Jerry Stein, MD

• Director, BMT Unit
• Department of Pediatric Hematology Oncology
• Schneider Children? Medical Center
• Petach Tikva, Israel

Clearance is proportional to organ blood flow and the intrinsic capacity of organs to metabolize or remove drug from the circulation treatment quadriceps tendonitis generic zerit 40 mg. Clearance can be measured by the rate of appearance of drug outside the body (similar to urinary creatinine clearance) or by the rate of disappearance of drug from the circulation compared with the circulating concentration treatment zone lasik discount zerit 40 mg on-line. Values for clearance and volume of distribution at different stages of preterm development are available for a few drugs and can be used to estimate the doses needed to achieve and maintain therapeutic concentrations associated with desired clinical responses treatment 4 addiction buy cheap zerit 40mg online. Studies of the analgesic fentanyl illustrate the developmental changes in its kinetics and how they can be used to calculate dosages to reach and maintain concentrations associated with effective analgesia medicine 360 buy zerit 40 mg overnight delivery. Analgesia has been associated with a serum fentanyl concentration of 1 to 2 ng/mL (Santeiro et al symptoms 9dpo cheap zerit 40 mg with visa, 1997) treatment 4 lung cancer zerit 40 mg. If analgesic treatment is initiated with a continuous infusion of fentanyl, five half-lives are needed to reach a steady state. It is important to consider that if drug clearance decreases, the steady state concentration during an infusion will increase proportionally. During repeated administration, the peak and trough levels after each dose increase for a time. Steady-state, or plateau, concentrations are reached when the amount of drug eliminated equals the amount of drug administered during each dosing interval. During repetitive dosing, the steady-state concentrations achieved are related to the half-life, dose, and dosing interval relative to the half-life (Buxton, 2006; Rowland and Tozer, 2010). Several important principles of pharmacokinetics are illustrated in this figure; the mathematics are described in detail elsewhere (Buxton, 2006). Drug concentrations rise and fall with drug administration (absorption) and elimination. For dosing intervals of one half-life, accumulation is 88% complete after the third dose, 94% complete after the fourth dose, and 97% complete after the fifth dose. At steady state, the peak and trough concentrations between doses are the same after each dose. If a drug is administered with a dosing interval equal to one half-life, the steady-state peak and trough concentrations are twofold those reached after the first dose. If the dosing interval is shortened to half of a half-life, the concentration decreases less before the next dose, more total drug is administered per day, and the steady-state peak and trough concentrations are considerably higher (3. In general, the initiation of analgesic treatment and increases in infusion doses of analgesics should begin with a loading dose based on the estimated volume of distribution in the central compartment (circulation) and desired concentration. The use of a loading dose shortens the time to reach higher effective analgesic concentrations, but also increases the likelihood of toxicity, as has been reported with digoxin. The linear graph of clearance versus gestational age from 38 neonates who began treatment within 47 hours after birth was used to derive mean rates of clearance at different gestational ages, as shown in Table 34-1. Other investigators studied single-dose fentanyl kinetics during anesthesia and found an apparent central volume of distribution of fentanyl in neonates of 1. Note that this distribution volume is smaller than the steady-state volume of distribution of 5. In turn, the apparent steady-state volume of distribution after a single bolus dose of a lipophilic drug is usually smaller than that associated with continuous drug infusions, during which tissues throughout the body become saturated with drug. The steady-state distribution volume for fentanyl during continuous infusions was calculated as 17 L/kg (Santeiro et al, 1997). It should be noted that because fentanyl is highly lipid soluble, it distributes rapidly from the central compartment into the peripheral tissue compartment. This large distribution volume likely reflects the period during the infusion when the drug is leaving the circulation to penetrate peripheral tissues, such as fat. Because it may take 15 to 60 hours to achieve a steady-state concentration (five half-lives) after a fentanyl infusion is begun or the infusion rate is increased, a patient may need repeated bolus doses to maintain effective plasma concentrations in the central compartment. The best approach is to repeat the calculated loading dose until the desired clinical effect is achieved. This also illustrates why, for sedation specifically, dosing should be adjusted to achieve the desired clinical effect. Clearance calculations, however, can guide the starting doses to achieve effective sedation, as illustrated later. This postnatal rise in clearance of fentanyl likely relates either to maturation of cytochrome P450 3A4 (the enzyme responsible for fentanyl metabolism) activity or to increased hepatic blood flow after birth, because fentanyl has a high hepatic extraction rate. For drugs like fentanyl with a high hepatic extraction ratio, the rate-limiting factor in clearance is the flow of blood to the liver (Saarenmaa et al, 2000). Some researchers have observed that increased intraabdominal pressure reduces fentanyl clearance, which is likely caused by reduced hepatic blood flow (Gauntlett et al, 1988; Koehntop et al, 1986). Clinical changes known to increase or decrease fentanyl clearance should be used to adjust starting dosages, but dosing should be adjusted primarily for the desired clinical effect. These models can identify clinical situations and conditions when doses are likely to require modification. Mathematical simulations create theoretical pharmacokinetic profiles for patients after a dose using the range of pharmacokinetic parameters determined from a patient population. These can then be calculated for 100 to 1000 hypothetical patients to define the expected range of concentrations that are likely after a dose. For drugs, such as antiinfectives with which serum concentrations have been correlated with effectiveness, this provides estimates of how large a dose is needed to reach effective concentrations. A recent study of fluconazole kinetics in newborns illustrates the application of this process (Wade et al, 2008). It appears that the distribution volume is greater than anticipated, because the peak concentration is lower than expected, and the half-life is longer than anticipated because the trough is higher than expected. The time of drug administration and blood sampling were confirmed (an important step), so the half-life is 18 hours, because the concentration decreases 50% from 5. The results were as follows: ll 24 hours: 40 g/mL ll 48 hours: 31 g/mL ll 72 hours: 25 g/mL ll 96 hours: 21 g/mL the maintenance dose (7 mg/kg) was resumed immediately after the 21 g/mL concentration was measured and produced a peak concentration of 30 g/mL after administration of the dose. These concentrations and doses can be used to calculate the volume of distribution and a dose to maintain the phenobarbital concentration between 20 and 30 g/mL as follows: Dose (mg/kg) Vd (L/kg) = C (g/mL = mg/L) = = 7. When two half-lives have passed after the fourth dose, the gentamicin concentration should be approximately 1. The variation between the peak and trough concentrations after the last dose is within the measurement error for gentamicin and should achieve the optimum concentrations defined previously. The concentration will decrease approximately 5 g/mL every 24 hours, or one third of a half-life. Dividing the halflife into fractions is an approximation because it estimates the change in concentration as linear rather than exponential. Although this approximation violates certain principles of pharmacokinetics, it allows estimation of the change in concentration for each one third of a half-life as one third of the change during one half-life. The following approach can be used to estimate the daily phenobarbital dose needed to return the concentration to 30 g/mL, a change in concentration of 5 g/mL: Dose (mg/kg) C (mg/L) = Vd (L/kg) 5 mg/L = Dose (mg/kg) 0. Seizures continued after two 20-mg/kg phenobarbital doses until an additional 10-mg/kg dose was administered. A maintenance dose of 7 mg/kg per day was started 24 hours after the loading doses were administered. The phenobarbital level measured in a blood specimen taken 2 hours after administration of the oral maintenance dose was 50 g/mL. Physician reviewers judged more than 90% of these errors to be preventable, and 16% were potentially lifethreatening or fatal. Pharmacologic studies in pediatric patients are difficult because of a variety of problems ranging from ethics to study design (Ward and Green, 1988). The difficulty of studying therapeutics in the newborn has created a situation in which a plethora of drugs is administered with a paucity of pharmacologic data. Failure to recognize drug-induced illness in the newborn often leads to further pharmacologic treatment as the first approach to correct unrecognized druginduced problems. This fact may reflect an expectation that drug therapy is usually effective and safe. Prudent management of newborns must recognize and weigh the potential benefits of unstudied drug therapy against potential druginduced adverse effects, morbidity, and mortality. Because chloramphenicol was considered well tolerated in older children and adults, it was regarded as nontoxic for newborns. Chloramphenicol was so effective in newborns that higher doses were used without pharmacokinetic study. Higher doses were administered to newborns despite recognition that its clearance required glucuronide conjugation, which was known to be immature in newborns. The unexpected finding that chloramphenicol in doses of 100 to 165 mg/kg per day could be lethal to newborns was demonstrated because the study conducted by Burns et al (1959) included appropriate control groups. Because the mortality rate from the most effective antibiotic treatment regimen was equivalent to that of no antibiotic treatment, these investigators discontinued prophylactic use of antibiotics in the nursery. Additional thoughtful consideration should be given to clinicians` response to therapeutic failure. Fewer drugs and lower doses may be safer and more effective than additional drugs in higher dosages. These doses are usually prepared by pharmacists and administered by nurses, respiratory therapists, and (rarely) physicians. In a study of 393 malpractice claims reported to the Physician Insurers Association of America, the secondmost common cause of malpractice claims was drug errors (Physician Insurers Association of America, 1993). Among 16 medical specialties with two or more claims, pediatric practice ranked sixth in the number of claims, yet it had the third highest average cost per indemnity. The medications most frequently involved in all claims were antibiotics, glucocorticoids, narcotic or non-narcotic analgesics, and narcotic antagonists. In pediatric practice, the medications most frequently involved were vaccines (diphtheria-pertussis-tetanus) and bronchodilators (theophylline). The manufacturer recommended doses of 50 to 100 mg/kg per day for patients weighing 15 kg or less. When Sutherland (1959) reported three cases of sudden death in newborns treated with high doses of chloramphenicol (up to 230 mg/kg per day), the drug was considered "well tolerated and nontoxic. The groups that received chloramphenicol (100 to 165 mg/kg per day), in regimens 2 and 4, had overall mortality rates of 60% and 68%, respectively, whereas groups receiving regimens 1 and 3 had mortality rates of 19% and 18%, respectively. The deaths of these newborns demonstrated the stereotyped sequence of symptoms and signs caused by chloramphenicol, designated the gray syndrome, which consisted of abdominal distention with or without emesis, poor peripheral perfusion and cyanosis, vasomotor collapse, irregular respirations, and death within hours of the onset of these symptoms. Weiss et al (1960) attributed the gray syndrome in newborns to high concentrations of chloramphenicol secondary to its prolonged half-life in newborns who received dosages of more than 100 mg/kg per day, which are usually used in older children. They recommended maximum doses of 50 mg/kg per day in term infants younger than 1 month, half that dose for premature infants, and careful monitoring of chloramphenicol blood concentrations. Additional information and time for communication and documentation may be needed. Physicians should keep the following recommendations in mind to ensure that their medication orders communicate more effectively: ll Write instructions in full rather than with abbreviations. The list of drugs clearly contraindicated during nursing is surprisingly short (American Academy of Pediatrics, Committee on Drugs, 2001). On average, the breastfeeding infant receives approximately 2% to 3% of a maternal dose through milk. Drugs that are organic bases or are lipid soluble may reach higher concentrations in milk than in maternal serum. Methods appropriate for the study of therapeutics in newborns present unique difficulties, but a review by Ward and Green (1988) may provide assistance for investigators. Drug therapy of newborns requires practical application of the principles of pharmacokinetics and pharmacodynamics-which describe the processes of drug absorption, distribution, metabolism, and excretion-to the estimation and individualization of dosages. Newer analytic techniques and more thorough pharmacokinetic studies have improved the available data in this area of neonatal pharmacology. Gleason Relief of human suffering is one of the most important goals of all health care providers. Assessing, managing, and trying to limit these clinical realities, particularly while caring for critically ill neonates, are challenging and increasingly controversial. Fortunately there has been considerable clinical and laboratory research and much clinical dialogue aimed at developing the best clinical practices in this problematic arena. This chapter describes the developmental biology, history, and public policies that have informed and shaped current clinical practices; it also summarizes relevant clinical and basic research regarding clinical assessment tools and both pharmacologic and nonpharmacologic management approaches. Management of neonatal pain and stress serves as an excellent example of this philosophy; therefore a brief history of neonatal pain management follows, beginning with the isolation of morphine from the opium poppy, which has been used to treat pain since approximately 3500 bc. Department of Health and Human Services, the Joint Commission, and other professional organizations. This statement made it clear that anesthesia and analgesia could be given relatively safely to neonates despite their age or cortical immaturity. A second influential document was issued by the Acute Pain Management Guideline Panel of the U. Agency for Health Care Policy and Research (Acute Pain Management Guideline Panel, 1992; Agency for Health Care Policy and Research Pain Management Guideline Panel, 1992). The result of the publication of these two documents was the initiation of research studies into the prevention and amelioration of neonatal pain. The 2003 accreditation standards required health care providers to look across the continuum of life, including the neonatal period, at the complex nature of the pain experience so as to create new foundations for care (Joint Commission International Accreditation Standards for the Care Continuum, 2003). However, these guidelines do not provide specific instructions for assessing or managing pain in neonates. Neonatal caregivers needed to assess and treat perceived neonatal pain and discomfort, but had little research-based evidence on which to base their assessment and therapy.

In addition medicine remix buy zerit 40 mg overnight delivery, at-risk infants should undergo serologic follow-up to detect rising serum IgG titers during the 1st year of age or persistence of IgG antibody beyond 12 to 15 months of age medicine 606 effective 40mg zerit, when maternal IgG antibody has disappeared (Robert-Gangneux et al medicine januvia generic 40mg zerit free shipping, 1999a medications mexico zerit 40 mg sale, 1999b) symptoms concussion buy zerit cheap online. However medicine 93 purchase cheap zerit on-line, insufficient data currently are available to recommend that such therapy be given routinely for this indication. Nevertheless, if such women previously have had toxoplasmic encephalitis, prophylaxis with pyrimethamine, sulfadiazine, and leucovorin (folinic acid) should be considered (Masur et al, 2002). A recent metaanalysis of the effectiveness of prenatal treatment of toxoplasmosis infection found no evidence that such treatment significantly decreased clinical manifestations of disease in infected infants (Thiebaut et al, 2007). Neonatal treatment has also resulted in reductions in sensorineural hearing loss and neurodevelopmental and visual handicaps. Table 38-2 shows the recommended guidelines for the treatment of congenital toxoplasmosis. In infants with congenital toxoplasmosis, the treatment consists of pyrimethamine, sulfadiazine, and folinic acids (Boyer and McAuley, 1994; McAuley et al, 1994; McLeod et al, 1992; Remington et al, 2001). The actual duration of therapy is not known, although prolonged courses of at least 1 year are preferred. Currently most experts recommend combined treatment until the patient is 1 year old (Remington et al, 2001; Villena et al, 1998a, 1998b). Complete blood cell counts and platelet determination must be monitored closely while the patient is receiving therapy, because granulocytopenia, thrombocytopenia, and megaloblastic anemia can occur. These parameters usually improve once a higher dose of folinic acid is administered or pyrimethamine and sulfadiazine are discontinued temporarily. The indications for adjunctive therapy with corticosteroids such as prednisone (0. Current therapies are not effective against encysted bradyzoites and therefore might not prevent reactivation of chorioretinitis and neurologic disease. Among infants born with congenital toxoplasmosis, the mortality rate has been reported to be as high as 12%. In addition, infants with congenital toxoplasmosis are at high risk for ophthalmologic, neurodevelopmental, and audiologic impairments, including mental retardation (87%), seizures (82%), spasticity and palsies (71%), and deafness (15%) (Eichenwald, 1960; Hohlfeld et al, 1989; Koppe et al, 1986; McAuley et al, 1994). Of neonates with subclinical infection, long-term follow-up reveals eye or neurologic disease in as many as 80% to 90% by the time they reach adulthood (Couvreur and Desmonts, 1962; Couvreur et al, 1984; McLeod et al, 2000; Saxon et al, 1973; Wilson et al, 1980). Data from the United States National Collaborative Treatment Trial show that treatment of neonates with congenital toxoplasmosis early and for 1 year resulted in more favorable outcomes than were reported for untreated infants or infants who were treated for only 1 month. On the basis of comparison with untreated historical controls, outcome is improved substantially by neonatal treatment. Spiramycin has been used in pregnant women with acute toxoplasmosis to reduce transplacental transmission of T. If fetal infection is confirmed after the 17th week of pregnancy, however, treatment with pyrimethamine, sulfadiazine, and folinic acid is recommended. Prenatal treatment of congenital toxoplasmosis is believed to reduce the clinical severity of infection in the newborn while shifting the disease to a more subclinical form. Monitor blood and platelet counts weekly; adjust dosage for megaloblastic anemia, granulocytopenia, or thrombocytopenia. When signs of inflammation or active chorioretinitis have subsided, dose can be tapered and eventually discontinued; use only in conjunction with pyrimethamine, sulfadiazine, and leucovorin. Such women should be taught to wear gloves when changing cat litter boxes or gardening and to wash hands after such activities. Daily changing of cat litter will also decrease the chance of infection, because oocysts are not infective during the first 1 to 2 days after passage. In addition, feeding cats commercially prepared foods rather than undercooked meats or wild rodents reduces the likelihood of their becoming infected and capable of transmitting the infection to a pregnant woman. Vegetables and fruits should be washed, and hands and kitchen surfaces should be cleaned after handling fruits, vegetables, and raw meat. Routine serologic screening of women during pregnancy has been an effective means of prevention in such countries as France and Austria, where the incidence of congenital toxoplasmosis is high. However, high-risk women, including those who are immunocompromised, should be screened early in pregnancy. Neonatal screening for IgM antibody has also been advocated so that asymptomatic infants can be detected and treated before neurologic symptoms develop (Peterson and Eaton, 1999). This strategy, however, has been hampered by the lack of readily available and reliable IgM test kits. Moreover, such screening will not detect the approximately 25% of infected infants who lack anti-Toxoplasma spp. Further study involving cost analyses is needed to define the best preventive strategy for congenital toxoplasmosis in specific populations, regions, and countries. In adults, this spirochete is transmitted through sexual contact, but infants acquire the infection from their mothers, either in utero or during delivery. During the 1930s and 1940s in the congenital syphilis clinic of the Harriet Lane Home (Baltimore, Md. Many more were lost to follow-up before completing their 2- to 3-year course of treatment. It was unusual if fewer than three or four new examples were discovered in the general outpatient department in the course of 1 week. Then, for several decades, the frequency of new cases of congenital syphilis declined. This increase is directly linked to a rise in primary and secondary syphilis in women from 2004 to 2007. Half of these cases were in infants born to black mothers, primarily in the South. Approximately 30% of the mothers of these infected infants did not receive prenatal care. When mothers did receive prenatal care and their infants still became infected, 27% were screened <30 days before delivery (likely resulting in a false negative test) and 24% screened positive but were not treated (Centers for Disease Control and Prevention, 2010a). An outbreak was also reported among Pima Indians in Arizona in 2007-2009 in which a total of 106 cases were identified, including six congenital cases, two of which resulted in stillbirth (Centers for Disease Control and Prevention, 2010b). A similar epidemic was seen in Alabama with a peak of 238 cases in 2006 with the largest increase seen in heterosexual women (Centers for Disease Control and Prevention, 2009). Worldwide more newborns are affected by congenital syphilis than by any other neonatal infection (Schmid, 2004). Countries such as Ethiopia, Swaziland, and Mozambique have prevalence rates of maternal syphilis as high as 12% to 13% (World Health Organization, 2007). There are an estimated 2 million pregnancies affected annually, and most women infected with syphilis within 1 year of their pregnancy will transmit the infection to their infant. Adverse outcomes in these pregnancies are severe: 17% to 40% result in stillbirth, 10% to 23% in neonatal death, and 10% to 30% result in congenital syphilis infection (World Health Organization, 2007). The extent of negative synergy between these two infections will become increasingly clear as research progresses. The American Academy of Pediatrics and the American Congress of Obstetricians and Gynecologists in Guidelines for Perinatal Care (2002) recommend screening all pregnant women at the first prenatal visit, after exposure to an infected partner, and at delivery. Reinforcing this recommendation is the Reaffirmation Recommendation Statement by the U. Preventive Services Task Force (2009) that "Grade A evidence" is present for screening all pregnant women for syphilis infection. P&S syphilis rates were calculated using bridged race population estimates for 2000-2007 based on 2000 U. National Electronic Telecommunication System for Surveillance, United States, 1995-2008. This delicate, corkscrew-shaped, flagellated, highly motile spirochete is almost identical in appearance to Treponema pertenue, which causes yaws. Instead, the liver, the immediate target of the invasion, is flooded with organisms that then penetrate all the other organs and tissues of the body to a lesser degree. Other sites of invasion include skin, mucous membranes of the lips and anus, bones, and the central nervous system. If fetal invasion has taken place early, the lungs may be heavily involved in a characteristic pneumonia alba, but this condition is usually life threatening. Under the microscope, the tissue alterations consist of nonspecific interstitial fibrosis with or without evidence of low-grade inflammatory response in the form of round cell inflammation. Localization and gumma formation are not common in the neonate; however, extramedullary hematopoiesis in the liver, spleen, kidneys, and other organs can be seen. Fetuses infected early may die in utero or are at high risk for significant neurodevelopmental morbidity. The usual outcome of a third-trimester infection is the birth of an apparently normal infant who becomes ill within the first few weeks of life. Virtually all infants born to women with primary or secondary infection have congenital infection, but approximately half are clinically symptomatic. It is critical that at-risk infants have a source of primary health care capable of tracking both maternal and infant syphilis status (Chhabra et al, 1993; Zenker and Berman, 1991). Early latent infection results in a 40% infant infection rate, and late latent infection results in a 6% to 14% infant infection rate (Wendel, 1988). Persistent rhinitis ("snuffles") was estimated to occur in two thirds of patients in the early literature, but is now less prevalent (Ingall et al, 2006). Prematurity and low birthweight is seen in 10% to 40% of infants (Saloojee et al, 2004). Additional diagnoses associated with congenital syphilis include nonimmune hydrops, nephrotic syndrome, and myocarditis. Cutaneous lesions can appear at any time from the 2nd week after birth and onward. Even more characteristic than their appearance is their distribution, which most frequently includes the perioral, perinasal, and diaper regions. Palms and soles are also involved, but the rash is soon replaced there by diffuse reddening, thickening, and wrinkling. These cracks are the beginnings of the radiating scars that may persist for many years as rhagades. Similar mucocutaneous lesions involve the anus and vulva, but in these locations, the white, flat, moist, raised plaques known as condylomata are also encountered, although less frequently. In most cases, the bone lesions are asymptomatic, but in a few they are severe enough to lead to subepiphyseal fracture and epiphyseal dislocation with an extremely painful pseudoparalysis of one or more extremities. Approximately 20% of asymptomatic, congenitally infected infants have metaphyseal changes consistent with congenital syphilis. Radiographic alterations include an unusually dense band at the epiphyseal ends, below which is a band of translucency whose margins are at first sharp but that later become serrated, jagged, and irregular. The shafts become generally more opaque, but spotty areas of translucency throughout may give them a moth-eaten look. Epiphyses separate because the dense end plate breaks away from the shaft by fracture through the subepiphyseal zone of decalcification. Signs of visceral involvement include hepatomegaly, splenomegaly, and general glandular enlargement. Palpable epitrochlear nodes are not pathognomonic, but are highly suggestive of congenital syphilis. Associated with this finding may be jaundice, which appears in the 2nd or 3rd weeks of life, is seldom intense, and does not persist for many days. Anemia, probably indicative of bone marrow infection and hematopoietic suppression, may become severe. Lesions in the gastrointestinal tract and pancreas can occur and produce distention and delay in the passage of meconium. Clinical signs of central nervous system involvement seldom appear in the newborn infant, although one third to half of those infected suffer such involvement. However, a serum-positive antibody test alone does not confer a diagnosis of congenital syphilis, because of transplacental transfer of maternal nontreponemal and treponemal IgG antibodies. She may have been successfully treated during pregnancy and yet still has antibodies in her blood, or she may not have received treatment at all and still has not passed the disease on to her fetus. IgM does not cross the placenta, so the presence of specific IgM antibodies in the infant is generally diagnostic. Comparison of maternal and infant nontreponemal serologic titers at delivery and followed over time are most informative for infant diagnosis. These titers should be accessed via the same test and in the same laboratory to ensure valid comparisons. Additional criteria for treatment in the neonate include inadequate maternal treatment in a mother with syphilis and the presence of clinical, laboratory, or radiographic evidence in the infant. Evaluation of an infant with a concerning physical examination result and maternal profile should include darkfield or fluorescent antibody test of skin lesions or mucous discharge. Clearly the evaluation for congenital syphilis is complex, and serial investigations may be necessary for definitive diagnosis. Other tests as clinically indicated: long-bone and chest radiographs, neuroimaging, auditory brainstem response, eye examination, liver function tests. Probenecid, 500 mg orally, four times per day for 10 to 14 days, should also be prescribed. Guidelines for maternal treatment are found in Table 38-4 and are tailored to the stage of disease. Treatment of an infected infant requires 10 days of intravenous or intramuscular penicillin. Specific dosing and treatment regimens are outlined in Table 38-5, followed by long-term follow-up recommendations in Table 38-6. Notably, if a single dose is missed during the treatment of an infected infant, restarting the entire series is recommended. Late manifestations of infection in untreated infants, even if initially asymptomatic, can occur years after birth. Mental retardation can also be a feature of late, untreated congenital syphilis (Brosco et al, 2006).

The first few breaths may require increased pressure if lung fluid has not been cleared symptoms 7dpo buy zerit 40mg on line, as occurs when the infant does not initiate spontaneous breathing symptoms 9f diabetes generic 40mg zerit visa. Newborn infants with specific pulmonary disorders such as pneumonia or pulmonary hypoplasia also frequently require increased inspiratory pressure symptoms norovirus cheap zerit online master card. It has been shown that using enough pressure to produce visible chest rise is associated with hypocarbia on admission blood gas evaluation (Tracy et al symptoms 0f ms zerit 40 mg low price, 2004) symptoms 4 dpo order 40mg zerit otc, and excessive pressure may decrease the effectiveness of surfactant therapy (Bjorklund et al medications list a-z buy discount zerit 40 mg on line, 1997). Choosing the actual initial inspiratory pressure is less important than continuously assessing the progress of the intervention. A manometer in the circuit during assisted ventilation provides the clinician with an indication of the administered pressure, although if the airway is blocked this pressure is not delivered to the lungs. The volume of air delivered to the lungs seems to be more important than the absolute pressure delivered in the development of lung injury. Tidal volume can be monitored with respiratory function monitors that are placed in the respiratory circuit (Schmolzer et al, 2010). If the condition of the infant does not improve after initiating ventilation, then the ventilation is most likely inadequate. In our experience the two most likely reasons for inadequate ventilation are a blocked airway and insufficient inspiratory pressure. The occluded airway can be noted using a colorimetric carbon dioxide device as described previously, and frequently it can be corrected with changes in position or suctioning while inadequate pressure is corrected by adjusting the ventilating device. This pattern of repeated inflation and deflation is frequently thought to be associated with lung injury. If assisted ventilation is necessary for a prolonged period of time or if other resuscitative measures have been unsuccessful, ventilation must be provided by a more secure device such as an endotracheal tube. If it has been difficult to maintain an open airway while ventilating via a face mask, an appropriately placed endotracheal tube will provide a stable airway. At this time intubation is required for administering surfactant, and it can be used to administer other medications such as epinephrine if necessary for resuscitation. Finally, for non-vigorous infants born through meconium-stained amniotic fluid, intubation is performed for suctioning of the airway. The intubation procedure is often critical for successful resuscitation, requires a significant amount of skill and experience to perform reliably, and may be associated with serious complications. The placement of a laryngoscope in the pharynx often produces vagal nerve stimulation, which leads to bradycardia. Assisted ventilation must be paused for the procedure, which if prolonged can lead to hypoxemia and bradycardia. Using pulse oximetry in the immediate newborn period, several investigators have established that this transition with an ultimate oxygen saturation level greater than 90% takes 5 to 15 minutes to occur in infants who do not otherwise require resuscitation. Expected oxygen saturation levels are slightly lower for preterm compared with term and for infants delivered via cesarean section compared with those delivered vaginally (Rabi et al, 2006). Oxygen saturation levels measured in preductal sites are 5% to 10% higher than those measured from postductal sites for approximately 15 minutes of life (Mariani et al, 2007). A great deal of variability occurs in the saturation values among different healthy individuals during the first 5 minutes of life, but a resuscitation team can expect that there be a steady, albeit slow, increase in levels over several minutes. If values are below a threshold at different time points or not progressively increasing, intervention should be considered. The use of pure oxygen for ventilation became routine practice in resuscitation simply because it seemed logical that oxygen would be beneficial. However, the recognition that oxygen could also be toxic led some investigators to question this previously well accepted practice. The toxicity of oxygen is anticipated when the cellular antioxidant capacity is impaired, as occurs during the reperfusion phase following an hypoxic-ischemic insult. After animal studies showed the potential harmful effects of oxygen (Poulsen et al, 1993; Rootwelt et al, 1992), clinical trials were conducted to evaluate the effects of oxygen use during resuscitation of depressed infants. Several worldwide trials have compared the use of pure (100%) oxygen with room (ambient) air (21% oxygen) as the initial ventilating gas for asphyxiated newborns. These trials found that air was as successful as oxygen in achieving resuscitation, and infants resuscitated with air had a shorter time to initiate spontaneous breathing and less evidence of oxidative stress (Ramji et al, 2003; Saugstad et al, 1998; Vento et al, 2001, 2003). Metaanalyses of several of the trials indicated that infants resuscitated with air had a lower risk of mortality than those resuscitated with pure oxygen (Rabi et al, 2007; Tan et al, 2005). These trials have been criticized because they were not all strictly randomized, and some sites were in developing countries; however, metaanalysis of the strictly randomized trials, which were mostly done in European centers, demonstrates significant benefit for survival with the use of air compared with pure oxygen (Saugstad et al, 2008). The preterm infant may be more susceptible to any harmful effects of excessive oxygen exposure, because of decreased antioxidant enzyme capacity. Some of the infants in the previous oxygen trials were preterm, but few weighed less than 1000 g. Trauma to the mouth, pharynx, vocal cords, and trachea are all possible complications of intubation. In addition, hypoxia and bradycardia are more likely when intubation attempts are prolonged beyond 30 seconds. Therefore it is most appropriate to make an attempt to stabilize the infant with noninvasive ventilation before performing the procedure, limiting each attempt to 30 seconds or less (Lane et al, 2004), and allow time for the infant to recover with noninvasive ventilation between attempts. If misplacement of the endotracheal tube in the esophagus goes unrecognized, the infant may experience further clinical deterioration. Clinical signs that the endotracheal tube has been correctly placed in the trachea include auscultation of breath sounds over the anterolateral aspects of the lungs (near the axilla), mist visible in the endotracheal tube, chest rise, and clinical improvement in heart rate and color or oxygen saturation. The use of a colorimetric carbon dioxide detector to confirm intubation significantly decreases the amount of time necessary to determine correct placement of the endotracheal tube from approximately 40 seconds to less than 10 seconds (Aziz et al, 1999; Repetto et al, 2001); this is the primary method of determining endotracheal tube placement. Successful placement of the endotracheal tube is not always easy and is sometimes not possible. A laryngeal mask airway is one such alternative that has been described for use in patients with Pierre Robin sequence or other airway anomalies (Yao et al, 2004). Some practitioners have reported using the laryngeal mask airway for all positive-pressure delivery after birth, with success noted in infants as small as 1. Administration of medications including surfactant and epinephrine through this device has undergone preliminary investigations (Chen et al, 2008; Trevisanuto et al, 2005). Several small trials of oxygen use during resuscitation of preterm infants have been performed in the last 3 years. Infants initiated on pure oxygen had higher pulse oximeter saturation (Spo2) levels during transition, but did not have any differences in heart rate, need for intubation, or survival. The infants provided air from the start of resuscitation all required an increase in inspired oxygen to obtain the specified oxygen saturation targets. Using 30% versus 90% oxygen at the start of resuscitation and adjusting the concentration based on the clinical status of the infant, Escrig et al (2008) found that infants initially receiving 30% oxygen had lower overall exposure to oxygen without any adverse effects. The group receiving 30% oxygen received increased oxygen concentrations up to approximately 55% at 5 minutes, but both groups received similar oxygen concentrations after 4 minutes of life, with a level of approximately 35% by 15 minutes of life (Escrig et al, 2008). In a more recent study, these investigators also reported a decrease in the incidence of bronchopulmonary dysplasia in infants initially receiving 30% oxygen compared with 90% oxygen (Vento et al, 2009). Larger trials of preterm infants treated with different oxygen strategies are necessary to determine the long-term effects of resuscitation with different oxygen concentrations. Oxygen use in the first minutes of life could affect survival and common neonatal morbidities associated with prematurity and free radical disease, such as neurodevelopmental impairment, retinopathy of prematurity, bronchopulmonary dysplasia, and necrotizing enterocolitis. The use of oxygen concentrations between 21% and 100% requires compressed air and a blender. Different organizations throughout the world have provided differing recommendations on the use of oxygen for newborn resuscitation. Our approach has been to begin with 40% oxygen and adjust slowly, attempting to mimic the gradual transition in Spo2 values that occur in healthy newborns transitioning from fetal oxygenation levels with an expected increase in Spo2 from the fetal level of approximately 50% to a target of 85% to 90% by 7 to 8 minutes, an increase of approximately 5% per minute. Additional circulatory assistance can include chest compressions, administration of epinephrine, and volume infusion. Ventilation remains the most critical priority in neonatal resuscitation; however, if adequate ventilation is provided for 30 seconds, and bradycardia with a heart rate less than 60 beats/min persists, chest compressions are initiated. Further attention to ventilation with the use of increased pressures or intubation may be required. Chest compressions are preferably provided with two thumbs on the sternum while both hands encircle the chest with (Menegazzi et al, 1993). Further circulatory support may be necessary if adequate chest compressions do not result in an increase in heart rate after 30 seconds. Epinephrine is then indicated as a vasoactive substance, which increases blood pressure by -receptor agonism, improves coronary perfusion pressure, and increases heart rate by -receptor agonism. Intravenous administration of epinephrine is more likely to be effective than endotracheal administration. Early placement of an umbilical venous catheter is critical to delivering intravenous epinephrine quickly enough to be effective. In order to place an umbilical catheter as quickly as possible, it is necessary to have the equipment readily available and to begin the procedure as soon as possible. This could be accomplished by the lead resuscitator assigning the task of placing the catheter as soon as chest compressions are initiated. If there is any prenatal indication that substantial resuscitation will be required, the necessary equipment for umbilical venous catheter placement should be prepared before delivery as completely as possible. Epinephrine can be given by endotracheal tube, but the efficacy of this delivery method is not as certain; therefore an increased dose (0. Epinephrine doses can be repeated every 3 minutes if heart rate does not increase. Excessive epinephrine can result in hypertension, which in preterm infants may be a factor in the development of intraventricular hemorrhage. The pulse rate, oxygen saturation, and oxygen concentration (FiO2) measured within 30 seconds of birth are displayed here. This infant was initially treated with 40% oxygen, and the concentration was adjusted to achieve SpO2 of 85% to 90% by 5 minutes of life. If the infant has not responded to all the prior measures, a trial of increasing intravascular volume should be considered, which involves administering crystalloid or blood. Situations associated with fetal blood loss are also frequently associated with the need for resuscitation. These situation include placental abruption, cord prolapse, and fetal maternal transfusion. Some of these clinical circumstances will have an obvious history associated with blood loss, whereas others might not be readily evident at the time of birth. Signs of hypovolemia in the newborn infant are nonspecific, but include pallor and weak pulses. Volume replacement requires intravenous access, for which emergent placement of an umbilical venous catheter is essential. Any infant who has signs of hypovolemia and has not responded quickly to other resuscitative measures should have an umbilical venous line placed and a volume infusion administered. The most common, and currently recommended, fluid for volume replacement is isotonic saline. If a substantial blood loss has occurred, the infant may require infusion of red blood cells to provide adequate oxygen-carrying capacity. This infusion can be accomplished emergently with noncrossmatched, O-negative blood, with blood collected from the placenta or with blood drawn from the mother, who will have a compatible antibody profile with her infant at the time of birth. Because not all blood loss is obvious and resuscitation algorithms usually discuss volume replacement as a last resort of a difficult resuscitation, the clinician needs to keep a high index of suspicion for significant hypovolemia so that action can be taken to correct the problem as promptly as possible. Therefore in situations where the possibility for hypovolemia is known before birth, it would be wise to prepare an umbilical catheter and an initial syringe of isotonic saline and discuss with the blood bank and the delivering physicians the possibility that non-crossmatched blood may be required. The most commonly discussed complication of intrapartum medication exposure is perinatal respiratory depression after maternal opiate administration. Naloxone has been used during neonatal resuscitation as an opiate receptor antagonist to reverse the effects of fetal opiate exposure. Infants of mothers who have a chronic opiate exposure can potentially have a sudden withdrawal syndrome, including seizures if they receive a narcotic antagonist. It is also critical that assisted ventilation be provided as long as spontaneous respirations are inadequate. It should be noted that the administration of a narcotic antagonist is never an acutely required intervention during neonatal resuscitation, because these infants can be treated with assisted ventilation. Some of these problems may be modifiable with interventions that could improve the course of the resuscitation. For example, an unrecognized pneumothorax could prevent adequate pulmonary inflation and if under tension could impair cardiac function. If the pneumothorax is recognized and drained, gas exchange and circulation can be improved. Some congenital anomalies that were not diagnosed antenatally make resuscitation more difficult. Congenital diaphragmatic hernia is difficult to recognize on initial inspection of the infant, but can cause significant problems with resuscitation. The abdominal organs are displaced into one hemithorax, and the lungs are unable to develop normally; this will cause ventilation to be difficult. If the intestines are displaced into the thorax and mask ventilation is provided, the intestines will become inflated, making ventilation more difficult. If the congenital diaphragmatic hernia is known before delivery or a presumptive diagnosis is made in the delivery room, the baby should be intubated early to prevent intestinal inflation. An orogastric suction tube should also be placed to decompress the inflated intestines. Many other congenital anomalies that can lead to a difficult resuscitation will be more visibly obvious when the baby is born. For example, hydrops fetalis occurring for any reason can be associated with difficult resuscitation.

Syndromes

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However symptoms 7dpiui discount zerit 40mg with visa, the clinical relevance of these animal studies regarding the long-term effects of neonatal opioids is difficult because of species differences in the timing of brain development medications similar to adderall order 40mg zerit fast delivery, the development of opiate receptors and major neurotransmitter systems medicine bow cheap 40 mg zerit fast delivery, and the pharmacokinetics of administered opioids treatment carpal tunnel purchase zerit 40mg without prescription. Place the cream on the area where anesthesia is desired and then cover it with an occlusive dressing for 1 hour before the procedure medications zovirax buy 40 mg zerit with mastercard. Longer application times provide deeper local anesthetic penetration symptoms zinc deficiency husky cost of zerit, but can lead to toxicity. A rare occurrence, methemoglobinemia can occur when hemoglobin is oxidized by exposure to prilocaine. Limited efficacy was noted with pain from venipuncture, arterial puncture, and percutaneous venous line placement. Bergman et al (1991) described reversible encephalopathic changes in neonates receiving long-term sedative and narcotic infusions. MacGregor et al (1998) demonstrated no adverse neurodevelopmental outcomes in a small group of newborns who received morphine for a median of 5 days. For painful procedures, an analgesic must be used in conjunction with the benzodiazepine. Benzodiazepines are administered to decrease irritability and agitation in infants and to provide sedation for procedures. In ventilated infants, benzodiazepines can help to avoid hypoxia and hypercarbia from breathing out of sync with the ventilator although, as noted for opioids, new synchronized infant ventilators make this clinical problem less likely. When given as continuous infusions, dosing often escalates rapidly to maintain apparent sedation resulting in need for prolonged weaning. In rats, prenatal exposure to diazepam results in long-term functional deficits and atypical behaviors (Kellogg et al, 1985); exposure of 7-day-old mice to diazepam induces widespread cortical and subcortical apoptosis (Bittigau et al, 2002); and midazolam potentiates pain behavior, sensitizes cutaneous reflexes, and has no sedative effect in newborn rats (Koch et al, 2008). Dexmedetomidine is a potent and relatively selective 2 adrenergic receptor agonist indicated for the short-term sedation of patients in intensive care settings, especially those receiving mechanical ventilatory support. The drug is administered by either bolus doses for short procedural sedation (1 to 3 g/kg) or continuous intravenous infusion (0. Because dexmedetomidine does not produce significant respiratory depression, it has been used for procedural interventions in spontaneously breathing infants (Barton et al, 2008; Chrysostomou et al, 2009). These interventions have been used either as the sole method of pain control or in combination with pharmacologic interventions. No one would argue with the statement that neonatal intensive care is associated with stress, pain, and discomfort. Because opioid analgesia and sedation have not been proved to be efficacious and may possibly be harmful, alternative methods of pain and stress relief need to be evaluated for efficacy and safety. As stated clearly by Golianu et al (2007), "These therapies may optimize the homeostatic mechanisms of the infant, thereby mitigating some of the adverse consequences of untreated pain, as well as facilitating healthy physiologic adaptions to stress. Nonnutritive sucking with pacifiers reduces pain responses to heel prick, injections, venipuncture, and circumcision procedures (Sexton and Natale, 2009; Shiao et al, 1997; South et al, 2005). Infant massage has been demonstrated to decrease plasma cortisol and catecholamine levels in preterm infants (Acolet et al, 1993; Kuhn et al, 1991). Maternal skin-to-skin contact (also termed kangaroo care) is associated with greater physiologic stability and reduced responses to acute pain (Bergman et al, 2004; Fohe et al, 2000; Gray et al, 2000; Johnston et al, 2003; Ludington-Hoe and Swinth, 1996). Kangaroo care can decrease Neonatal Infant Pain Scale scores after vitamin K injections (Kashaninia et al, 2008). Maternal rocking has been shown to diminish neonatal distress (Jahromi et al, 2004). Breastfeeding reduces the physiologic and behavioral responses to acute pain and stress in neonates and has been recommended as the first line of treatment (Osinaike et al, 2007; Shah et al, 2006). Another approach is multisensory stimulation of preterm infants undergoing painful procedures. This approach entails simultaneous gentle massage, soothing vocalizations, eye contact, smelling a perfume, and sucking on a pacifier. This technique was associated with analgesia and calming of the infants in several reports from one unit (Bellieni et al, 2001, 2002, 2007). Music therapy may reduce the behavioral and physiologic responses to acute procedural pain (Hartling et al, 2009). Oral sucrose (versus intragastric) reduces pain behavior in preterm and term infants and is used widely (Stevens et al, 1997, 2004). The mechanism of oral sucrose analgesia is believed to be the sweet taste stimulation of endogenous opioid release (Shide and Blass, 1989). Of all methods and techniques discussed, oral sucrose has been the most widely used. As more data regarding the limitations of pharmacologic treatment are published, consideration of nonpharmacologic interventions will likely become more important and commonplace. Tolerance is a reduction in the drug effects after repeated administration, or the need to increase the dose to achieve the same clinical effect. Infants are not capable of becoming psychologically addicted, but they clearly develop tolerance and dependence. In addition, when an opioid dosage is being tapered, the infant should be assessed for the presence of pain a minimum of every 4 hours. If an infant is receiving both an opioid and a benzodiazepine, it is prudent to taper and stop only one class of medication at a time. Many patients can tolerate a relatively large initial decrease in dose, but subsequent decreases may need to be smaller. It should be noted that the potential onset of withdrawal symptoms varies according to the half-life of the opioid or benzodiazepine and the half-life of active metabolites, which may be much longer than that of the parent compound (Tobias, 2000). Traditionally, initiation of palliative care occurs when further medical interventions are no longer curative and death of the infant is expected. Such care is an active process that includes familycentered care with attention to physical, emotional, and spiritual issues (Papadatou, 1997). Several good reviews of neonatal end-of-life care have been published (De Lisle-Porter and Podruchny, 2009; Institute of Medicine of the National Academies, 2003; Moro et al, 2006). Box 35-1 provides a comprehensive listing of the many aspects of end-of-life care that should be considered for the dying neonate. Palliative treatments focus on relief from clinical symptoms such as dyspnea, pain, agitation, vomiting, and seizures, in addition to maintaining dignity and providing warmth. Palliative care should also include attention relieving psychological stress in caregivers such as loneliness, depression, anxiety, grief, and separation from family and loved ones. They need to be provided with a description of the dying process that includes mention of the potential for gasping respiratory efforts and an estimate of the length of the dying process. Opportunities to create memories for the family should be offered, such as pictures, footprints, locks of hair, hats, or blankets. Placement of the infant and the family on a postpartum ward with other parents and their healthy infants is also suboptimal. Ideally, for deaths likely to occur in the hospital, the infant and family should be placed in a private room with enough space for all family members to be present to support the parents in their grieving process. Care providers should discuss autopsy, discuss follow-up discussion times, and provide ongoing bereavement support to the family for as long as needed. Despite significant progress in the understanding of human neurodevelopment, pharmacology, and more careful attention to the care of sick infants, there is still have much to learn. Because protecting and comforting these patients are important, and because external regulatory forces have required intervention to minimize distress, what is known about adult patients must be applied to infants. It is important to minimize pain and distress in these patients to avoid more aggressive interventions. When pharmacologic intervention is necessary for pain control, use the least amount of drug that controls the pain. As newer techniques and medications are introduced to clinical practice, it must be demonstrates that such additions achieve the goal of pain control. It must also be demonstrates that neonatal interventions are safe over the lives of the patients. It provides the bedside nurse with alternative ways to encourage parents to perform normal parenting activities, such as bathing, holding, and picture taking with their infant, in the time surrounding his death. These activities may be the only, and sometimes last, opportunity the mother and father will have to parent their infant. Many nurses have not received sufficient training to support families or themselves through this bereavement process. Many nursing programs lack or have only recently added curricula regarding end-of-life care (Romesberg, 2004). This lack of protocols, along with the limited education available to professionals, serves to decrease the chance that infants and their families will receive the end-of-life care they deserve. Palliative care consists of three components: (1) pain and comfort management, (2) assistance with end-of-life decision making, and (3) bereavement support (March of Dimes, 2010). American Academy of Pediatrics Committees on Fetus and Newborn and on Drugs, Sections on Anesthesiology and on Surgery; Canadian Paediatric Society Fetus and Newborn Committee: Prevention and management of pain and stress in the neonate, Pediatrics 105:454-461, 2000. Carbajal R, Lenclen R, Jugie M, et al: Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates, Pediatrics 115:14941500, 2005. Carbajal R, Roussit A, Danan C, et al: Epidemiology and treatment of painful procedures in neonates in intensive care units, J Am Med Assoc 300:60-70, 2008. Fitzgerald M: the development of nociceptive circuits, Nature Rev Neurosci 6:507520, 2005. Howard R, Carter B, Curry J, et al: Quick reference summary of recommendations and good practice points, Pediatr Anesth 18(Suppl 1):4-13, 2008b. Lago P, Garetti E, Merazzi D, et al: Guidelines for procedural pain in the newborn. For the Pain Study Group of the Italian Society of Neonatology, Acta Paediatr 98:932-939, 2009. The contrasting functions of the fetal, neonatal, and maternal immunologic responses. The diversity and importance of these mechanisms are suggested by the heterogeneity and frequency of the infectious problems encountered in newborns. Differences in immunologic responsiveness between adults and newborns should not be considered defects or abnormalities. Just as the ductus arteriosus, a cardiopulmonary necessity in the intrauterine environment, closes at different rates in different infants, human fetal and newborn infant immunologic response mechanisms are developmentally and genetically programmed to change from graft preservation to identification and destruction of invading pathogens at different rates. The fetus represents a hemiallogenic graft that expresses paternal antigens, which under ordinary circumstances would be rejected as foreign tissue. The fact that such rejection ordinarily does not occur cannot be explained by systemic suppression of the maternal immune system. Most studies of maternal immune function during pregnancy have not shown significant abnormalities (AagaardTillery et al, 2006) and are consistent with the clinical observation that pregnant women are not at increased risk for opportunistic infection. Furthermore, maternal acceptance of the fetus does not occur exclusively as a result of physical separation between immunogenic fetal and maternal tissues. Trophoblastic tissue expressing paternal antigens comes into direct contact with maternal immune cells, and fetal cells can readily be detected in maternal peripheral blood (Price et al, 1991). Conversely, maternal leukocytes and somatic cells are present in significant numbers in the fetus and may persist into adult life in a phenomenon known as microchimerism (Bianchi et al, 1996; Lo et al, 1996; Maloney et al, 1999). As a result, mechanisms must exist whereby antigen-specific responses against paternal antigens either are not initiated or are specifically suppressed. Beginning with the seminal studies of Peter Medawar more than 50 years ago, significant progress has been made in unraveling the immunologic mechanisms underlying maternal-fetal tolerance (Seavey and Mosmann, 2008; Trowsdale and Betz, 2006). Currently it appears that no single factor can explain the commensal immunologic relationship that exists between mother and fetus throughout pregnancy. Rather, several distinct but complementary innate and adaptive immune mechanisms contribute to this process. Before fertilization, both systemic and local immunologic changes occur in the endometrium to favor acceptance of the fetal allograft. For example, progesterone induced by ovulation can reduce the proliferation of T cells and inhibit antigen-presenting cells (Ehring et al, 1998; Miyaura and Iwata, 2002). In addition, as discussed later, T cells with immunosuppressive properties accumulate cyclically in the endometrium during normal menses. These molecules help to induce a local inflammatory cell infiltrate containing macrophages, neutrophils, and dendritic cells, which may help to break down endometrial mucin and thereby facilitate adherence of the blastocyst to the endometrium (Dekel et al, 2010). However, semen contains immunosuppressive factors that teleologically are necessary to inhibit initiation of an immunologic reaction against sperm antigens. Prostacyclin is expressed by uterine tissues by day 5 of gestation and is required for blastocyst adherence and subsequent placental decidualization (Lim et al, 1999). In summary, an orchestrated series of specific proinflammatory and tolerogenic mechanisms support implantation and early fetal allograft survival. This approach clearly is not the entire explanation for tolerance of the fetal allograft. Indeed, fetal antigenic maturity in eliciting a maternal immunologic response has been well documented (Beer and Billingham, 1976; Billington, 1987). The view that maternal tolerance is an active process is further supported by observations that, at least in mice, maternal T lymphocytes specific for paternal antigens in particular are activated during pregnancy. In addition, the fact that paternally derived tumor cells are not rejected by pregnant female mice supports a central role for antigen-specific systemic immune inhibition (Tefuri et al, 1995); therefore, tolerance appears to be at least in part a metabolically active process. Nevertheless, several unique features of the maternal-fetal interface undoubtedly contribute to attenuation of antifetal immunity (Table 36-1). This fact undoubtedly contributes to reduced alloantigenic recognition at the fetal-maternal interface. Its expression is primarily limited to fetal tissue, but it can be detected on some adult tissues, and its expression can be induced on other cells in response to infection, inflammation, or malignant transformation (Carosella et al, 2008). Several additional interesting molecules expressed at the maternal-fetal interface confer unique immunologic properties to this environment. Fas ligand (FasL) is expressed in both maternal and fetal components of the uteroplacental unit throughout gestation. Activated T cells express the Fas receptor, which delivers an apoptotic (death) signal when bound by FasL.

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