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Pilot dose-finding and safety study of bivalirudin in infants <6 months of age with thrombosis. Successful use of argatroban during the third trimester of pregnancy: case report and review of the literature. Oxygen deserves its place in any pharmacopoeia because, like any other drug, oxygen can do a lot of harm as well as a lot of good. While lack of oxygen can be damaging, the body can manage with blood that is only about 50­60% saturated as long as the quantity of oxygen delivered to the tissues is adequate. Were this not true, the fetus would be in substantial trouble before birth, as would the brain of the baby with cyanotic heart disease. Cardiac output and tissue perfusion matter more than blood pressure, and anaemia can undermine oxygen delivery as much as overt cyanosis. Prolonged exposure to more than ~60% oxygen can damage the pulmonary epithelium, and hyperbaric oxygen can cause convulsions. The new understanding of the significance of oxidative stress that emerged towards the ends of the twentieth century contributed to an increased focus on oxygenation in newborn babies both in and beyond the delivery room. Pathophysiology Administration Oxygen may be given into an incubator, especially in small babies, but cot nursing using a nasal cannula is a valuable (and economic) alternative that simplifies parental involvement. Some form of humidification is, however, called for if the baby is getting much oxygen this way. A humidified head box is the only satisfactory way of providing more than 50% oxygen to a baby requiring incubator care. Measurement in air the amount of oxygen each baby is breathing (as a percentage) should be recorded regularly, and those given oxygen via a nasal catheter should have the ambient concentration needed to provide an equivalent arterial saturation documented periodically, because the relationship between catheter flow and the inspired concentration varies. It is said that there must be 50 g/l of desaturated haemoglobin for cyanosis to be visible. Cyanosis is certainly difficult to detect by eye until 25% of the blood is desaturated, and in the neonate, this often only occurs when the arterial partial pressure (PaO2) is <35 mmHg (or 4. Arterial catheters can reduce the pain and trauma caused by repeated capillary sampling, but there is no evidence that use improves long-term outcome. Transcutaneous pressure and saturation monitors are valuable but not free from error. Five trials are currently trying to identify what range of saturation optimises long-term outcome. Supply Piped hospital supplies result in our taking the provision of oxygen for granted: the same is not true in many developing countries. Arrangements for providing oxygen for home use in the United Kingdom have recently undergone a major, and initially unsettling, change. The supply of an oxygen concentrator and of lightweight cylinders by one of four commercial companies must now be authorised by a designated official in each hospital. Humidification Piped supplies and cylinders are devoid of water vapour, and humidification is essential to avoid excessive drying of the respiratory tract when giving >40% oxygen. A range of commercial equipment (such as the Vapotherm) has now become available for delivering a flow of warm well-humidified gas with variable oxygen content. For babies breathing high concentrations of head-box oxygen in an incubator, reasonable humidification can be achieved without a heated humidifier by bubbling oxygen through a small bottle situated inside the incubator. Arterial oxygen tension (PaO2) values in infants <29 weeks of gestation at currently targeted saturations. Resuscitation of newborn infants with 21% or 100% oxygen: an updated systematic review and meta-analysis. Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants: a randomized clinical trial. Increased 36-week survival with high oxygen saturation target in extremely preterm infants. Pharmacology Oxytocin is a synthetic nonapeptide identical to the naturally occurring hypothalamic hormone. Crude pituitary extracts were first used clinically in 1909 and became commercially available in 1928. A sudden bolus can cause vasodilatation and tachycardia, and secondary hypotension can be dangerous in patients with underlying heart disease.

Few areas of maternity care are more in need of a collaborative, team-based, approach. Plans for post-delivery care should also be made ahead of delivery, and the mother should know what these are. Fashions change, but combined addiction to heroin and temazepam is common in the United Kingdom. The problem only becomes an addiction if abrupt discontinuation causes serious physical and mental symptoms to appear. Babies exposed to opiates throughout pregnancy, or to high sustained benzodiazepine usage, often exhibit a range of symptoms (see box) 12­72 hours after birth. None of these, on their own, need treatment, but treatment is called for if sucking is so in-coordinate that tube feeding is required, if there is profuse vomiting, or watery diarrhoea or the baby remains seriously unsettled after two consecutive feeds despite gentle swaddling and the use of a pacifier. If the nurse or doctor has not cared for such a baby before, how can they decide on the severity of the symptoms? A better approach is to make the mother aware before delivery that her baby will need to be watched for a period, to involve the mother in this and to care for both mother and baby. Most mothers already feel guilty about their drug habit and fear having their children taken from them. Knowledge of antenatal drug intake (even if accurate) is only of limited value in predicting whether the baby will develop symptoms, and mothers need to be aware of this. If mother and baby have been cared for together, both can be discharged home after 72 hours if no serious symptoms have developed. If symptoms serious enough to make the baby unwell do develop, then the logical approach is to wean the baby slowly from the drug to which the mother is habituated, rather than introducing yet another drug. Babies of mothers taking an opiate should be weaned using a slowly decreasing dose of morphine or methadone. Morphine is widely used, and the dose can be easily and rapidly adjusted up or down, but methadone may provide smoother control. The same approach can be used where the mother is addicted to buprenorphine, codeine or dihydrocodeine. The use of paregoric for the baby, or tincture of 38 Maternal drug abuse opium, lacks any rational justification. Benzodiazepine dependency is harder to manage using this strategy, because nearly all these drugs have such a long half-life. Some use chloral hydrate in this situation but this can over-sedate the baby, and chlorpromazine may be a better choice. For the occasional mother with barbiturate dependency, phenobarbital should be considered but, while this may provide sedation, it does nothing to control gastrointestinal symptoms. Although there have been many small controlled trials looking at strategies for managing neonatal withdrawal, assessors have generally merely looked to see how many symptoms there were rather than how distressing and disabling the symptoms were. In addition, the assessors have usually been aware of how the babies were being treated. Breastfeeding can be generally encouraged in the period immediately after birth even if the mother has been taking several drugs, since these babies seem to show fewer features of withdrawal. No baby should be left in the care of anyone taking a hallucinogen, and few would condone the possible exposure of a baby to such a drug in breast milk. Screening urine, or meconium, for drugs serves little purpose unless serious thought is being given to care proceedings, since it is unlikely to influence management. If you tell the mother you plan to do this, you imply that you do not believe what she has told you about her drug history. If you tell her later, she will merely conclude that you are another person she cannot trust. Continuous use for even a few days can produce tolerance (the need for a progressively larger dose) and dependency (addiction). Management is the same as for addiction acquired in utero ­ a slow tapered withdrawal of treatment.

An infantile form characterized by non-specific signs and symptoms such as irritability, decreased muscular activity and lethargy. With early detection and treatment, cardiomyopathy can be resolved and death can be prevented. A later onset form manifested by muscle pains and weakness, which is induced by strenuous physical activities or prolonged episodes of fasting. If detected early and treatment is started, metabolic imbalances and complications to the kidneys can be prevented. When inconclusive, they are followed by enzyme studies in fibroblasts to establish a diagnosis. Administration of certain drugs such as valproic acid, antibiotics containing pivalic acid, and other compounds like benzoic acid and can cause false positive results. An illness or period of fasting can precipitate a metabolic crisis manifested by hypoglycemia and can lead to death. Treatment must begin immediately upon diagnosis before irreversible damage occurs. If the baby has abnormal diagnostic lab results, maternal samples may be requested as well. Acute episodes are associated with vomiting, diarrhea, failure to thrive, and seizures. Intercurrent infections or increased protein intake can precipitate a metabolic crisis leading to coma and death if left untreated. The frequency of decompensation falls with age and is not common after the age of ten. With early detection and treatment, the child has a better chance of normal neurodevelopmental outcomes. Families must be taught how to monitor urinary ketones to be alert for impending metabolic crisis. Typically between 2-18 months of age, a nonspecific illness such as a respiratory or gastro-intestinal infection, or even an adverse reaction to immunization may lead to an acute metabolic crisis progressing to neurologic complications. Early signs of an encephalopathic crisis include irritability, lethargy, and hypotonia. Hence, a metabolic decompensation must be treated aggressively to avoid permanent brain damage. With early detection and treatment, neurodevelopmental complications can be prevented but for patients who are already neurologically impaired, treatment can minimize further brain damage. This enzyme is active in the liver, kidneys, fibroblasts and leukocytes and helps break down lysine, hydroxylysine and tryptophan. This condition can cause brain damage and rapidly progresses to coma and death from cerebral edema or hemorrhage. Acute episodes are associated with nonspecific signs and symptoms such as vomiting, irritability, seizures, and lethargy progressing to coma and death. With early detection and treatment, infants can survive the neonatal period without serious complications or neurologic damage. A later-onset form occurs in the first year of life and is often triggered by respiratory infections or excessive consumption of protein. It presents with failure to thrive and recurrent episodes of vomiting, lack of appetite and lethargy. With early detection and treatment, mental disability, speech and other developmental delays can be avoided. Aspirin and benzoic acid will block the beneficial effects of glycine, and should be avoided. The result will be reported as "invalid" and a follow-up screen will be recommended when treatment is concluded. Metabolic imbalances can cause brain damage and rapidly progress to coma and death. Early detection and treatment reduces the mortality and morbidity associated with these disorders. The early onset, severe form is characterized by poor feeding, vomiting, dehydration, respiratory distress, lethargy, seizures, posturing or poor muscle tone.

The fundamental principles discussed above, while illustrated for single-substrate enzymes, apply also to multisubstrate enzymes. The mathematical expressions used to evaluate multisubstrate reactions are, however, complex. While a detailed analysis of the full range of multisubstrate reactions exceeds the scope of this chapter, some common types of kinetic behavior for two-substrate, two-product reactions (termed "BiBi" reactions) are considered below. If so, this violates the assumption, implicit in classical steady-state kinetics, that the concentration of free inhibitor is independent of the concentration of enzyme. Sequential or Single-Displacement Reactions In sequential reactions, both substrates must combine with the enzyme to form a ternary complex before catalysis can proceed (Figure 8­13, top). Sequential reactions are sometimes referred to as single-displacement reactions because the group undergoing transfer is usually passed directly, in a single step, from one substrate to the other. Sequential Bi-Bi reactions can be further distinguished on the basis of whether the two substrates add in a random or in a compulsory order. One explanation for a compulsory-order mechanism is that the addition of A induces a conformational change in the enzyme that aligns residues that recognize and bind B. Irreversible Inhibitors "Poison" Enzymes In the above examples, the inhibitors form a dissociable, dynamic complex with the enzyme. Fully active enzyme can therefore be recovered simply by removing the inhibitor from the surrounding medium. However, a variety of other inhibitors act irreversibly by chemically modifying the enzyme. Since these covalent changes are relatively stable, an enzyme that has been "poisoned" by an irreversible inhibitor such as a heavy metal atom or an acylating reagent remains inhibited even after removal of the remaining inhibitor from the surrounding medium. Ping-Pong Reactions the term "ping-pong" applies to mechanisms in which one or more products are released from the enzyme before all the substrates have been added. Ping-pong reactions involve covalent catalysis and a transient, modified form of the enzyme (see Figure 7­4). The group undergoing transfer is first displaced from substrate A by the enzyme to form product P and a modified form of the enzyme (F). The subsequent Mechanism-Based Inhibition "Mechanism-based" or "suicide" inhibitors are specialized substrate analogs that contain a chemical group that can be transformed by the catalytic machinery of the target enzyme. Center: A random Bi-Bi reaction, characteristic of many kinases and some dehydrogenases. Bottom: A ping-pong reaction, characteristic of aminotransferases and serine proteases. An increase in concentration of one substrate (S1) while that of the other substrate (S2) is maintained constant changes both the x and y intercepts, but not the slope. Destroy or impair the growth, invasiveness, or development of invading pathogens 2. Most Bi-Bi Reactions Conform to Michaelis-Menten Kinetics Most Bi-Bi reactions conform to a somewhat more complex form of Michaelis-Menten kinetics in which Vmax refers to the reaction rate attained when both substrates are present at saturating levels. Each substrate has its own characteristic Km value, which corresponds to the concentration that yields half-maximal velocity when the second substrate is present at saturating levels. As for single-substrate reactions, doublereciprocal plots can be used to determine Vmax and Km. If the lines obtained for several fixed-substrate concentrations are plotted on the same graph, it is possible to distinguish between a ping-pong enzyme, which yields parallel lines, and a sequential mechanism, which yields a pattern of intersecting lines (Figure 8­14). Product inhibition studies are used to complement kinetic analyses and to distinguish between ordered and random Bi-Bi reactions. For example, in a random-order Bi-Bi reaction, each product will be a competitive inhibitor regardless of which substrate is designated the variable substrate. However, for a sequential mechanism (Figure 8­13, top), only product Q will give the pattern indicative of competitive inhibition when A is the variable substrate, while only product P will produce this pattern with B as the variable substrate. The other combi- By virtue of their diverse physiologic roles and high degree of substrate selectivity, enzymes constitute natural targets for the development of pharmacologic agents that are both potent and specific. Statin drugs, for example, lower cholesterol production by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (Chapter 26), while emtricitabine and tenofovir disoproxil fumarate block replication of the human immunodeficiency virus by inhibiting the viral reverse transcriptase (Chapter 34). Enzyme Kinetics Defines Appropriate Screening Conditions Enzyme kinetics plays a crucial role in drug discovery. Second, enzyme kinetics provides the means for quantifying and comparing the potency of different inhibitors and defining their mode of action.

Radiological findings: Skull X-ray images show a premature closure of the anterior part of metopic suture, which runs from the top of the head at the anterior fontanel, resulting in deformation of the anterior portion of the calvarium and a triangular-shaped forehead (trigonocephaly). Case 4 A 2-year-old boy has fever, sore throat, dysphagia, and neck pain for 1 week. Multiple bilateral frontal and orbital fractures with air in the brain can be seen (images B and C). The 3-D reconstructed image revealed bilateral frontal fractures (arrows in image C). Radiology Review 549 Case 6 Case 7 A 15-year-old boy with a history of travel to South America presented with muscular pain, severe headache, and recurrent seizures. Note: Neuroblastoma is the third most common malignant neoplasm of childhood, after leukemia and brain tumors. Case 10 A premature baby presented with sudden unexplained drop in hematocrit levels, a transfontanelle ultrasonography ordered immediately. Radiological findings: Extensive intraventricular hemorrhage (coronal and sagittal) with extension to the brain tissues around the right lateral ventricles (arrows). Clinical examination showed papilledema and A 10-year-old boy is presented with two months history of headaches, a recent history of vomiting and ataxia. Case 13 A 2-year-old girl is presented with 10 days history of lowgrade fever, runny nose, and discharge in both ears. Final diagnosis: Bilateral sinusitis, otitis media, and mastoiditis complicated by a left subperiosteal abscess. Case 12 A 5-year-old girl presented with short neck, low hairline at the back of the head, and restricted mobility of the upper spine along with standing torticollis. Radiological findings: Lateral X-ray view of cervical spine showing fusion of cervical vertebrae and tracheal deviation to the left side (arrow on images A and B). Radiological findings: Transfontanelle ultrasonography shows periventricular calcifications (big arrows on image 552 A. Notes: Brainstem gliomas are the most common brain tumors in children between 7 and 9 years of age. They account for approximately 25 % of all posterior fossa tumors without any gender or racial predilection. Radiological findings: Depressed skull fracture in the left parietal bone (arrows on images A, B, and C) without any associated intracranial hemorrhage. Case 15 A 13-year-old boy presented with a history of long-standing headache and frequent seizures. A 10-year-old boy presented with a history of progressive headache, abnormal gait, and visual problems. Radiology Review 553 Case 17 Case 18 A 4-year-old girl presented with growth retardation and polyurea. Image C: T1 C + (Gd) shows cystic hypointense lesion without contrast enhancement; however, a thin enhancing rim of surrounding compressed pituitary tissue may be seen. A 3-month-old boy presented with high fever, vomiting, poor feeding, and bulging anterior fontanelle. Case 19 the densities become coalescent in many areas and heart borders are completely obliterated (image B). Note the malposition of the endotracheal tube (small arrow in image A) and thorax drain for pneumothorax (big arrow on image A). Case 21 A 1-day-old newborn boy presented with cyanosis, which improves when he cries. Differential diagnosis: Bronchogenic cyst, esophageal duplication cyst, neurenteric cyst, lymphangioma, and pericardial cyst. Case 20 Case 22 A 2-week-old preterm infant, born at 28th week, presented with tachypnea, tachycardia, increased respiratory efforts with retractions, nasal flaring, grunting, and frequent desaturations. Radiological findings: Chest radiography shows overaerated lungs with diffuse rope-like densities separated in some areas by hyperlucent zones (image A). After a few days, A 3-month-old boy presented with rapid noisy breathing since birth and difficulty in feeding, dry cough, blueness on crying, tachypnea, tachycardia, and trachea shifted to the right. Radiology Review 555 Case 23 Case 25 A 9-month-old boy presented with chronic cough, failure to thrive, and sweat chloride testing > 60 mEq/L.