectantly managed group (23%) was significantly greater than those in the active induction group (10%). This suggests that routine induction for women with diabetes on or before 39 weeks’ gestation does not increase the risk of cesarean delivery and may reduce the risk of macrosomia
- If the fetus is not macrosomic and results from biophysical testing are reassuring, the obstetrician can await spontaneous labor. In patients with GDM and superb glycemic control, continued fetal testing and expectant management can be considered until 41 weeks’ gestation. In a fetus with an abdominal circumference measurably larger than the head circumference or with an estimated fetal weight of greater than 4000 g, consider induction. After 40 or more weeks’ gestation, the benefits of continued conservative management are likely to be less than the danger of fetal compromise. Induction of labor before 41 weeks’ gestation in pregnant women with diabetes, regardless of the readiness of the cervix, is prudent
- Thus, an optimal time for delivery of most diabetic pregnancies is typically on or after the 39th week. Only deliver a patient with diabetes before 39 weeks’ gestation without documented fetal lung maturity for compelling maternal or fetal indications. For elective induction, fetal lung maturity should be verified via amniocentesis.
- Because the risk of shoulder dystocia and fetal injury in labor is increased 3-fold in diabetic pregnancy, elective cesarean delivery should be considered if the fetus is suspected to be significantly obese. The American College of Obstetricians and Gynecologists recommends offering diabetic patients cesarean delivery if the fetal weight is estimated to be 4500 g or more.
MEDICATION
Clinicians and GDM patients are reluctant to start insulin therapy, but it is key to achieving a good outcome. Research suggests that early intervention with insulin or glyburide is superior to diet therapy alone. Determine the choice of insulin and regimen based on the patient’s individual glucose profile. Postprandial glucose levels become consistently above the target with diet therapy. When more than 20% of postprandial blood glucose levels exceed 130 mg/dL, administer lispro insulin (4-8 U SC initially) before meals. If more than 10 U of regular insulin is needed before the noon meal, adding 8-12 U of NPH insulin before breakfast helps achieve control. When more than 10% of fasting glucose levels exceed 95 mg/dL, initiate 6-8 U NPH insulin hs. Titrate doses prn according to blood glucose levels.
Drug Category: Insulins
Essential in regulating carbohydrate, protein, and fat metabolism. Primarily affect carbohydrate homoeostasis by binding to specific cell-surface receptors on insulin-sensitive tissues (eg, liver, muscles, adipose tissue).
| Drug Name | Insulin (Novolin, Humulin, Humalog, Novolog, Lente, Iletin, NPH) |
|---|---|
| Description | DOC for all types of diabetes mellitus during pregnancy. Stimulates proper use of glucose by cells and reduces blood glucose levels. |
| Adult Dose | 0.5-1 U/kg/d SC in divided doses; base dose on IBW; titrate dose to maintain a premeal and bedtime glucose level of 80-110 mg/dL; combine short- and longer-acting insulin to maintain blood glucose within target |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity; hypoglycemia |
| Interactions | Medications that may decrease hypoglycemic effects include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin Medications that may increase hypoglycemic effects include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone |
| Pregnancy | B – Usually safe but benefits must outweigh the risks. |
| Precautions | Hyperthyroidism may increase renal clearance, and more may be needed to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments may be necessary in patients diagnosed with renal and hepatic dysfunction |
| Drug Name | Glyburide (Micronase, DiaBeta, Glynase, PresTab) |
|---|---|
| Description | Appears to acutely lower blood glucose by stimulating release of insulin from pancreas, an effect dependent on functioning beta cells in pancreatic islets. Mechanism by which DiaBeta lowers blood glucose during long-term administration not clearly established. |
| Adult Dose | No fixed dosage; fasting blood glucose must be measured periodically to determine minimum effective dose 2.5-5 mg/d PO, with breakfast or first may meal, is usual starting dose; not to exceed 20 mg/d PO; patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg/d PO |
| Pediatric Dose | Not established. |
| Contraindications | Documented hypersensitivity; diabetic ketoacidosis, with or without coma; type 1 diabetes mellitus |
| Interactions | Clofibrate, fenfluramine, histamine H2 antagonists, androgens, azole antifungals, anticoagulants, chloramphenicol, fluconazole, gemfibrozil, magnesium salts, methyldopa, MAOIs, probenecid, salicylates, sulfinpyrazone, urinary acidifiers, NSAIDs, and sulfonamides may enhance hypoglycemic effects; closely observe patient for hypoglycemia; when such drugs are withdrawn, closely observe patient for loss of control Possible interaction between glyburide and fluoroquinolone antibiotics has been reported, resulting in potentiation of hypoglycemic action of glyburide; mechanism not known Possible interactions between glyburide and coumarin derivatives have been reported that may either potentiate or weaken effects of coumarin derivatives; mechanism not known Nicotinic acid, oral contraceptives, isoniazid, hydantoins, estrogens, diazoxide, corticosteroids, cholestyramine, beta-blockers, calcium channel blockers, phenothiazines, rifampin, thiazide diuretics, urinary alkalinizers, and sympathomimetics may decrease hypoglycemic effects; closely monitor patient for loss of control; when withdrawn, closely observe patient for hypoglycemia Potential interaction between PO miconazole and PO hypoglycemic agents leading to severe hypoglycemia has been reported; whether interaction also occurs with IV, topical, or vaginal preparations of miconazole is not known May increase effects of digitalis glycosides |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Caution in hepatic and renal impairment; cardiovascular disorders may occur; risk factors include elderly age, malnutrition, irregular eating, impaired renal function, and possibly hepatic dysfunction (if prolonged or recurrent, hospital admission should be strongly considered); may cause rash; nausea, vomiting, leukopenia, agranulocytosis, aplastic anemia (very rare), intrahepatic cholestasis (very rare), disulfiram reaction, flushing, headache, nausea, and SIADH causing hyponatremia |
FOLLOW-UP
Further Inpatient Care
- Maintenance of intrapartum metabolic homeostasis optimizes postnatal infant transition by reducing neonatal hyperinsulinemia and subsequent hypoglycemia.
- The use of a combined insulin and glucose infusion during labor to maintain maternal blood sugars in a narrow range (80-110 mg/dL) during labor is a common and clinically efficient practice. Typical infusion rates are 5% dextrose in Ringer lactate solution at 100 mL/h and regular insulin at 0.5-1.0 U/h. Capillary blood sugar levels are monitored hourly in these patients.
- For patients with diet-controlled GDM or mild type 2 diabetes, avoiding dextrose in all intravenous fluids normally maintains excellent blood glucose control. After 1-2 hours of monitoring, typically no further assessments of capillary blood sugar are necessary.
- The most critical metabolic problem affecting IDMs is hypoglycemia. Unmonitored and uncorrected hypoglycemia can lead to neonatal seizures, brain damage, and death. The strongest predictor of neonatal hypoglycemia is the maternal mean blood glucose level during labor.
- IDMs also appear to have disorders of both catecholamine and glucagon metabolism and have a diminished capability to mount normal compensatory responses to hypoglycemia.
- Thus, current recommendations specify frequent blood glucose checks and early oral feeding when possible (ideally from the breast), with infusion of intravenous glucose if oral measures prove insufficient. Most neonatologists maintain strict monitoring of the glucose levels of newborn IDMs for at least 4-6 hours (frequently 24 h), often necessitating admission to a newborn special care unit.
- Current evidence indicates that with proper encouragement, sustained breastfeeding is possible for a significant proportion of patients with overt diabetes. In fact, recent evidence indicates that breastfed infants have a much lower risk of developing diabetes than those exposed to cow’s milk proteins.
- Recent studies of breastfeeding women with diabetes indicate that lactation, even for a short duration, also has a beneficial effect on overall maternal glucose and lipid metabolism. For postpartum women who had GDM during their pregnancies, breastfeeding may offer a practical low-cost intervention that helps reduce or delay the risk of subsequent diabetes in women with prior GDM.
- In 1995, Webster et al longitudinally compared breastfeeding habits among women with diabetes and without diabetes. At discharge, 63% of IDMs and 78% of mothers without an IDM were breastfeeding. At 8 weeks, the proportions of each were nearly identical (58% and 56%, respectively). At 3 months, 47% of mothers with diabetes and 33% mothers without diabetes continued to breastfeed.
- Intensive management of women with glucose intolerance during pregnancy has resulted in markedly improved outcomes in recent years. Despite these advances, care of the infant of a mother with diabetes continues to require vigilance and meticulous monitoring with a full understanding of the quality of glycemic milieu in which it developed.
Deterrence/Prevention
- Prevention of gestational diabetes is an attractive concept, but no progress has been made, despite attempts in smaller studies. Because body fat and diet contribute to the risk of GDM, patients who lose weight prior to pregnancy and follow an appropriate diet may lower their risk of GDM. However, the pregnancy hormones impose such a high degree of insulin resistance that in very susceptible individuals, even marked weight loss and attention to diet are not likely to be successful.
Patient Education
- Education is the cornerstone of effective metabolic management of the patient with diabetes during pregnancy. The American Diabetes Association offers educational curricula specific to each type of diabetes encountered during pregnancy (type 1 diabetes mellitus, type 2 diabetes mellitus, GDM), specifically organized around each phase of pregnancy. This information can be transmitted to the patient by office staff and labor/delivery nurses. However, specially trained and certified nurses and dietitians (ie, certified diabetes educators) are the most effective in this regard. Most large programs treating women with diabetes during pregnancy assist the patient with a staff that includes a registered nurse, a certified diabetes educator, a dietitian knowledgeable about pregnancy, and a social worker. Successful management of diabetic pregnancy is optimized when this type of team care is available.
- The diabetes-in-pregnancy team is also able to help the patient during the puerperal period with the challenges of lactation, diet, sleep, and glycemic control. This team is also most effective in providing a smooth return to nonpregnant metabolic management.
- For excellent patient education resources, visit eMedicine’s Diabetes Center or Pregnancy and Reproduction Center.
MISCELLANEOUS
Medical/Legal Pitfalls
- Structural defects occur in 3-8% of offspring of diabetic pregnancy, but this rate drops 3- to 4-fold if excellent glycemic control is maintained during the period of embryogenesis.
- Thus, it is incumbent upon the medical provider, when discussing pregnancy plans with a woman with preexisting diabetes, to mention the preventability of these birth defects with good periconceptional glycemic control.
- The patient should be advised to use a reliable method of contraception until she has achieved a preconceptional HbA1C level within the reference range. This counseling should be recorded in the patient’s medical record.
- Permanent palsy of the arm and hand after a difficult delivery of an obese fetus usually leads to litigation and, in some cases, large judgments. Although current scientific data establishing the foreseeability and preventability of these injuries remain inadequate, defending obviously high-risk cases can be difficult.
- The obstetrician managing the patient’s third-trimester prenatal care and labor may be judged at fault should an injury occur during delivery if an ultrasound suggests that fetal weight exceeds 10 lb, labor proceeds slowly, or a difficult forceps or vacuum procedure is necessary to deliver the fetal head. Thus, obtaining an ultrasound-based estimation of fetal weight in the last 2-3 weeks prior to delivery and offering cesarean delivery to a patient with an estimated fetal weight of more than 4500 g or a labor course that is protracted such that she is unable to expel the fetal head spontaneously after 2-3 hours of pushing effort are prudent.
Add comment February 1, 2007
Food Allergies
Synonyms and related keywords: adverse immunologic reactions to foods, allergic reactions to foods, food hypersensitivity, food intolerance, adverse food reactions, lactose intolerance, bacterial food poisoning, peanut allergy, protein-induced enterocolitis syndrome, food hypersensitivity, allergen exposure, anaphylactic reactions, food-induced anaphylactic reaction, oral allergy syndrome, dietary protein enterocolitis, food-induced asthma, food-induced pulmonary hemosiderosis, Heiner syndrome, egg allergy, milk allergy, peanut allergy, soy allergy, fish allergy, shellfish allergy, tree nut allergy, wheat allergy
INTRODUCTION
Background Adverse food reactions can be broadly classified into 2 categories. The first category consists of immunologically-mediated adverse reactions to foods; these reactions are unrelated to any physiologic effect of the food or food additive. These reactions include disorders mediated by immunoglobulin E (IgE) antibodies (eg, IgE-mediated reaction to peanuts), which begin during or soon after exposure to the food, and others resulting from non–IgE-mediated mechanisms (eg, non–IgE-mediated reactions such as protein-induced enterocolitis syndrome), which generally take several hours to evolve. The second category is food intolerance. These reactions include any adverse physiologic response to a food or food additive that is not immunologically mediated (eg, lactose intolerance, bacterial food poisoning). Allergic reactions to food are IgE-mediated or non–IgE-mediated. Immune responses mediated by specific IgE antibodies are the most widely recognized mechanism of food hypersensitivity. Patients with atopy produce IgE antibodies to specific epitopes of the food allergen. These antibodies bind to high-affinity IgE receptors on circulating basophils and tissue mast cells present in the skin, gastrointestinal tract, and respiratory tract. Subsequent allergen exposure binds two adjacent IgE antibodies, resulting in receptor cross-linking and intracellular signaling that initiates the release of numerous mediators, including histamine, prostaglandins, leukotrienes, chemotactic factors, and cytokines. The effects of these mediators on surrounding tissues result in vasodilatation, smooth muscle contraction, and mucus secretion, which, in turn, are responsible for the spectrum of clinical symptoms observed during allergic reactions to food. Food allergens are typically water-soluble glycoproteins resistant to heating and proteolysis with molecular weights of 10-70 kd. These characteristics facilitate the absorption of these allergens across mucosal surfaces. Numerous food allergens are purified and well-characterized, such as peanut Ara h1, Ara h2, and Ara h3; chicken egg white Gal d1, Gal d2, and Gal d3; soybean-Gly m1; fish-Gad c1; and shrimp-Pen a1. Closely related foods frequently contain allergens that cross-react immunologically (ie, lead to the generation of specific IgE antibodies detectable by skin prick or in vitro testing) but less frequently cross-react clinically. Finally, cross-reactive allergens have been identified among certain foods and airborne pollens (see Pollen-food allergy syndrome). Conserved homologous proteins shared by pollens and foods likely account for this cross-reactivity. General surveys report that as many as 25-30% of households consider at least 1 family member to have a food allergy. This high rate is not supported by controlled studies in which food challenges are used to confirm patient histories. The actual prevalence of food allergies is estimated to be approximately 6% in infants and children and 3.7 % in adults. Several published prospective investigations have determined the prevalence of certain common food allergies in children (eg, cow milk, 2.5%; eggs, 1.3%; peanuts, 0.8%; wheat, 0.4%; soy, 0.4%). Prospective studies from several different countries indicate that approximately 2.5% of newborn infants experience hypersensitivity reactions to cow milk in the first year of life. A hypersensitivity reaction to peanuts occurs in approximately 0.5% of children in the United Kingdom. Surveys from the United Kingdom indicate that 1.4-1.8% of adults experience adverse food reactions and 0.01-0.23% of adults are affected by adverse reactions to food additives. Studies from the Netherlands demonstrate that approximately 2% of the adult Dutch population is affected.
Pathophysiology
Frequency
United States
International
Mortality/Morbidity
Race
Sex
Age
History
- Develop a complete list of all foods suspected to cause symptoms.
- Discuss the manner of preparation of the food (cooked, raw, added spices or other ingredients).
- Determine the minimum quantity of food exposure required to cause the symptoms.
- Determine the reproducibility of symptoms upon exposure to the food.
- Obtain a thorough description of each reaction, including the following:
- The route of exposure (ingestion, skin contact, inhalation, injection) and dose
- The timing of the onset of symptoms in relation to food exposure
- All observed symptoms and each one’s severity
- The duration of the reaction
- The treatment provided and the clinical response to treatment
- The most recent reaction
- Inquire about a personal or family history of other allergic disease.
- These are the most common clinical manifestations of an allergic reaction to a food or food additive.
- Symptoms range from acute urticaria (most common) to flushing to angioedema to exacerbations of atopic dermatitis.
- Food allergy is rarely the cause of chronic urticaria or angioedema.
- Significant controversy surrounds the role of food allergy in the pathogenesis of atopic dermatitis. Studies show that of patients with moderate chronic atopic dermatitis, 35-40% have IgE-mediated food allergy contributing to their skin disease.
- Both food-specific IgE-mediated and cellular mechanisms appear responsible for chronic eczematous inflammation.
- Removal of a specific food allergen leads to reduction or resolution of clinical symptoms in affected patients; reintroduction of the food exacerbates the atopic dermatitis. Reintroduction of a suspected food allergen should be performed under medical supervision because, in some instances, initial reintroduction of the food after a period of dietary elimination has resulted in more significant symptoms than were observed when the food was regularly ingested.
- Prophylactic studies show that avoiding particular foods (eg, cow milk, eggs, peanuts) helps delay the onset of atopic dermatitis.
- This is an unusual form of non-IgE cell-mediated hypersensitivity related to celiac disease. It manifests clinically with a chronic and intensely pruritic rash with a symmetrical distribution that has some similarities to the typical rash distribution of atopic dermatitis.
- Elimination of gluten from the diet usually leads to resolution of skin symptoms.
- These food allergy reactions include immediate hypersensitivity reactions and the pollen-food allergy syndrome (oral allergy syndrome).
- Specific gastrointestinal symptoms include nausea, vomiting, abdominal pain, and cramping. Diarrhea is found less frequently.
- Patients with this syndrome develop itching or tingling of the lips, tongue, palate, and throat following the ingestion of certain foods. In addition, edema of the lips, tongue, and uvula and a sensation of tightness in the throat may be observed. In fewer than 3% of cases, symptoms progress to more systemic reactions, such as laryngeal edema or hypotension.
- This syndrome is caused by cross-reactivity between certain pollen and food allergens. For example, individuals with ragweed allergy may experience oropharyngeal symptoms following the ingestion of bananas or melons, and patients with birch pollen allergy may experience these symptoms following the ingestion of raw carrots, celery, potato, apple, hazelnut, or kiwi.
- Typical symptoms include postprandial nausea, abdominal pain, and a sensation of early satiety.
- One of the hallmarks in children is weight loss or failure to thrive.
- CBC count and differential findings may show eosinophilia in approximately 50% of patients; however, this is not diagnostic. Typically, endoscopy and biopsy must be performed in order to establish the presence of eosinophils in the intestinal wall. While a dense eosinophil infiltrate may be seen anywhere from the lower esophagus throughout the large bowel, involvement is patchy and variable.
- Ultimately, an elemental or oligoantigenic diet is necessary to aid in the diagnosis.
- If the patient does not respond to the elemental diet, a trial of systemic oral corticosteroids can be useful for resolving the clinical symptoms.
- Dietary protein enterocolitis is a syndrome that typically manifests in the first few months of life in a child who has severe projectile vomiting, diarrhea, and failure to thrive.
- Cow milk and soy protein formulas are usually responsible for these reactions, which occur 2 or more hours after food ingestion.
- Infants typically appear lethargic, wasted, and dehydrated. To establish the diagnosis, an oral challenge study must be performed.
- Upper respiratory reactions typically include nasal congestion, sneezing, nasal pruritus, or rhinorrhea. They are usually observed in conjunction with ocular, skin, or gastrointestinal symptoms.
- IgE-mediated pulmonary symptoms may include laryngeal edema, cough, or bronchospasm.
- The role of food allergy in the pathogenesis of asthma is a controversial area of investigation.
- At the National Jewish Center for Immunology and Respiratory Medicine, 67 of the 279 children (24%) with a history of food-induced asthma were documented to have a positive result after a blinded food challenge, which included wheezing. Interestingly, only 5 (2%) of these patients had wheezing as their only objective adverse symptom.
- In a related report, 320 children with atopic dermatitis undergoing blinded food challenges at Johns Hopkins Hospital were monitored for respiratory reactions. Overall, 34 of 205 (17%) children with positive results from food challenges developed wheezing as part of their reaction. Therefore, a conservative estimate is that 5-10% of patients with asthma have food-induced allergy symptoms.
- In a pediatric case-controlled study comparing 19 children who required ventilation for an exacerbation of asthma and 38 control subjects matched by sex, age, and ethnicity, coincident food allergy was found to be independently associated with life-threatening asthma.
- Wheezing as the only manifestation of an allergic reaction to food is rare.
- Children with atopic dermatitis, especially those with food reactions confirmed during blinded food challenges, appear to have a higher risk for developing food-induced asthma.
- The primary clinical effect is not acute bronchopulmonary obstruction, but chronic asthma symptoms or difficulty in controlling the asthma.
- This is a rare disorder characterized by recurrent episodes of pneumonia associated with pulmonary infiltrates, hemosiderosis, gastrointestinal blood loss, iron deficiency anemia, and failure to thrive in infants.
- While the precise immunologic mechanism is unknown, it is thought to be secondary to a non-IgE hypersensitivity process.
- Following the ingestion of food, severe anaphylactic reactions (ie, systemic allergic reactions), including death, can occur.
- Symptoms may include the following:
- Oropharyngeal pruritus
- Angioedema (eg, laryngeal edema)
- Urticaria
- Ocular injection, ocular pruritus, conjunctival edema, periocular swelling
- Nasal congestion, nasal pruritus, rhinorrhea, and sneezing
- Stridor
- Dysphonia
- Cough
- Dyspnea
- Wheezing, bronchospasm
- Nausea
- Emesis
- Abdominal pain
- Diarrhea
- A feeling of impending doom
- Cardiovascular collapse
- Risk factors for fatal reactions include the following:
- The presence of asthma, especially in patients with poorly controlled disease
- Previous episodes of anaphylaxis with the incriminated food
- Failure to recognize early symptoms of anaphylaxis
- Delay or lack of immediate use of emergency medications (eg, epinephrine, antihistamines)
Physical
- The physical examination findings are most useful for assessing overall nutritional status, growth parameters, and signs of other allergic disease, such as atopic dermatitis, allergic rhinitis, or asthma.
- Findings from a comprehensive physical examination can help rule out other conditions that may mimic food allergy.
Causes
- Any food protein can trigger an allergic response, and allergic reactions to a large number of foods have been documented; however, only a small group of foods account for most of these reactions.
- Eggs, milk, peanuts, soy, fish, shellfish, tree nuts, and wheat are the foods most often implicated in allergic reactions that have been confirmed in well-controlled blinded food challenges.
- Investigations of near-fatal or fatal anaphylactic reactions following food ingestion reveal that most are caused by peanuts, tree nuts, and shellfish.
DIFFERENTIALS
Anorexia Nervosa
Bulimia
Celiac Sprue
Clostridium Difficile Colitis
Constipation
Diverticulitis
Dumping Syndrome
Esophageal Motility Disorders
Esophageal Spasm
Esophageal Stricture
Esophagitis
Factitious Disorder
Food Poisoning
Gastritis, Acute
Gastritis, Chronic
Gastroenteritis, Bacterial
Gastroenteritis, Viral
Gastroesophageal Reflux Disease
Giardiasis
Hiatal Hernia
Inflammatory Bowel Disease
Intestinal Motility Disorders
Irritable Bowel Syndrome
Lactose Intolerance
Trichosporon Infections
Urethral Diverticula
Urticaria
VIPomas
Vocal Cord Dysfunction
Wasp Stings
Whipple Disease
WORKUP
Lab Studies
- Specific IgE antibodies to foods can be measured by in vitro laboratory methods (eg, IgE radioallergosorbent testing), which offers advantages when dermatographism, generalized dermatitis, or a clinical history of severe anaphylactic reactions to a given food limit skin testing.
- This form of testing provides information similar to prick skin tests, but it is more expensive and generally less specific.
- The CAP System fluorescent-enzyme immunoassay (FEIA) (Pharmacia Diagnostics, Uppsala, Sweden) provides a more quantitative method of determining allergen-specific IgE to food allergens.
- When compared with the outcome of well-controlled oral food challenges, results of the CAP system FEIA are generally similar to those of prick skin tests in predicting symptomatic food allergy.
- Quantitating food-specific IgE antibodies with this automated system can help identify patients who are highly likely to have allergic reactions (>95% probability).
- Published positive and negative predictive values using this system are available. These predictive values aid in making the diagnosis, thereby reducing the need for confirmatory food challenges in some patients.
- Currently, the predictive values of CAP System FEIA results are limited to several major food allergens (ie, egg, milk, peanut, fish).
-
The predictive values developed using the CAP System FEIA are useful in predicting the likelihood of a reaction but do not predict the severity of a reaction
Peripheral serum measurements of eosinophils or total IgE concentrations: Results from these tests support but do not confirm the diagnosis of food allergy. Likewise, normal values do not exclude diagnosis.
Other Tests
- Diet diary
- This consists of keeping a chronological record of all foods eaten and any associated adverse symptoms. It is an inexpensive endeavor that documents the frequency of symptoms and their occurrence in relationship to food ingestion. In addition, it encourages patients to focus on their diet.
- This record is occasionally helpful for identifying the food implicated in an adverse reaction; however, it is not usually diagnostic, especially when symptoms are delayed or infrequent.
- Occasionally, review of the diet diary reveals that the patient is not experiencing a reaction even when eating, as an ingredient in other foods, a significant amount of a food to which they were thought to be allergic.
- Elimination diet
- This is used in determining the diagnosis as well as in the treatment and prevention of food allergy.
- When used as a diagnostic tool, the elimination diet requires complete avoidance of suspected foods or groups of foods for a given time period (usually 7-14 d) while monitoring for an associated decrease in symptoms.
- Success depends on identifying the correct food allergen and completely eliminating it in all forms from the diet. These diets are increasingly difficult to develop and follow as more foods or foods that commonly occur in the diet are eliminated.
- Additional limitations of this method include potential effects of patient or physician biases, variable patient compliance, and the time-consuming nature of the endeavor.
- When the elimination diet is used as treatment, identified food allergens are removed from the diet indefinitely unless evidence exists that the food allergy has been outgrown.
- Skin testing
- Prick and puncture tests are the most common screening tests for food allergy and can even be performed on infants in the first few months of life. However, the reliability of the results depends on multiple factors, including use of the appropriate extracts and testing technique, accurate interpretation of the results, and avoidance of medications that might interfere with testing (eg, antihistamines).
- When used in conjunction with a standard criterion of interpretation and appropriate controls (eg, histamine: positive, saline: negative), these tests provide useful and reproducible clinical information in a short period (ie, 15-20 min) with minimal expense and negligible risk to the patient.
- This is a reliable method of excluding IgE-mediated food allergies. The negative predictive accuracy is greater than 95%; however, the positive predictive accuracy is generally less than 50%, which limits clinical interpretation of positive skin test results.
- Positive skin test results, in addition to the suggestion of clinical reactivity based on the history, must often be confirmed by an oral food challenge unless the patient has a thoroughly convincing history of significant food allergy.
- Intradermal skin testing
- The risk of inducing a systemic reaction with this type of testing is increased in comparison to the prick or puncture method; as a result, intradermal skin testing should be avoided.
- In addition, the results obtained by using this method are less specific compared to those obtained by using prick or puncture testing.
- Tests with uncertain diagnostic value: The diagnostic value of performing the following tests is not currently supported by objective scientific evidence:
- Results from food-specific immunoglobulin G (IgG) or IgG subclass antibody concentration testing have not been proven to be helpful with diagnosis.
- Testing for food antigen-antibody complexes has no proven diagnostic value.
- Performing leukocyte cytotoxic tests is not supported by objective scientific evidence.
- Results from subcutaneous provocation and neutralization testing have not been proven to be helpful for diagnosis.
- Kinesiology-based testing is not recommended because objective scientific evidence has indicated this type of testing does not aid in diagnosis.
Procedures
- Food challenge confirmation of food allergy
- This includes properly conducted elimination of and subsequent oral challenge with foods suspected of causing allergic reactions based on the medical history, skin testing results, or in vitro testing results.
- Of these procedures, the double-blind placebo-controlled food challenge (DBPCFC) is the most reliable method to help diagnose and confirm food allergy and other adverse food reactions because it eliminates both patient and observer bias. However, in a clinical setting where minimal bias is suspected, open food challenges may be preferable because blinding of the food is often not required.
- Conduct any food challenge in a clinic or hospital setting with the personnel and equipment necessary to treat a systemic allergic reaction available at all times. Patients undergoing a food challenge should not be on beta-blocker medications or any medication that might interfere with the treatment of anaphylaxis. Obtain intravenous access in patients with history findings that indicate the potential for a systemic reaction.
- If the history of the patient suggests an anaphylactic reaction is possible following food ingestion, do not perform an oral food challenge.
- Open food challenge
- This test involves the patient ingesting the suspected food, prepared in its customary fashion (ie, the challenge food is not disguised in any way).
- Both the patient and the observer (eg, physician, nurse) are aware of the food being ingested.
- The open food challenge is best used in clinical practice when patient and physician bias is minimal.
- This type of challenge is typically used when the skin test results for the suspect food are negative or if a specific food reaction is unlikely.
- Whenever the results are equivocal, perform a blinded challenge.
- Patients with histories of a previous reaction should never perform an open food challenge at home, even if the chance they will develop severe symptoms is remote.
- Single blinded food challenge
- This challenge involves the patient ingesting the suspected food disguised in a challenge food so the patient is unaware of the contents.
- This type of challenge, which is suitable for clinical practice and some research investigations, is designed to reduce patient bias during the procedure. However, subjective attitudes regarding the outcome of the challenge cannot be completely eliminated.
- This test is also useful for screening patients for entry into studies in which the findings will be unequivocally confirmed by DBPCFC results.
- Double-blind placebo-controlled food challenge
- DBPCFC involves ingestion of the suspected food disguised in another food so that both the patient and observer are unaware of the contents of the challenge.
- This type of challenge is designed to reduce both patient and observer bias and subjective attitudes during the procedure.
- Always perform this challenge in a clinic or hospital setting.
- Consider this the criterion standard for diagnosing food allergy, especially in research investigations. Currently, it is the only completely objective method for determining the validity of the history of an adverse reaction to a food.
- Do not perform a challenge if the patient has a clearly convincing history of a severe life-threatening anaphylactic reaction following the isolated ingestion of a specific food.
TREATMENT
Medical Care
- Education is of paramount importance for patients with food allergies.
- Patients can obtain useful resource information by contacting the Food Allergy and Anaphylaxis Network (toll-free phone number is 800-929-4040) and the International Food Information Council (phone number is 202-296-6540 and email address is foodinfo@ific.org).
- Remember that appropriate restriction and complete avoidance of the relevant food allergen(s) is the only current effective therapy.
- Once a food allergy is diagnosed, strict elimination of the offending food allergen from the diet and avoidance of any contact with the food either by ingestion, skin contact, inhalation, or injection is necessary.
- Elimination and strict avoidance is the only proven medical therapy for this allergic disease.
Consultations
- Consultation with a nutritionist or nutrition service is invaluable in the overall management. The elimination diet can be reviewed and appropriate substitutions can be recommended. Dietary deficiencies can be anticipated and prevented.
- Consultation with a gastroenterologist is also useful in the evaluation of selected patients. For example, patients presenting with possible anatomic gastrointestinal abnormalities, eosinophilic esophagitis or gastroenteritis, failure to thrive, and malabsorption syndromes may benefit from consultation with both an allergist and a gastroenterologist.
Diet
- A properly managed well-balanced elimination diet (eg, allergen restriction) can lead to resolution of symptoms and help avoid nutritional deficiencies.
- Educate the patient and family about how to properly read food labels and identify common words used for indicating the presence of the food allergen of concern (eg, casein and whey for milk).
- With elimination diets, only exclude those foods confirmed to provoke allergic reactions.
- Review obvious and hidden sources of food allergens. Be aware of the potential for exposures by routes other than ingestion, such as skin contact, inhalation, or injection.
- Anticipate potential candidates for food allergen cross-reactivity, such as the following:
-
- Eggs and chicken (less than 5%)
- Cow milk and beef (10%)
- Cow milk and goat milk (>90%)
- Fish (>50%)
- Peanuts and related legumes (less than 10%)
- Soy and related legumes (less than 5%)
- Wheat and other grains (25%)
- Tree nuts and other nuts (>50%)
- Encourage avoidance of high-risk situations (eg, buffets, picnics), where accidental or inadvertent ingestion of food allergens can occur.
MEDICATION
Despite following stringent avoidance measures for clinically relevant food allergens, accidental or inadvertent ingestions occur all too often. Therefore, a concise written plan for the treatment of allergic reactions resulting from accidental exposure to the food must be available to the patient. For patients with a history of a mild reaction, such as urticaria and pruritus following the ingestion of a food allergen, treatment may be limited to an oral antihistamine. However, the potential for a more severe reaction on subsequent exposures must be taken into consideration because of the possibility of the ingestion of a larger dose than previously ingested or an unexpected or unrecognized increase in the patient’s degree of sensitivity.
If the patient has significant systemic symptoms, the treatment of choice is epinephrine administered by intramuscular injection in the lateral thigh. Examples of systemic manifestations of food allergy include generalized urticaria, laryngeal edema, lower respiratory symptoms (eg, chest tightness, dyspnea, wheezing), and hypotension. Administer epinephrine to any patient with history of a severe allergic reaction as soon as ingestion of the food allergen is discovered and the first symptoms appear.
For the medical therapy of food allergen–induced allergic reactions, the use of antianaphylactic agents, antihistamines, bronchodilators, and corticosteroids in combination with the administration of intravenous fluids and oxygen (when indicated), is suggested.
Drug Category: Adrenergic agonists
Used in the emergency management of systemic allergic reactions or anaphylaxis (eg, urticaria, angioedema, bronchospasm, cardiovascular collapse). Effects are immediate and dramatic. Appropriate use of this class of medication can be lifesaving, especially in the emergency management of anaphylaxis.
| Drug Name | Epinephrine (Adrenaline, EpiPen) |
|---|---|
| Description | DOC for treating anaphylaxis. Helps decrease symptoms of anaphylaxis by increasing systemic vascular resistance, elevating diastolic pressure, producing bronchodilation, and increasing inotropic and chronotropic cardiac activity. In addition, helps reduce urticaria, angioedema, laryngeal edema, and other systemic manifestations of anaphylaxis. |
| Adult Dose | 0.3 mL SC of 1:1000 aqueous injected (usual range is 0.2-0.5 mL) q10-15min, not to exceed 3 doses; may need to decrease dose to 0.2 mL in elderly persons or those with known cardiac conditions 0.3 mL IM of 1:1000 dilution q10-15min; IV route (1:10,000) seldom used; not to exceed 0.25 mg; given very slowly and with extreme caution 0.3-mg self-injectable devices (Epi-Pen) |
| Pediatric Dose | IM dosing in children based on weight or 0.01 mL/kg IM of 1:1000 dilution; not to exceed 0.3 mL IM 1:2000 dilution q10-15min0.15-mg self-injectable devices (Epi-Pen Jr) |
| Contraindications | Documented hypersensitivity; cardiac arrhythmias, coronary artery insufficiency, or angle-closure glaucoma; local anesthesia in areas such as fingers or toes because vasoconstriction may produce sloughing of tissue; do not use during labor (may delay second stage of labor) |
| Interactions | Increases toxicity of beta- and alpha-blocking agents and that of halogenated inhalational anesthetics, ie, drugs that may sensitize the heart to arrhythmias |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Dose may be decreased in elderly patients to 0.2 mL; may cause disturbing reactions such as fear, anxiety, tenseness, restlessness, throbbing headache, weakness, dizziness, pallor, respiratory difficulty, palpitation, tachycardia, tremor, and arrhythmia; use with caution in patients with cardiovascular disease, hyperthyroidism, and diabetes; properly train patients with use of self-injectable devices; advise patients to seek medical attention if using self-injectable devices to manage allergic reactions |
Drug Category: Antihistamines (histamine-1 blockers)
Inhibit many responses to histamine. Histamine, via H1 receptors, causes smooth muscle contraction, increased capillary permeability, and formation of edema. During hypersensitivity reactions, histamine is one of the major potent mediators released. Blocking effects of this mediator with specific antihistamines is useful in emergency management of allergy symptoms.
| Drug Name | Diphenhydramine (Benadryl, Benylin) |
|---|---|
| Description | Frequently used antihistamine for management of acute allergic symptoms. Medication has significant antimuscarinic activity and pronounced tendency to induce sedation. Approximately half of those treated with conventional doses experience some degree of somnolence. |
| Adult Dose | 25-50 mg PO q6h 50-75 mg IV/IM q6h; IV drip may afford better control of symptoms (5 mg/kg/d); not to exceed 300 mg in 24 h |
| Pediatric Dose | 1-2 mg/kg/dose PO q6h 1-2 mg/kg/dose IV/IM q6h; IV drip may afford better control of symptoms (5 mg/kg/d) |
| Contraindications | Documented hypersensitivity; MAO inhibitors; glaucoma, gastrointestinal obstruction, hyperthyroidism, hypertension, and cardiovascular disease; may limit use in elderly patients |
| Interactions | Potentiates effect of CNS depressants; due to alcohol content, do not give syrup dosage form to patient taking medications that can cause disulfiramlike reactions |
| Pregnancy | B – Usually safe but benefits must outweigh the risks. |
| Precautions | Adverse anticholinergic effects and drowsiness; large doses may depress respiration; use can potentially worsen glaucoma, gastrointestinal or urinary obstruction, hyperthyroidism, and hypertension; dizziness, paradoxical excitement, gastritis, and blood dyscrasias; caution with performing certain motor skills (eg, operating heavy machinery, driving a motor vehicle) |
Drug Category: Antihistamines (histamine-2 blockers)
| Drug Name | Ranitidine (Zantac) |
|---|---|
| Description | H2-receptor antagonists competitively inhibit the interaction of histamine with H2 receptors. These are highly selective and have little or no effect on H1 receptors. H2-receptor antagonists are primarily used for the management of active duodenal or benign gastric ulcer disease. They are also used in the healing of duodenal or benign gastric ulcers. |
| Adult Dose | 150 mg PO q8-12h 50 mg IV q6-8h |
| Pediatric Dose | Safety not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin |
| Pregnancy | B – Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in renal or liver impairment and nursing mothers; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment |
| Drug Name | Cimetidine (Tagamet) |
|---|---|
| Description | H2-receptor antagonists competitively inhibit interaction of histamine with H2 receptors. These are highly selective and have little or no effect on H1 receptors. Used in hypersecretory conditions, intractable duodenal ulcers, and for prevention of upper gastrointestinal bleeding. |
| Adult Dose | 300 mg PO q6-8h 300 mg IV q6-8h |
| Pediatric Dose | less than 16 years: Not recommended >16 years: 20-40 mg/kg/d PO/IV |
| Contraindications | Documented hypersensitivity |
| Interactions | Can increase blood levels of theophylline, warfarin, TCAs, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine |
| Pregnancy | B – Usually safe but benefits must outweigh the risks. |
| Precautions | Elderly patients may experience confusional states; may cause impotence and gynecomastia in young males; may increase levels of many drugs; adjust dose or discontinue treatment if changes in renal function occur |
| Drug Name | Famotidine (Pepcid) |
|---|---|
| Description | H2-receptor antagonists competitively inhibit the interaction of histamine with H2 receptors. Highly selective and have little or no effect on H1 receptors. Used for active duodenal ulcers, maintenance of healed duodenal ulcers, and active benign gastric ulcers. Also used for gastroesophageal reflux disease and associated esophagitis. Individualize and adjust dose based on response. |
| Adult Dose | 20-40 mg PO/IV q12h |
| Pediatric Dose | less than 1 years: Not recommended 1-16 years: 0.5 mg/kg/d divided doses PO/IV; not to exceed 40 mg/d |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of ketoconazole and itraconazole |
| Pregnancy | B – Usually safe but benefits must outweigh the risks. |
| Precautions | Reduce dose or prolong dosing interval with severe renal insufficiency (CrCl less than 10 mL/min); not recommended for nursing mothers; adverse reactions include headache, dizziness, constipation, diarrhea, somnolence, seizures, palpitations, depression, and injection site reactions |
Drug Category: Bronchodilators
Patients experiencing significant adverse respiratory symptoms as part of their food-induced allergic reaction must be managed aggressively with nebulized bronchodilators. Nebulized adrenergic agonists or bronchodilators are usually administered for treatment of bronchospasm. Supplemental oxygen can also be administered with nebulizations. In selected cases, parenteral agents may be employed to achieve sufficient bronchodilation.
| Drug Name | Albuterol (Proventil, Ventolin) |
|---|---|
| Description | Common bronchodilator used in clinical medicine. |
| Adult Dose | 2.5-5 mg (0.5 mL of 5% solution diluted to a final volume of 3 mL with 0.9% saline) nebulized over 5-15 min q20min, not to exceed 6 doses; also available in unit dose vials (3 mL of 0.083% solution) for nebulization |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; avoid excessive use with cardiac disease, arrhythmia, hypertension, hyperthyroidism, seizure disorders, labor, and delivery; not recommended for nursing mothers |
| Drug Name | Metaproterenol (Alupent, Dey-Dose, Prometa) |
|---|---|
| Description | Beta2-adrenergic agonist that relaxes bronchial smooth muscle with little effect on heart rate. |
| Adult Dose | 0.3 mL of 5% solution diluted in 2.5 mL of 0.45% or 0.9% normal saline nebulized over 5-15 min q4h |
| Pediatric Dose | 0.1-0.2 mL of 5% solution diluted in 3 mL of 0.45% or 0.9% normal saline nebulized over 5-15 min q4h |
| Contraindications | Documented hypersensitivity; arrhythmia associated with tachycardia |
| Interactions | Decreases effect of beta-receptor blockers; increases toxicity of MAOIs, TCAs, and sympathomimetics |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Caution in hypertension, cardiovascular disease, congestive heart failure, hyperthyroidism, diabetes, and seizures; not recommended for nursing mothers; adverse reactions include tachycardia, headache, nervousness, dizziness, tremor, gastrointestinal upset, hypertension, paradoxical bronchospasm, and cough |
| Drug Name | Theophylline (Aquaphyllin, Aminophyllin) |
|---|---|
| Description | Potentiates exogenous catecholamines and stimulates endogenous catecholamine release and diaphragmatic muscular relaxation, which, in turn, stimulates bronchodilation. |
| Adult Dose | 5-6 mg/kg IV loading dose in 20 mL D5W over 10-15 min, followed by a maintenance dose of 0.5-1 mg/kg/h |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; uncontrolled arrhythmias, peptic ulcers, hyperthyroidism, and uncontrolled seizure disorders |
| Interactions | Aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop diuretics, charcoal, hydantoins, phenobarbital, phenytoin, rifampin, isoniazid, and sympathomimetics may decrease effects; effects may increase with allopurinol, beta-blockers, ciprofloxacin, corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine, carbamazepine, cimetidine, erythromycin, macrolides, propranolol, and interferon |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Caution in peptic ulcer, hypertension, tachyarrhythmias, hyperthyroidism, and compromised cardiac function; do not inject IV solution >25 mg/min; patients with pulmonary edema or liver dysfunction are at greater risk of toxicity because of reduced drug clearance |
Drug Category: Corticosteroids
Ameliorate delayed effects of anaphylactoid reactions and may limit biphasic anaphylaxis. In severe cases of serum sickness, parenteral steroids may be beneficial to reduce inflammatory effects of this immune complex–mediated disease.
| Drug Name | Methylprednisolone (Medrol, Adlone, Solu-Medrol) |
|---|---|
| Description | For treatment of inflammatory and allergic reactions. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation. |
| Adult Dose | 60-80 mg IV for 1 dose; then q6h |
| Pediatric Dose | 1-2 mg/kg/dose IV q6h; not to exceed 60-80 mg |
| Contraindications | Documented hypersensitivity; viral, fungal, or tubercular infections |
| Interactions | Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use |
| Drug Name | Hydrocortisone (Cortef) |
|---|---|
| Description | Has mineralocorticoid and glucocorticoid effects. Useful in management of inflammation caused by immune response. |
| Adult Dose | 100-200 mg IV q6-8h |
| Pediatric Dose | Not to exceed 5-10 mg/kg IV q6-8h |
| Contraindications | Documented hypersensitivity; viral, fungal, or tubercular infections |
| Interactions | Corticosteroid clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Caution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis |
| Drug Name | Prednisone (Deltasone, Meticorten, Sterapred) |
|---|---|
| Description | Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. |
| Adult Dose | 20-40 mg PO qd with quick taper |
| Pediatric Dose | 1-2 mg/kg/d PO with quick taper; not to exceed 20-40 mg |
| Contraindications | Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease |
| Interactions | Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use |
FOLLOW-UP
Deterrence/Prevention
- Provide a written emergency treatment plan for the patient. Have copies of this plan available in appropriate places (eg, daycare, schools, work locations, college dormitory advisors).
- Patients with food allergies should be advised to obtain and wear Medic Alert tags or bracelets indicating their specific food allergies.
- Ensure that the patient has an emergency contact number available (eg, 911, their physician’s office phone number, or a local emergency department) that can be used in the event of a major food-induced allergic reaction.
- Anticipatory guidance measures cannot be overemphasized; for example, educate the patient about potential sources of accidental or inadvertent exposure to relevant food allergens (eg, daycare, school, travel, picnics, dining out).
- Ensure that the patient has self-injectable epinephrine readily available at all times. Also ensure that the patient receives proper training regarding when and how to use the device. An antihistamine (syrup or chewable tablet) should also be available. Patients with food allergies and asthma should always have access to a rapid-acting bronchodilator.
- Self-injectable epinephrine is typically available by prescription (ie, Epi-Pen, Epi-Pen Jr, Twinject). These devices should be stored properly (avoiding extremes of temperature) and replaced before the expiration date.
- Injectable epinephrine is the drug of choice for the initial management of a food-induced anaphylactic reaction.
Prognosis
- Developing intolerance
- In general, most infants and young children outgrow or become clinically tolerant of their food hypersensitivities.
- Well-controlled prospective investigations of food allergy in infants and children demonstrate that by following proper elimination diets, 85% of confirmed symptoms resolve by 3 years of age.
- Adults with food allergy can also lose their clinical allergic reactions to foods after implementation of appropriate food elimination diets.
- Approximately one third of all children and adults lose their clinical reactivity to specific food allergens after 1-2 years of appropriate food allergen elimination therapy. Patients with allergies to peanuts, tree nuts, fish, and shellfish rarely lose their clinical reactivity.
- Avoidance of allergen
- How strictly the patient complies with the allergen avoidance diet appears to be directly associated with the ultimate clinical outcome (ie, development of oral tolerance).
- Patients with allergic reactions to peanuts, tree nuts, shellfish, and fish rarely lose their clinical reactivity.
- Breastfeeding
- While exclusive breastfeeding is frequently promoted as a means of preventing food allergy and atopic disease in general, considerable controversy remains regarding the effectiveness of this practice.
- Some investigations suggest that lactating mothers should eliminate highly allergenic foods (eg, peanuts, tree nuts, shellfish) that may induce life-long allergic sensitivity in their infants.
- Further studies are needed to clarify the role of early elimination diets and breastfeeding in the prevention of food allergy.
Patient Education
- Preparation
- Always carry an epinephrine self-injectable device that has been properly stored and is current (ie, not expired).
- Have an H1-blocker medication (again, properly stored and not expired) in a syrup or chewable tablet form available.
- Avoidance of allergen
- Complete avoidance of the offending food allergen is the best strategic approach and the only proven therapy once the diagnosis of food hypersensitivity is established; therefore, these patients should be properly taught to recognize relevant food allergens that must be eliminated from their diet.
- Instruct the patient about the proper reading of food labels and the need to inquire about food ingredients when dining out.
- Encourage the patient to become familiar with recognizing different words that signify particular food allergens (eg, for cow milk, terms such as casein, whey, beta-lactoglobulin, alpha-lactalbumin).
- If the patient is in doubt about a food or food ingredient, suggest avoidance of the food in question.
- Support groups
- Inform patients with food allergies how to identify and use support groups.
- One such organization is the Food Allergy and Anaphylaxis Network (10400 Eaton Place, Suite 107, Fairfax, VA, 22030-2208 USA; fax: 703-691-2713; phone: 703-691-3179 or 800-929-4040; email: faan@foodallergy.org).
- Another such organization is the International Food Information Council (1100 Connecticut Avenue NW, Suite 43, Washington, DC, 20036 USA; fax: 202-296-6547; phone: 202-296-6540; email: foodinfo@ific.org).
- Early detection
- Educate patients regarding recognition of the early signs and symptoms of a food-induced allergic reaction, and provide them with a written management plan for successfully dealing with these reactions.
- Write a specific list of clinical signs and symptoms to look for if a reaction may be occurring, and include a clear management plan. An excellent example of such a plan is available on The Food Allergy and Anaphylaxis Network Web site.
- Demonstrate to the patient and family how to actually administer medications, especially injectable epinephrine, in the event of an allergic reaction. To accomplish this, use demonstration trainer devices in the clinic setting. Reinforce that if injectable epinephrine is administered, the patient must be immediately evaluated in a medical setting.
- For excellent patient education resources, visit eMedicine’s Allergy Center and Allergic Reaction and Anaphylactic Shock Center. Also, see eMedicine’s patient education articles Food Allergy and Severe Allergic Reaction (Anaphylactic Shock).
MISCELLANEOUS
Medical/Legal Pitfalls
Special Concerns
- Because specific laboratory tests for some food hypersensitivities are not available, diagnosing non–IgE-mediated food allergies (eg, cow milk–induced and soy-induced enterocolitis syndromes, allergic eosinophilic gastroenteritis) is more difficult than diagnosing IgE-mediated food allergies.
- In cases of allergic eosinophilic gastroenteritis, a biopsy may need to be performed. Elimination diets with gradual reintroduction of foods and supervised oral food challenges are often needed to help identify the causative foods.
- For food protein–induced enterocolitis syndrome, perform a food challenge with 0.15–0.30 grams of protein per kilogram of body weight of the implicated protein and observe the patient for several hours. Positive reactions (eg, profuse vomiting and diarrhea) are typically accompanied by a rise in the absolute neutrophil count of more than 3500 cells/mm3. Because of the potential for shock, these challenges are best performed in the hospital setting.
- When the history of an allergic reaction to a food suggests that the onset of symptoms is delayed by hours or days following ingestion, adjust the timing and monitoring of the challenge to correspond to these characteristics.
- The successful administration of oral food challenges to young children requires a great deal of preparation, patience, and creativity. Young children may refuse to ingest the challenged food. Prior planning with the family is important to choose proper vehicles (eg, juice, cereal, solid food) for disguising the challenged substance.
- Recent scientific data support the routine 1-dose administration of the measles-mumps-rubella vaccine to all patients with egg allergy, even those with severe anaphylactic reactions following egg ingestion. In the child with a history of a previous reaction to the measles-mumps-rubella vaccine, consider the possibility of allergy to gelatin or neomycin.
- If the patient has a clinical history of egg allergy and has experienced systemic reactions (eg, anaphylaxis) following the ingestion of egg, the administration of the influenza vaccine requires special diagnostic consideration. Test the patient’s skin with diluted preparations of the influenza vaccine (ie, puncture skin testing and, if needed, intradermal skin testing). If skin test results with the vaccine are positive, the vaccine can be safely given in a graded, multidose scheme. If results are negative, the vaccine may be administered in the routine 1-dose manner.
Add comment February 1, 2007
Allergic and Environmental Asthma
Synonyms and related keywords: reactive airways disease, RAD, occupational asthma, reversible airway obstruction, increased bronchial reactivity, airway inflammation, passive smoke inhalation, allergic disease, aeroallergen exposure, viral respiratory illness, allergen-specific immunoglobulin E, allergen-specific IgE, airway hyperreactivity, AHR, airway remodeling, status asthmaticus, atopy, asthma triggers, nonallergic rhinitis, early allergic response, EAR, late allergic response, LAR, mite antigens, cockroach antigens, occupation-induced airway disease, occupation-induced asthma, industry-induced airway disease, industry-induced asthma, industrial asthma, occupational asthma, seasonal pollen allergens, mold spore allergens, dust mite allergens, animal allergens, food allergens, breath-actuated inhaler, BDI, dry-powder inhaler, DPI, metered-dose inhaler, MDI, breath actuated inhaler, dry powder inhaler, metered dose inhaler
INTRODUCTION Asthma is a clinical syndrome characterized by episodic reversible airway obstruction, increased bronchial reactivity, and airway inflammation. Asthma results from complex interactions among inflammatory cells, their mediators, airway epithelium and smooth muscle, and the nervous system. In genetically susceptible individuals, these interactions can lead to symptoms of breathlessness, wheezing, cough, and chest tightness. Risk factors for asthma include a family history of allergic disease, the presence of allergen-specific immunoglobulin E (IgE), viral respiratory illnesses, exposure to aeroallergens, obesity, and lower socioeconomic status. Environmental exposure in sensitized individuals is a major inducer of airway inflammation, which is a hallmark finding in the asthmatic lung. Although triggers induce inflammation through different pathways, the resulting effects all lead to increased bronchial reactivity. Exposure to dust mites within the first year of life is associated with later development of asthma and, possibly, atopy. Mite and cockroach antigens are common, and exposure and sensitization has been shown to increase asthma morbidity. Allergies trigger asthma attacks in 60-90% of children and in 50% of adults. Approximately 75-85% of patients with asthma have positive (immediate) skin test results. In children, this sensitization is associated with disease activity. The level of IgE is associated with the prevalence and severity of airway hyperresponsiveness (AHR) and asthma. Although most people with asthma have aeroallergen-induced symptoms, some individuals manifest symptoms with nonallergic triggers. As many as 3-10% of people with asthma are sensitive to nonsteroidal anti-inflammatory drugs (NSAIDs). Approximately 5-10% of people with asthma have occupation- or industry-induced airway disease. Many individuals develop symptoms after viral respiratory tract infections. Allergen avoidance and other environmental control efforts are feasible and effective. Symptoms, pulmonary function test findings, and AHR improve with avoidance of environmental allergens. Removing even one of many allergens can result in clinical improvement. However, patients frequently are not compliant with such measures. The allergic response in the airway is the result of a complex interaction of mast cells, eosinophils, T lymphocytes, macrophages, dendritic cells, and neutrophils. Inhalation-challenge studies with allergens reveal an early allergic response (EAR), which occurs within minutes and peaks at 20 minutes following inhalation of the allergen. Clinically, the manifestations of the EAR in the airway include bronchial constriction, airway edema, and mucus plugging. These effects are the result of mast cell–derived mediators. Four to 10 hours later, one sees the late allergic response, which is characterized by infiltration of inflammatory cells into the airway and is most likely caused by cytokine-mediated recruitment and activation of lymphocytes and eosinophils. Antigen-presenting cells (ie, macrophages, dendritic cells) in the airway capture, process, and present antigen to helper T cells, which, in turn, become activated and secrete cytokines. Helper T cells can be induced to develop into TH1 (ie, interferon-gamma, interleukin [IL]–2) or TH2 (ie, IL-4, IL-5, IL-9, IL-13). Allergens drive the cytokine pattern towards TH2, which promotes B-cell IgE production and eosinophil recruitment. Subsequently, IgE binds to the high-affinity receptor for IgE, Fc-epsilon-RI, on the surface of mast cells and, with subsequent exposure to the allergen, the IgE is cross-linked. This leads to degranulation of the mast cell. Preformed mast cell mediators, such as histamine and proteases, are released, leading to the EAR. Newly formed mediators such as leukotriene C4 and prostaglandin D2 also contribute to the EAR. Proinflammatory cytokines (IL-3, IL-4, IL-5, tumor necrosis factor-alpha) are released from mast cells and are generated de novo after mast cell activation. These cytokines contribute to the late allergic response by attracting neutrophils and eosinophils. The eosinophils release major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase into the airway, causing epithelial denudation and exposure of nerve endings. The lymphocytes that are attracted to the airway continue to promote the inflammatory response by secreting cytokines and chemokines, which further potentiate the cellular infiltration into the airway. The ongoing inflammatory process eventually results in hypertrophy of smooth muscles, hyperplasia of mucous glands, thickening of basement membranes, and continuing cellular infiltration. These long-term changes of the airway, referred to as airway remodeling, can ultimately lead to fibrosis and irreversible airway obstruction in some, but not most, patients. Prevalence is difficult to determine because definitions and survey methods vary, but it is likely increasing as a result of greater sensitization to common allergens and the redefinition of some nonatopic wheezing as asthma. From 1982-1992, the average age-adjusted prevalence rate increased 42% (from 34.7/1000 to 49.4/1000). Asthma may affect 31 million people, including 9.2 million children (7.2% of adults by self-report). Asthma affects more than 100 million people worldwide. Some reports suggest asthma prevalence has peaked at 8-12%, perhaps because of improved management or because asthma has already been induced in the maximal number of genetically available individuals. The classic history consists of wheeze, cough, and dyspnea. The predictive value of any single parameter is approximately 30% but is much higher when parameters are combined. Chest discomfort (eg, pain, tightness, congestion, inability to take a full breath) is also common. Some patients may have cough without other symptoms. Recurrent or refractory chest colds may also suggest the diagnosis.
Background
Pathophysiology
Frequency
United States
International
Mortality/Morbidity
Race
Sex
Age
CLINICAL
History
- Age of onset
- Frequency and severity of daytime and nocturnal symptoms
- Symptom triggers, such as exercise, animals, irritants (smoke), and occupation (worse on workdays)
- Seasonal and geographic variation
- Limits on activity, lost work or school days, and quality of life
- Number of ED and urgent clinic visits, hospital admissions, intensive care unit (ICU) stays, and need for mechanical ventilation
- Past treatments, including oral and inhaled steroids, frequency of rescue inhaler use, immunotherapy, and environmental avoidance
- Family history of asthma
- Personal or family history of atopy, allergy, rhinitis (including nonallergic rhinitis), or sinusitis
- Gastroesophageal reflux symptoms
- Food allergy
- Growth (children)
- Atopic dermatitis
- Allergic
- Perennial symptoms – Pet in the home (especially in the bedroom, bed, or both), school, day care, or work environment; moisture, dampness, and humidifier use; mold and musty odors in any part of the home; cockroaches in the home; worsening of symptoms after vacuuming rugs (typical of dust mite allergen)
- Seasonal symptoms (may extend beyond one season in temperate or tropical climates) – Early spring (trees), late spring and summer (grasses), summer and fall (dry molds), and fall (weeds)
- Environmental
- Personal or secondary tobacco smoke exposure in or out of the home
- Stoves, fireplaces, or heaters used in home
- Sprays or chemical agents at work, home, or with hobbies
- Symptoms only at one place (ie, at work during week with no symptoms on weekends)
- School or business associates with similar problems
- Symptoms after eating (seafood or dried, canned, or processed food)
- Medications such as beta-blockers (including eye drops), aspirin, or other NSAIDs
Physical
Physical examination findings are often normal.
- Head and neck: Nasal mucosal swelling, discharge, polyps, or sinus percussion tenderness may suggest associated allergic rhinitis or sinusitis. Wheezing heard only or mostly over the neck may suggest vocal cord dysfunction (VCD) or other laryngeal abnormality, though VCD can be present without a localizing wheeze.
- Cardiac: Findings are normal. Patients with status asthmaticus may have a pulsus paradoxus greater than 10 mm Hg.
- Respiratory: During an acute asthma exacerbation, lung examination findings may include wheezing, rhonchi, hyperinflation, or prolonged expiratory time. With severe disease, lung auscultation may reveal absent breath sounds (indicating poor air movement) or signs of respiratory distress and failure (eg, nasal flaring, grunting, accessory muscle use, cyanosis). Focal wheezing may indicate foreign body or other airway obstruction such as a tumor.
- Skin: Check the patient for atopic dermatitis.
- Extremities: Digital clubbing should not be present.
Causes
The etiology of asthma is likely multifactorial. Genetic factors may control individual predispositions to asthma and responses to medications. Genetics alone cannot account for the significant increases in prevalence, as genetic factors take several generations to develop, and asthma and atopy are not always co-inherited. Several environmental or lifestyle factors have been implicated.
- A hygienic hypothesis proposes that cleaner environments have led to less immunological stresses, preventing the development of an asthma-protective TH1 cytokine phenotype.
- Measles infection, BCG vaccine administration, hepatitis A seropositivity, and other stimuli that increase production of interferon-gamma and IL-12 may inhibit the TH2 allergic response.
- In selected series, vaccinations, fewer childhood infections, liberal use of antibiotics, more processed food in diets, smaller families, and less exposure to day care environments have been associated with increased atopy and asthma. Asthma, atopy, and AHR are more prevalent in western Germany, while bronchitis is more common in eastern Germany.
- One theory to explain the increased prevalence of allergic disease is that with fewer infectious stimuli in the environment, the in utero TH2 allergic cytokine state never switches to the TH1 state.
- Causes or triggers of asthma can be divided as follows:
- Allergic: Aeroallergens can include seasonal pollen, mold spores, dust mites, animal allergens, and food (especially in children). Monosodium glutamate does not appear to be an allergen.
- Nonallergic: These may include smoke, odors, cold air and weather, chemicals, medications (eg, aspirin, other NSAIDs, beta-blockers), exercise, hormonal changes (eg, pregnancy, menstrual cycle), and bisulfite food additives.
Other Problems to be Considered Children and young adults Adults
DIFFERENTIALS
Bronchiolitis
Bronchitis
Chronic Bronchitis
Emphysema
Foreign Body Aspiration
Immunoglobulin G Deficiency
Mixed Connective-Tissue Disease
Pulmonary Embolism
Sarcoidosis
Sinusitis, Chronic
Undifferentiated Connective-Tissue Disease
Vascular Rings
Cystic fibrosis
Congenital cardiac anomalies
Pulmonary anomalies
Gastroesophageal reflux
Vocal cord dysfunction
Endobronchial lesion
Churg-Strauss syndrome (allergic angiitis and granulomatosis)
Allergic bronchopulmonary aspergillosis
Reactive airway dysfunction syndrome: This is a distinct entity caused by exposure to a single, large, inhaled agent leading to asthma symptoms within 24 hours and lasting 3 months or longer.
WORKUP
Lab Studies
Imaging Studies
Other Tests
- Obstruction is defined as a ratio less than 70% of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC). FEV1 is normally greater than 80% of values predicted by age. Young patients with a supranormal FVC can sometimes have a reduced FEV1-to-FVC ratio without having obstructive lung disease.
- Reversibility can be shown by administering a short-acting beta-2 agonist inhaler with a resultant 10-12% and more than 200-mL improvement in FEV1 or FVC. If no response, 2-3 weeks of oral or inhaled corticosteroids (20 mg twice daily for the average patient) may be required to demonstrate an improvement in airflow. Note that airflow obstruction in some patients with chronic obstructive pulmonary disease may be partially reversible.
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A 15% drop in FEV1 after 6 minutes of running or other exercise can be diagnostic of exercise-induced bronchospasm.
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A 20% variation in the peak expiratory flow rate (PEFR) between high and low values is highly suggestive of asthma, but formal pulmonary function testing (as above) is recommended because the PEFR is extremely effort-dependent.
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An asthma specialist can perform bronchoprovocation testing with exercise, histamine, methacholine, or eucapnic voluntary hyperventilation. The results from these tests have a very high negative predictive value and are useful for excluding the diagnosis of asthma. The authors most commonly use a challenge with increasing doses of inhaled methacholine. A 20% decline in FEV1 with a methacholine concentration of 8 mg/mL or less is considered a positive (abnormal) test result. This testing should be avoided during pregnancy because of the risk of precipitating an asthma attack and because methacholine is a class C drug.
- Testing is recommended for antigens to which the patient is exposed rather than testing with a standard panel.
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Skin test findings have very high positive and negative predictive values; however, a negative test finding does not rule out the possibility that an allergen is having an impact on the patient’s asthma. Conversely, a positive test finding does not mean that a patient is exposed to an allergen or that he or she will react to it in a natural exposure.
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Antihistamine medications, but not short courses of oral glucocorticoids at moderate doses, interfere with allergy skin testing.
- Testing should not be performed during an asthma exacerbation, and the testing site should be equipped for the treatment of rare life-threatening reactions.
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Skin testing is performed with controls (eg, histamine and saline) to avoid false-positive (dermatographism) or false-negative results.
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Identification of allergen triggers can assist in formulating an environmental control strategy.
An RAST may be used in place of skin testing if dermatologic disease is generalized, antihistamine or tricyclic antidepressant (TCA) use cannot be suspended (these will not interfere with RAST results), or skin testing is relatively contraindicated. However, skin testing is more specific, more sensitive, and usually less expensive than the RAST.
Procedures
- Direct and indirect laryngoscopy are indicated if VCD or another laryngeal abnormality is suggested. A flow-volume curve on pulmonary function test may demonstrate extrathoracic obstruction, supporting the diagnosis of VCD.
- Cardiac stress testing, cardiopulmonary exercise testing, or both may be indicated if the etiology of dyspnea cannot be determined.
Histologic Findings
The diagnosis of asthma is not made histologically. However, autopsy and bronchoscopic biopsy findings include mucus plugging, inflammatory cell infiltrates and debris, vascular permeability, mucosal edema, and epithelial exfoliation. Remodeling, consisting of hypertrophy of smooth muscle, squamous and goblet cell metaplasia, mucous gland hypertrophy, and basement membrane thickening due to collagen and other matrix protein deposition, is present.
Sputum analysis results show creola bodies (ie, bronchial regenerative cells with nuclear atypia), Charcot-Leyden crystals (ie, residual product of eosinophils), and Curschmann spirals (ie, concentric layers of mucous and debris).
Staging
The National Asthma Education and Prevention Program, Expert Panel Report 2 (1997) from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes Health suggests the following stepwise approach to the diagnosis and treatment of adults and children older than 5 years. Updates were published in 2002. In addition, see Medication.
- Step 1 – Mild intermittent
- Daytime symptoms 2 or fewer times per week
- Nocturnal symptoms 2 or fewer times per month
- PEFR or FEV1 equal to 80% of normal or better
- PEFR variation less than 20%
- Treatment with short-acting inhaled bronchodilators only as needed
- Systemic glucocorticoids for severe exacerbations
- Step 2 – Mild persistent
- Daytime symptoms more than twice per week, but not daily
- Nocturnal symptoms more than twice per month
- PEFR or FEV1 equal to 80% of normal or better
- PEFR variation 20-30%
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Treatment with daily low-dose inhaled glucocorticoids and short-acting inhaled bronchodilators as needed
- Alternative daily therapy – Mast cell stabilizers (cromolyn or nedocromil) can be considered before inhaled steroids, especially in children. Leukotriene pathway modifier agents and even low-dose sustained release theophylline can also be considered, though these are less firmly established. In selected patients, allergy immunotherapy may be useful.
- Step 3 – Moderate persistent
- Daily symptoms
- Nocturnal symptoms more than once per week
- PEFR or FEV1 equal to 60-80% of normal
- PEFR variation more than 30%
- Treatment with daily low-to-medium–dose inhaled glucocorticoids – A recent warning from the US Food and Drug Administration (FDA) about possible adverse effects observed with combinations of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) indicates that some caution should be applied with the use of these products. However, experience indicates that combinations of inhaled CCS and LABA are extremely effective in step 3 asthmatics. All patients require short-acting bronchodilators as needed.
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Alternate daily therapy – Increase inhaled glucocorticoids (to medium dose) or low-to-medium–dose inhaled glucocorticoids and either a leukotriene modifier or theophylline
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Leukotriene synthesis inhibitors, such as zileuton
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Allergy immunotherapy for appropriately selected patients
- Step 4 – Severe persistent
- Continual daytime symptoms
- Frequent nocturnal symptoms
- PEFR or FEV1 less than or equal to 60% of normal
- PEFR variation more than 30%
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Treatment with daily high-dose inhaled glucocorticoids and daily long-acting inhaled beta-agonist and short-acting bronchodilators as needed
- Additionally, if needed, oral glucocorticoids at lowest dose and for the shortest duration required for relief (less than 2 mg/kg/d, ie, less than 60 mg/d) or consider alternative or contributing diagnoses
- Zileuton (may be helpful in some patients)
- Omalizumab (anti-IgE), in allergic patients requiring high-dose inhaled or oral CCS
- For children younger than 5 years, the guidelines also indicate the preferred therapy for moderate and severe persistent asthma consists of inhaled corticosteroids with the addition of long-acting beta-agonists.
TREATMENT
Medical Care
The goals of treatment are to minimize symptoms, improve quality of life, decrease need for urgent care or hospitalizations, normalize pulmonary function test results, and decrease the inflammatory process that leads to airway remodeling. For this discussion, treatment is divided into pharmacotherapy, environmental control, allergen immunotherapy, antibodies against IgE, and education.
- Pharmacotherapy
- The most important facet of medical care is the use of anti-inflammatory medication (usually inhaled glucocorticoids) in patients at all stages beyond mild intermittent asthma. These medications improve the long-term outcomes for children with asthma and do not appear to have significant adverse effects at moderate doses (eg, on growth, bone density, eyes, adrenal sufficiency). Unfortunately, in some series, fewer than half the patients admitted to the hospital for asthma were receiving the recommended anti-inflammatory medications.
- NHLBI guidelines suggest that initial medical care should be aggressive to rapidly gain control and then should be tapered as tolerated.
- Severe exacerbations require standard care that includes supplemental oxygen (goal PaO2 >60 mm Hg, arterial oxygen saturation >90%), nebulized medications, intravenous fluids, and even noninvasive or invasive ventilatory support. Heliox (helium-oxygen gas mixture) is an option but has not been systematically shown to be helpful.
- Antibiotics offer no added benefit during an asthma exacerbation.
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In emergency situations, nebulized magnesium sulfate during acute asthma attacks—when added to short-acting beta-2 agonists—may improve pulmonary function and reduce admissions, based on a limited number of studies.
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All patients should receive assistance with quitting tobacco use. While smoking cessation is essential for a number of reasons, it particularly appears to increase corticosteroid responsiveness in patients with asthma.
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All patients should receive an annual flu shot. A pneumococcal pneumonia vaccination is not required unless indicated based on age (ie, >65 y). Asthma symptoms do not increase after these shots because the antigens in the vaccinations are not alive.
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Evaluating and treating patients for associated conditions (eg, rhinitis, GERD, sinusitis) can be important components of therapy. In one study, treating the GERD symptoms of patients with asthma with a proton pump inhibitor for 6 months reduced asthma exacerbations and improved quality of life but did not improve asthma symptoms or pulmonary function or reduce albuterol usage.
- In addition, see Staging and Medication.
- Environmental control
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Allergen avoidance takes different forms depending on the specific allergen size and characteristic. Improvement in symptoms after avoidance of the allergen may take 1-6 months.
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Efforts should focus on the home, where 30-60% of time is spent. Patients should clean and dust their homes regularly. If patients cannot avoid vacuuming, they should use a face mask or a double-bagged vacuum with a high-efficiency particulate air filter. Consideration can be given to moving to a higher floor in the house (less dust and mold) or different neighborhood (fewer cockroaches) if possible. Active smoking and exposure to passive smoke must be avoided. Room air ionizers have not been proven effective to help persons with chronic asthma and the generation of ozone by these machines may be harmful to some. Other factors related to the home include the following:
- Dust mites (Dermatophagoides pteronyssinus or “dead skin feeders,” size 30 µm): The primary allergen is an intestinal enzyme on fecal particles. The allergen settles on fabric because of its relatively large size; therefore, air filtration is not as important. Measures to avoid dust mites include using impervious covers (eg, on mattresses, pillows, comforters), washing other bedding in hot water (130°F [54.4°C] most effective), removing rugs from the bedroom, limiting upholstered furniture, reducing the number of window blinds, and putting clothing away in closets and drawers. Minimize the number of soft toys, and wash them weekly or periodically put them in the freezer. Decrease room humidity (less than 50%); this is difficult in hot, humid climates.
- Cats and other animals (dander or saliva, urine, or serum proteins, size 1-20 µm): Because of its small size, this allergen is predominantly an airborne indoor allergen. Avoidance involves removing animals from the home (or at least from the bedroom), using dense filtering material over heating and cooling duct vents, and washing cats and dogs as often as twice weekly.
- Cockroaches (size 30 µm): Twenty percent of homes without visible infestation still produce sensitizing levels of allergen. Successful allergen elimination measures are difficult, especially in poor living conditions. To control cockroaches, exterminate and use poison baits and traps, keep food out of the bedroom, and never leave food out in the open.
- Wet molds (size 1-150 µm): Avoidance includes keeping areas dry (eg, remove carpets from wet floors), removing old wallpaper, cleaning with bleach products, and storing firewood outdoors.
- Pollen (size 1-150 µm): Avoidance includes closing windows and doors, using air conditioning and high-efficiency particulate air filters in the car and home, staying inside during the midday and afternoon when pollen counts are highest, wearing glasses or sunglasses, and wearing a face mask over the nose and mouth when mowing the lawn. In addition, consider increasing medications preseason and vacationing out of the area.
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- Allergen immunotherapy
- Repeated injections of small doses of allergen have been used for more than 90 years to treat allergic rhinitis. This treatment is clearly effective, and positive effects may persist even years after treatment is stopped. This treatment is also considered mandatory for life-threatening bee and wasp sting reactions. The role of repeated allergen injections in patients with asthma has been more controversial, ranging from a relative indication to no indication. Benefit has been shown in individuals with allergy-induced asthma.
- Supporters argue that compliance can be ensured, and evidence shows that the underlying disease process can be modified or even prevented (eg, preventing asthma in children with allergic rhinitis).
- In a 2003 review of 75 randomized controlled trials, Abramson et al reported that immunotherapy decreased asthma symptoms and need for medication. Another study showed improved PEFR and decreased use of medications in a highly selected group of children, but only for the first year of therapy.
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The cost may be $800 for the first year and then $170/y thereafter (1996 estimate). No direct comparisons with medical therapy have been made to allow a cost-benefit analysis.
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Allergen immunotherapy should be considered if specific allergens have a proven relationship to symptoms; the individual is sensitized (ie, positive skin test or RAST findings); the allergen cannot be avoided and is present year-round (eg, industrial); or symptoms are poorly controlled with medical therapy, and a vaccine to the allergen is available. As discussed above, this treatment is especially useful if asthma is associated with allergic rhinitis.
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Referral to an allergist is required. The patient must commit to a course of 3-5 years of therapy (although a trial of several months can be considered).
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Precautions include serious adverse reactions (occurring in 1 per 30-500 people, usually within 30 min). The estimated crude annual death rate is 0.7 deaths per million population. Monitoring and resuscitation personnel and equipment are required. Also, allergen immunotherapy should be avoided if the patient is taking beta-blockers or is having an asthma exacerbation (ie, PEFR less than 70% of patient’s personal best) or has moderate or worse fixed obstruction. A major risk factor for immunotherapy-related fatalities includes uncontrolled asthma; therefore, appropriate caution should be exercised.
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Dosing of allergen extracts is in bioequivalent allergy units (BAU), weight per volume (w/v), or protein nitrogen units (PNU), but “major allergen content” may be a more standardized and reliable method of dosing and characterizing allergen extracts.
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Sublingual immunotherapy has been shown to improve allergic rhinitis symptoms, but effectiveness compared with the standard injection type is unclear. Sublingual immunotherapy and allergoids (modified or peptide-associated allergens) are not currently used in the United States.
- Antibodies to IgE antibody – Omalizumab
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Omalizumab (Xolair) was approved by the FDA in 2003 for adults and adolescents (>12 y) with moderate-to-severe persistent asthma who have a positive skin test result or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids.
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This is a humanized murine IgG antibody against the Fc component of the IgE antibody (the part that attaches to mast cell surfaces). Use of this antibody prevents IgE from binding directly to the mast cell surface, thereby preventing cell degranulation.
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Therapy has been shown to decrease IgE antibody levels by 99% and cell receptor sites for IgE antibody by 97%. This decrease, in turn, is associated with reduced histamine production (90%), early-phase bronchospasm (40%), and late-phase bronchospasm (70%) and a decrease in the number, migration, and activity of eosinophils. levels drop quickly and remain low for at least a month.
- This therapy is also effective for allergic rhinitis.
- Multiple phase 3 trials show that, compared to placebo injections, treatment is associated with larger median inhaled steroid dose reduction (83% vs 50%), higher percentage of discontinuation of inhaled steroids (42% vs 19%), and fewer asthma exacerbations (approximately 15% vs 30%). Quality of life and use of rescue inhaler and the emergency department may also be improved. Omalizumab is approved for reduction of exacerbations.
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Adverse effects are rare and include upper respiratory infection symptoms, headache, urticaria (2%) without anaphylaxis, and anaphylaxis (0.1%). Transient thrombocytopenia has also been noted but not in humans. Antibodies are formed against the anti-IgE antibody, but these do not appear to cause immune-complex deposition or other significant problems. To date, decreased IgE levels have not been shown to inhibit one’s ability to fight infection (including parasites). Registration trials raised a question of increased risk of malignancy, but this has not been seen in the postmarketing data.
- Omalizumab is given by subcutaneous injection every 2-4 weeks based on initial serum IgE level and body weight. Patients are usually treated for a trial period lasting at least 12 weeks. Costs may be $12,000/y, so omalizumab is likely to be cost-effective only in patients with severe persistent asthma who have frequent exacerbations requiring hospitalization.
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- Education: See Patient Education.
Consultations
- Consult a pulmonologist, allergist/immunologist, or both for any of the following:
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- Difficulty controlling disease after 3-6 months, including frequent attacks, need for rescue inhaler (>1 rescue inhaler used per mo), use of oral steroids more than 2 times per year, or step 4 therapy required (or step 2 or higher if aged less than 3 y)
- Poor quality of life
- Immunotherapy under consideration
- Intensive education needed
- Refractory cough
- Abnormal chest radiograph findings
- Life-threatening asthma exacerbation
- Patient or parent request
- Appropriate referral is needed if significant psychological, social, or family problems are present.
Diet
Aside from avoiding known food allergens or additives, diet is not restricted.
Activity
Maintaining physical activity and exercise is essential to avoid deconditioning. Susceptible individuals should decrease outdoor activity during midday and afternoon when pollen counts are highest. A short-acting beta-2 agonist and/or cromolyn metered-dose inhaler (MDI) can be used 15-30 minutes before exercise if needed.
MEDICATION
Anti-inflammatory medications (especially inhaled glucocorticosteroids) are now the mainstay of therapy and the single most effective therapy for adults with asthma. Anti-inflammatory medications are proven to improve lung function (ie, FEV1, AHR) and to decrease symptoms, exacerbation frequency, and the need for rescue inhalers.
Short-acting inhaled beta-2 agonists, as needed, are most effective for rapid relief of asthma symptoms. No benefit and some risk of developing tolerance occur with regular long-term use. These agents should still be available to the patient, even if he or she is using a long-acting beta-2 agonist (eg, salmeterol).
Of note, the list of medications that combine 2 drugs in a single delivery device in an effort to increase patient convenience and compliance is expanding. These include a combination of albuterol and ipratropium bromide (Combivent) and a combination of fluticasone and salmeterol (Advair). Another combination product, composed of formoterol and budesonide (Symbicort), may be approved in the United States within 2 years.
Glucocorticoids may increase cell beta-2 agonist receptors, which, in turn, may enhance the action of the combination products.
According to the 1998 Leukotriene Working Group, leukotriene pathway modifiers may be useful as first-line therapy for mild persistent asthma or as an add-on or glucocorticoid-sparing medication in others. These agents are less effective than glucocorticoid inhalers but tend to improve compliance because dosing is oral and once daily, and usage appears more reasonable for those unable or unwilling to take glucocorticoids. Leukotriene synthesis inhibitors montelukast, zafirlukast, and zileuton are available.
When adding to a medication regimen for asthma (referred to as stepping up therapy), consider adding LABA for persistent symptoms with impaired FEV1. Patients with symptoms but normal lung function (especially those with symptomatic allergic rhinitis) might benefit first from a leukotriene pathway modifier. Of course, some patients will ultimately be treated with both types of medications for optimum management.
Mast cell stabilizers can also be used. Cromolyn sodium (Intal) indirectly blocks calcium influx into mast cells, preventing inflammatory mediator release. Adults can use it in an MDI (2-4 puffs 3-4 times daily) or in a nebulized form (1 ampule 3-4 times daily). Because of its safety profile, this agent is often tried in children; however, it may take a month to work. The pediatric dose is 1-2 puffs via an MDI 3-4 times daily or 1 ampule via a nebulizer 3-4 times daily. Cromolyn sodium tends to work best in young and highly allergic patients.
Nedocromil (Tilade) has similar effects, although it is structurally distinct. The adult dose is 2-4 puffs via an MDI 2-3 times daily. The pediatric regimen is 1-2 puffs via an MDI 2-4 times daily. MDIs may be used with a spacer as necessary (mask if less than 2 y). Patients should activate the MDI while breathing in slowly, and then they should hold their breath for 10 seconds if possible.
Using a spacer or holding the inhaler 2 inches from the mouth may improve delivery. The recent change from chlorofluorocarbon to hydrofluoroalkane propellants with smaller particle size may help deliver more medication. The only reliable way to determine if the inhaler is empty is to count the number of doses. Patients should rinse their mouths with water and spit after glucocorticoid inhaler use to prevent oral thrush and dysphonia. An alcohol-containing mouthwash may be more effective than water.
Breath-actuated inhalers are easier to use for less-coordinated individuals. A dry-powder inhaler (DPI) allows rapid inhalation. These devices also often have built-in dose counters.
Consider recommending a nebulizer if the patient is younger than 2 years or is unable to use an MDI or DPI because of cough, severe dyspnea, or poor coordination.
Additionally, recombinant DNA-derived humanized immunoglobulin G monoclonal antibodies to IgE are now available to treat moderate-to-severe persistent asthma in patients who react to perennial allergens and whose symptoms are not controlled by inhaled corticosteroids.
Drug Category: Bronchodilators
Provide immediate relief of bronchospasm. Preferentially (but not exclusively) bind beta2-adrenergic receptors, resulting in conversion of ATP to cyclic AMP, relaxation of bronchial smooth muscle, and decreased release of inflammatory mediators. Anticholinergic agent ipratropium is included here because it has an additive beneficial effect when given with bronchodilators in acute, severe asthma.
| Drug Name | Albuterol (Proventil, Ventolin, Airet) |
|---|---|
| Description | Beta-agonist. Relaxes bronchial smooth muscle by action on beta-2 receptors with little effect on cardiac muscle contractility. |
| Adult Dose | 4 mg PO q12h; not to exceed 32 mg/d MDI: 1-2 puffs q4-6h prn; not to exceed 12 puffs/d Nebulizer: 2.5 mg tid/qid |
| Pediatric Dose | PO less than 12 years: 0.3-0.6 mg/kg/d, not to exceed 8 mg/d >12 years: Administer as in adults MDI less than 4 years: Not established >4 years: Administer as in adults Nebulizer 2-12 years: 0.1-0.15 mg/kg/dose, not to exceed 2.5 mg tid/qid prn >12 years: Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; used regularly during pregnancy; can cause paradoxical bronchospasm; increasing need for this rescue medication may indicate clinical destabilization that requires medical reevaluation |
| Drug Name | Ipratropium (Atrovent) |
|---|---|
| Description | DOC for beta-2 agonist-induced bronchospasm. Chemically related to atropine and has antisecretory properties. Inhibits vagally mediated reflexes by increasing cyclic GMP, causing local bronchial smooth muscle dilation. Not effective for exercise-induced symptoms. Additive to, but slower than, effects of beta-2 agonists. |
| Adult Dose | Nebulizer: 1 U dose vial (500 mcg) q30min for 3 doses, then q2-4h prn MDI: 4-8 puffs prn initially; not to exceed 12 puffs/d |
| Pediatric Dose | Nebulizer: 250 mcg q20min for 3 doses, then q2-4h prn MDI: 4-8 puffs prn initially; not to exceed 6 puffs/d |
| Contraindications | Documented hypersensitivity |
| Interactions | Drugs with anticholinergic properties (eg, dronabinol) may increase toxicity; albuterol may increase effects |
| Pregnancy | B – Usually safe but benefits must outweigh the risks. |
| Precautions | Not indicated for acute episodes of bronchospasm; caution in narrow-angle glaucoma, prostatic hypertrophy, and bladder neck obstruction |
| Drug Name | Bitolterol (Tornalate); Pirbuterol (Maxair) |
|---|---|
| Description | Stimulates beta-2 receptors directly to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance. |
| Adult Dose | Bitolterol: 2 puffs q8h prn Pirbuterol: 1-2 puffs q4-6h prn |
| Pediatric Dose | less than 12 years: Not established >12 years: Administer as in adults |
| Contraindications | Documented hypersensitivity; tachycardia resulting from cardiac arrhythmia |
| Interactions | Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; can cause paradoxical bronchospasm; increased need for this rescue medication may indicate clinical destabilization that requires medical reevaluation |
| Drug Name | Metaproterenol (Alupent, Metaprel) |
|---|---|
| Description | Relaxes bronchial smooth muscle by action on beta2-adrenergic receptors with little effect on cardiac muscle contractility. Generally not recommended because of excessive cardiac stimulation, especially in high doses. |
| Adult Dose | MDI: 2-3 puffs q3-4h prn Nebulizer: 0.01 mg/kg; not to exceed 0.3 mL of 5% solution q4h prn PO: 20 mg tid/qid |
| Pediatric Dose | les than 6 years: 2 mg/kg/d PO 6-9 years: 10 mg PO tid/qid >9 years: Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; can cause paradoxical bronchospasm; increased need for this rescue medication may indicate clinical destabilization that requires medical reevaluation |
| Drug Name | Terbutaline (Brethaire, Brethine, Bricanyl) |
|---|---|
| Description | Acts directly on beta-2 receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance. |
| Adult Dose | MDI: 2 puffs q4-6h prn SC: 0.25 mg PO: 5 mg tid |
| Pediatric Dose | less than 12 years: Not established 12-15 years: 2.5 mg PO tid >15 years: Administer as in adults |
| Contraindications | Documented hypersensitivity; tachycardia resulting from cardiac arrhythmias |
| Interactions | Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents |
| Pregnancy | B – Usually safe but benefits must outweigh the risks. |
| Precautions | Through intracellular shunting, may decrease serum potassium levels, which can produce adverse cardiovascular effects; decrease is usually transient and may not require supplementation |
| Drug Name | Salmeterol (Serevent) |
|---|---|
| Description | Long-acting bronchodilator – works by relaxing smooth muscles of bronchioles and relieving bronchospasms. Effect may also facilitate expectoration. Inhaler does not replace anti-inflammatory medications but can be added to decrease rescue inhaler use. Evening dose may be useful for nocturnal symptoms. SR PO albuterol has greater systemic sympathomimetic adverse effects and is considered an alternate therapy only. WARNING: Data from a large placebo-controlled US study (SMART trial) that compared the safety of salmeterol or placebo added to usual asthma therapy showed a small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179). |
| Adult Dose | PO: 4 mg q12h MDI: 2 puffs (or 1 blister pack) q12h |
| Pediatric Dose | PO: 0.3-0.6 mg/kg/d; not to exceed 8 mg MDI: 1-2 puffs (or 1 blister pack) q12h |
| Contraindications | Documented hypersensitivity; angina, tachycardia, and cardiac arrhythmia associated with tachycardia |
| Interactions | Concomitant use of beta-blockers may decrease bronchodilating and vasodilating effects of beta-agonists; concurrent administration with methyldopa may increase pressor response; coadministration with oxytocic drugs may result in severe hypotension; ECG changes and hypokalemia due to diuretics may worsen |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Not indicated to treat acute asthmatic symptoms; sympathomimetic responses (tremor, tachycardia) can occur and may be significant in some patients with cardiovascular disease; onset of action can be delayed (does not preclude need for short-acting bronchodilators) |
| Drug Name | Theophylline (Theo-24, Theolair, Theo-Dur, Slo-bid) |
|---|---|
| Description | Structurally classified as a methylxanthine, it acts as a bronchodilator. Potentiates exogenous catecholamines and stimulates endogenous catecholamine release and diaphragmatic muscular relaxation, which, in turn, stimulates bronchodilation. For bronchodilation, near toxic (>20 mg/dL) levels are usually required. Less effective than glucocorticoids but may be glucocorticoid-sparing agent. Routine drug level monitoring required (goal: 5-15 mcg/mL). |
| Adult Dose | 10 mg/kg/d (not to exceed 300 mg) PO initially; not to exceed 800 mg/d maintenance |
| Pediatric Dose | less than 1 year: 0.2 (times age in wk) plus 5 (estimated in mg/kg/d) maximum PO >1 year: 16 mg/kg/d PO; not to exceed 400 mg/d; alternatively, 10 mg/kg/d IV |
| Contraindications | Documented hypersensitivity; uncontrolled arrhythmia; peptic ulcers; hyperthyroidism; uncontrolled seizure disorders |
| Interactions | Aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop diuretics, charcoal, hydantoins, phenobarbital, phenytoin, rifampin, isoniazid, and sympathomimetics may decrease effects Effects may increase with allopurinol, beta-blockers, ciprofloxacin, corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine, carbamazepine, cimetidine, erythromycin, macrolides, propranolol, and interferon |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Caution in peptic ulcer, hypertension, tachyarrhythmia, hyperthyroidism, and compromised cardiac function; do not inject IV solution >25 mg/min; patients diagnosed with pulmonary edema or liver dysfunction are at greater risk of toxicity because of reduced drug clearance |
Drug Category: Monoclonal antibodies
Recombinant, DNA-derived agents inhibit IgE binding to the high-affinity IgE receptor on mast cells and basophils, causing a decrease in release of mediators of the allergic response.
| Drug Name | Omalizumab (Xolair) |
|---|---|
| Description | Recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE receptor on surface of mast cells and basophils. By inhibiting IgE binding, release of mediators of allergic response is inhibited. Indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids. |
| Adult Dose | 150-375 mg SC q2-4wk; inject slowly over 5-10 seconds due to viscosity; not to exceed 150 mg/injection site Precise dose and frequency established by serum total IgE level (IU/mL) |
| Pediatric Dose | less than 12 years: Not established >12 years: Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Not effective to treat acute asthma; do not abruptly discontinue inhaled corticosteroids when initiating omalizumab; malignancy rate among treated patients (0.5%) was numerically higher than among control patients (0.2%); malignancies varied, and further long-term observation needed to fully assess risk; may cause injection-site reaction |
Drug Category: Glucocorticoids
Maintenance medications that decrease inflammatory mediators to limit airway remodeling. Must be taken regularly to be beneficial. Do not relieve acute bronchospasm; short-acting bronchodilators must be available. The multiple formulations are not equivalent on a per-dose or per-mcg basis. Inhaled corticosteroids are one of the most important developments in asthma management because they decrease inflammation. Proven to improve lung function (ie, FEV1, airway hyperactivity) and decrease symptoms, exacerbation frequency, and need for rescue inhalers. Dose ranges as recommended by NHLBI.
| Drug Name | Beclomethasone (Beclovent, Vanceril) |
|---|---|
| Description | Inhibits bronchoconstriction, produces direct smooth muscle relaxation, decreases number and activity of inflammatory cells, and decreases airway hyperresponsiveness. |
| Adult Dose | Low dose: 2-6 puffs (84-mcg MDI) or 4-12 puffs (42-mcg MDI) Medium dose: 6-10 puffs (84-mcg MDI) or 12-20 puffs (42-mcg MDI) High dose: >10 puffs (84-mcg MDI) or >20 puffs (42-mcg MDI) |
| Pediatric Dose | Low dose: 1-4 puffs (84-mcg MDI) or 2-8 puffs (42-mcg MDI) Medium dose: 4-8 puffs (84-mcg MDI) or 8-16 puffs (42-mcg MDI) High dose: >8 puffs (84-mcg MDI) or >16 puffs (42-mcg MDI) |
| Contraindications | Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma |
| Interactions | Coadministration with ketoconazole may increase plasma levels but does not appear to be clinically significant |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Not for acute attack; weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma |
| Drug Name | Budesonide (Pulmicort Respules, Pulmicort Turbuhaler, Rhinocort Aqua Intranasal) |
|---|---|
| Description | Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness. |
| Adult Dose | DPI Low dose: 200-600 mcg Medium dose: 600-1200 mcg High dose: 1200 mcg |
| Pediatric Dose | Inhalation suspension for children Low dose: 0.5 mg Medium dose: 1 mg High dose: 2 mg |
| Contraindications | Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma |
| Interactions | None reported |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma |
| Drug Name | Flunisolide (AeroBid) |
|---|---|
| Description | Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness. |
| Adult Dose | Low dose: 2-4 puffs Medium dose: 4-8 puffs High dose: >8 puffs |
| Pediatric Dose | Low dose: 2-3 puffs Medium dose: 4-5 puffs High dose: >5 puffs |
| Contraindications | Documented hypersensitivity: bronchospasm, status asthmaticus, other types of acute episodes of asthma |
| Interactions | None reported |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma |
| Drug Name | Fluticasone (Flovent) |
|---|---|
| Description | Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a weak hypothalamic-pituitary-adrenocortical axis inhibitory potency when applied topically. |
| Adult Dose | MDI Low dose: 88-264 mcg Medium dose: 264-660 mcg High dose: >660 mcg DPI Low dose: 100-300 mcg Medium dose: 300-600 mcg High dose: >600 mcg |
| Pediatric Dose | MDI Low dose: 88-176 mcg Medium dose: 176-440 mcg High dose: >440 mcg DPI Low dose: 100-200 mcg Medium dose: 200-400 mcg High dose: >400 mcg |
| Contraindications | Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma |
| Interactions | None reported |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma |
| Drug Name | Triamcinolone (Azmacort) |
|---|---|
| Description | Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability. |
| Adult Dose | Low dose: 4-10 puffs Medium dose: 10-20 puffs High dose: >20 puffs |
| Pediatric Dose | Low dose: 4-8 puffs Medium dose: 8-12 puffs High dose: >12 puffs |
| Contraindications | Documented hypersensitivity, bronchospasm, status asthmaticus, other types of acute episodes of asthma |
| Interactions | Coadministration with barbiturates, phenytoin, and rifampin decreases effects |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma |
| Drug Name | Prednisone (Deltasone, Orasone) |
|---|---|
| Description | Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Goal is lowest dose and shortest duration effective for disease control. Conversion: methylprednisolone (Medrol) dose equal to four fifths of desired prednisone dose. Prednisolone (Prelone, Pediapred) dose equal to prednisone dose. |
| Adult Dose | 40-60 mg/d PO for 3-10 d as burst; 5-60 mg/d PO qd or qod for long-term use prn for disease control; divided doses (20 mg tid) are more effective than 60 mg qd but are also associated with more adverse effects |
| Pediatric Dose | 1-2 mg/kg/d PO for 3-10 d as burst; not to exceed 60 mg/d; 0.25-2 mg/kg qd or qod for long-term use prn for disease control |
| Contraindications | Documented hypersensitivity; peptic ulcer disease, hepatic dysfunction; viral infection, connective tissue infections, fungal or tubercular skin infections; GI disease |
| Interactions | Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Category C for methylprednisolone and prednisolone; abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, weight gain, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur; qod therapy lessens adverse effects |
Drug Category: Leukotriene-modifying agents
Consist of leukotriene receptor antagonists (eg, zafirlukast and montelukast) and synthesis inhibitors (eg, zileuton).
| Drug Name | Zafirlukast (Accolate), montelukast (Singulair), zileuton (Zyflo) |
|---|---|
| Description | Leukotriene pathway inhibitors. Not for use in acute episodes of asthma. |
| Adult Dose | Zafirlukast: 20 mg PO bid Montelukast: 10 mg PO qd Zileuton: 600 mg PO qid |
| Pediatric Dose | less than 12 years (zafirlukast and zileuton): Not established >6 years (montelukast): 5 mg PO qd |
| Contraindications | Documented hypersensitivity |
| Interactions | Warfarin and theophylline levels must be followed closely if coadministered with zafirlukast or zileuton; do not take with food |
| Pregnancy | B – Usually safe but benefits must outweigh the risks. |
| Precautions | Category C for zileuton; association with Churg-Strauss vasculitis (zileuton), although may be unrelated and only reflect coincidental corticosteroid withdrawal; monitor liver enzymes; not a bronchodilator; have appropriate rescue medication available |
FOLLOW-UP
Further Inpatient Care
-
A reduced FEV1 or PEFR to less than 50% of the patient’s personal best, normocapnia or hypercapnia, severe symptoms, or mental status changes warrants admission to an ICU.
-
If the patient responds to therapy, examination findings are normal 1 hour after the last medication dose, and the FEV1 or PEFR is greater than 70% of patient’s personal best, consider discharging the patient home on therapy to include oral steroids and scheduling a follow-up visit within 1 week.
Further Outpatient Care
- Medical office visits should occur every 6-12 months (every 1-6 mo if severe) and should include the following assessments:
- Reassess severity, compliance, and response to therapy. Consider giving patients a written questionnaire. (See ACT scorecard.)
- Objectively measure pulmonary function; initially check office spirometry, then measure peak flow and review peak-flow log at each visit.
- Reinforce inhaler technique and asthma management plan.
- Ensure compliance with environmental avoidance techniques, and consider additional efforts (add one at a time).
- Consider arranging a home visit to screen for environmental exposures and assess compliance with avoidance measures.
Prognosis
- Signs that may indicate a poor prognosis (ie, risk factors for death) are as follows:
-
- Severe exacerbations – Intubation, ICU stay, 2 or more hospitalizations per year, 3 or more urgent clinic or ED visits per year
- More than 2 short-acting beta-2 agonist MDIs per month
- Glucocorticoid dependence
- Poor patient perception of airflow obstruction
- Significant medical comorbidities
- Psychiatric disease
- Illicit drug use
- Sensitivity to Alternaria species (a mold)
Patient Education
- The American Lung Association has recently endorsed the Asthma Control Test (ACT), a 5-question self-assessment tool for patients. The ACT asks about symptoms experienced during the previous 4 weeks. Scores of 19 or less (out of a possible 25) suggest inadequate asthma control worthy of discussion with a physician.
- Patient compliance rates for medications can be as low as 50%. Compliance with environmental measures, including mattress covers for dust mites, may be even worse. Physicians and other health care professionals are also at fault, with only 63% of internists and only 81% of asthma specialists prescribing inhaled glucocorticoids according to recommended guidelines. In one study, more than 40% of patients did not feel that their asthma was well-controlled. Education reduces ED visits, but objective evidence for other outcome measures is limited. Adequate education programs for parents and/or patients include the following:
- Asthma disease description
- Proper medication use: Take off the cap and shake the inhaler (not needed for DPI). Breathe out deeply and hold the inhaler with lips pursed around the orifice or as far as 2 inches from the face or use a spacer. Depress the inhaler concurrent with slow inspiration. Hold breath for 10 seconds. Repeat until the desired dose is achieved (wait 1 min for short-acting beta-agonists).
- How to identify and control environmental triggers
- Upper airway allergic symptoms: These can be an early warning system for allergic asthma.
- Written self-management plan according to PEFR, exposure, and symptoms: For example, a drop below 80% is considered the yellow zone, and additional intervention is needed; a drop below 50% is considered the red zone (severe exacerbation), and the patient should seek medical assistance.
- Parents with a history of allergies: These parents should be advised that some evidence suggests that environmental control measures may potentially prevent sensitization in their children. Simple but unproven measures include reducing the number of bedroom carpets, avoiding passive smoke exposure, venting unvented gas appliances, increasing fish and vegetable intake, and allowing breastfeeding.
- Additional resources for physicians and other health care professionals are available on the Internet and include the following:
- American Academy of Allergy, Asthma, and Immunology
- American College of Allergy, Asthma and Immunology
- Lung information from the NHLBI
- American Lung Association
- National Library of Medicine Breath of Life Program
- National Asthma Education Program
- National Jewish Medical and Research Center
- American Academy of Family Physicians
- For excellent patient education resources, visit eMedicine’s Asthma Center. Also, see eMedicine’s patient education articles Asthma, Asthma FAQs, Occupational Asthma, and Understanding Asthma Medications.
Systemic glucocorticoids may increase the risk of preeclampsia and decreased birth weight but should be used if asthma exacerbation is severe because untreated asthma bears its own risks on the pregnancy.
MISCELLANEOUS
Medical/Legal Pitfalls
Special Concerns
Add comment February 1, 2007
