Professor of Anesthesiology and Critical Care Medicine
Chief, Division of Adult Anesthesia
Johns Hopkins University School of Medicine
Johns Hopkins Hospital
Baltimore, Maryland
The main reason for low side effects is due to microscopic doses of medicine being used medicine 8 - love shadow cheap 5mg methotrexate with mastercard. Human body is unique in the sense that at higher dose aspirin will cause tinnitus (noise in the ears) but a homeopathic dose of aspirin will get rid of any tinnitus present in a patient medications that cause hair loss methotrexate 2.5 mg low price. Similarly garlic causes tearing in the eyes 7r medications cheap methotrexate 2.5mg free shipping, so a homeopathic dose of allan sativum will stop any chronic tearing in the eyes medicine 2355 generic 5 mg methotrexate with amex. So you have learned lesson one that is homeopathic medicine will do exactly the opposite of what a regular medicine does medications that cause hyponatremia buy 10 mg methotrexate with mastercard. So in a patient having renal failure with swelling in extremities and pain you will prescribe Aphis Melphica (which is honey bee remedy) medicine zantac generic 5 mg methotrexate visa. In homeopathy the dose usually goes from 1x which is the strongest dose to the weakest which is called the Mother tincture. In the third minute you will learn another difference in homeopathy that is the price of the remedy. Lets take another case, you used 200x Apis and the swelling got worse, then you need to switch to a lower potency of 20 and see the response if good use that if not then try the 1x potency. So whenever a homeopathic remedy makes a case worse please just try to change the dose of the remedy rather then changing the remedy itself. Most of the important homeopathic remedies are given in the appropriate chapters of this book. It helps acute emotional upset that come on from anxiety, intense fear or pain, and shocking or violent situations. It is used after surgery, in early inflammation, fever, colds, headaches, and insomnia. Aconite is helpful for a person who is fearful and restless and experience sudden nausea and vomiting. Apis is prepared from whole honey bees and used to relieve bee sting-type symptoms, such as a burning sensation red swelling. Apis is used in insect stings and bites, sunburn, skin irritations, hives, boils, and frostbite. Apis is effective against pain that is typically improved by cold and made worse by pressure. Derived from the whole fresh arnica plant (Arnica montana), it is the first medicine given after an injury or a fall, to counter bruising, swelling, and local tenderness. Unlike herbal preparations of Arnica, homeopathically diluted Arnica tablets are safe for internal consumption. It is used before and after surgery and childbirth to prevent bruising and speed recovery. Arsenicum is a homeopathic remedy prepared from arsenic trioxide, a compound of the poisonous chemical element arsenic. In micro-dilute homeopathic dosages, Arsenicum is used to treat certain skin rashes, anxiety-induced asthma, vomiting, diarrhea, or stomach upsets from food poisoning. Arsenicum is typically recommended for people who are anxious, restless, pale, and fearful. Belladonna is a homeopathic remedy derived from the extremely poisonous deadly nightshade plant (Atropa belladonna) of Europe. In dilutions, it is used to treat sudden onset conditions characterized by redness, throbbing pain, and heat, including certain types of cold, high fever, earache, sore throat, and sunstroke. Belladonna may be recommended for a person who has a flushed face, hot and dry skin, and dilated pupils. Bryonia is a homeopathic remedy prepared from the poisonous root of wild hops (Bryonia alba), a European climbing perennial. In dilutions, it is used to treat certain types of flu, fevers, and coughs and colds, especially those that come on slowly. Bryonia may be helpful for a person who is typically irritable and aggravated by motion. Calendula is derived from the whole calendula plant and used much like herbal preparations are to promote the healing of minor Cuts and scrapes, cool Sunburns, and relieve skin irritations. Homeopathic calendula is principally a topical remedy but is available in pellet and tablet form for the same symptoms. It comes in ointments (usually 1X strength, a 10 percent calendula extract), tinctures, oils, and "calendulated" soap bars. Chamomilla is derived from the whole fresh chamomile plant (Matricaria recutita or Anthemis nobilis). Chamomile is used to treat restlessness and insomnia, toothaches and childhood teething pains, colic, earaches, fever, and joint pain. Euphrasia is a homeopathic remedy made from dilutions of the juice of the eyebright plant (Euphrasia officinalis). It is most frequently used as an external and internal - 72 - treatment for various injuries to the eyes, especially when there is profuse watering, burning pain, and swelling and redness of the eyelids. It is used primarily for the early stages of inflammatory and feverish conditions that develop gradually, including colds, flu, and viral illnesses. It is also widely used as a first-aid treatment for sprained and bruised muscles, and as a childhood remedy for ailments like headaches, earaches, and nosebleeds. Gelsemium is derived from the flowering yellow jasmine plant (Gelsemium semper virens) native to the southeastern U. It is used principally to relieve dull, heavy aches and pains associated with colds, the flu, tension headache, jet lag, and fatigue. It is also recommended to help relieve bedwetting among nervous children, middle ear infections, and blurred vision. It is used topically and internally to relieve pain related to nerves and the central nervous system, causesing shooting pain that travels the length of a nerve, and for wounds to an area of many nerve endings, such as the ends of the fingers and toes (neuropathy). It also speeds the healing of jagged cuts and relieves the pain from dental surgery, toothaches, injuries to the tailbone, and some burns. Ledum is prepared from the leaves and twigs of wild rosemary (Ledum palustre), a small evergreen shrub. Homeopaths use dilutions to treat puncture wounds from various sharp objects, including nails and needles, and bites by insects (especially mosquitoes) and small animals. It is also used to relieve stiff joints, sprained ankles, black eyes, and severe or persisting bruises. Nux vomica is derived from the toxic, strychnine-containing seeds of the poison nut evergreen tree (Strychnos nux vomica). Homeopathically diluted, it is used principally to treat nausea and vomiting, especially from ailments due to overeating or drinking. The remedy may be beneficial for flatulence, constipation, or indigestion and tenesmus. It is also used to treat motion sickness and some types of colic, coughs, backaches, fevers, headaches, and insomnia. In homeopathic dilutions, people take it internally for colds characterized by a profusely running nose and coughing. Homeopaths also recommend it for certain eye and ear ailments, skin eruptions, allergies, insomnia, fainting episodes, and gastric upsets, particularly when the patient is sensitive and prone to crying. Rhus toxicodendron is prepared from leaves of the poison ivy plant (Rhus toxicodendron). Dilutions are taken to alleviate poison ivy and other skin conditions that - 73 - are red and swollen, like rashes, hives, and burns, as well as joint stiffness. Rhus toxicodendron is also a prominent sports medicine used for pain and swelling that affect muscles, ligaments, and tendons, such as from sprains and overexertion. It is known as the "rusty gate" remedy: It works best for the person who feels stiff and sore at first but better after movement. It is used to treat injuries to the periosteum, the tough connective tissue that covers the shin and other bones. Homeopaths also recommend it for bruised kneecaps and elbows, sprained wrists and ankles, torn tendons, stretched ligaments, and tennis elbow. Sulphur is derived from the naturally occurring yellowish chemical element sulfur. It is commonly taken for certain chronic (as opposed to acute) conditions and skin problems, and during the early stages of fIu. Depending on the symptoms, it may also be used to treat sore throats, allergies, and earaches. It is primarily used to treat bruises (especially black eyes), bone injuries, and sprains. It comes in pellets, tablets, lotions, and ointments Urtica is a first-aid remedy prepared from fresh flowering stinging nettles (Urtica urens). It may be taken internally or applied topically to treat skin conditions characterized by red, raised, rash-like welts, including bites, stings, burns, hives, and prickly heat. From reading this chapter if you remember that Arinica is a rescue treatment for all injuries, shock and a preventative treatment for injuries which you can take before a trip or a game. Chapter 16- Immune System Immune system is our defence and intelligence gathering forces which act as a double edged sword; they act as defenders against microorganisms and toxins and rarely in disease this (immune system) mistakenly will attacks the persons own body (Friendly Fire). At the heart of the immune response is the ability to distinguish between self and non-self. The organs of the immune system, are positioned throughout the body, called lymphoid organs. Lymph nodes are small, bean-shaped - 74 - structures that are laced throughout the body along the lymphatic routes. Lymph nodes contain specialized compartments where immune cells congregate, and where they can encounter antigens. Thymus the master immune gland located in the chest makes T-cells; they are released in the bloodstream after being tested in the thymus that they will not attack their own body cells. Tonsils are one of the primary sites of the immune system which encounters bacteria and triggers an immune response. In autoimmune & immune deficiency diseases replacing the stem cell provides a new immune system. The attacking cells in our immune system are of two following subtypes of cells called leukocytes: the phagocytes are scavengers that engulf and destroy the germs. Two types of Lymphocytes are part of the immune system, B-lymphocytes and T lymphocytes. B-lymphocytes are the Bodyguards, which look for invaders and make specific antibodies against them. A foreign substance invading the body has many antigens example (body parts of H-pylori or Mycoplasma). On detection of an antigen, immune cells activate the B-lymphocytes to produce specific antibodies. In autoimmune disease the T-cell is deceived into attacking the body by a process called molecular mimicry. If the same antigen is presented again, the antibodies already present do their job of attaching to the antigen and these antigen antibody complexes are then destroyed by the phagocyte. If we get measles once, then we do not get measles again, as antibodies against measles are present. Immunization is used to prevent diseases by injecting an attenuated antigen which produces antibodies for protection, thus an attack by the real germ should have no effect, as antibodies are already present. IgG is the most important antibody and helps us - 75 - fight infections; IgG has four sub types called (IgG subclass-1, IgG subclass-2, IgG subclass-3, and IgG subclass-4. Antibodies will find an antigen and attach to it; to destroy antigens tagged by antibodies is the job of the T-cell. In an infection an antibody will attach to the bacteria and then comes the phagocyte to eat them up. Lymphocytes, including both T-cells and B-cells, secrete lymphokines, while monocytes and macrophages secrete monokines. Cytokines encourage cell growth, promote cell activation, direct inflammatory traffic, and destroy target cells including cancer. Antibodies produced by B-cells can neutralize toxins (poisonous or damaging substances) produced by different organisms. Antibodies can activate a group of proteins called complement that are also part of the immune system. Complement assists in killing bacteria, viruses, or infected cells by destroying the cell walls. Complement is activated and increases in heart attack patients after streptokinase is given, but can be lowered by a high dose of magnesium sulphate. Innate Immunity: Innate immunity provides a swift response against infectious agents prior to the initiation of adaptive immune responses. Adaptive Immunity: A slower response by lymphocytes, developed by repeated exposure to infections and vaccination. The lymphocytes are learning cells, they remember the attacking organism and send out T-cells, to hunt the attacking cells. Passive Immunity: this is a temporary immunity provided to the body, which is removed in a month. This can help protect the infant against infection during the early months of childhood. Adults get fewer infections as compared to children, adult immune system learns to recognize and immediately attack many of the viruses that cause colds and flu. They are activated when a cell is exposed to environmental stresses like heat, cold and oxygen deprivation. Inside the cell, heat shock proteins take these peptides (antigens) and hand them over to other molecules. The immune system sees these peptides as red flags, which triggers an immune response.
Testicular cancer typically presents with a firm symptoms 5 weeks 3 days discount 10 mg methotrexate, painless testicular mass; nonseminomatous tumors may present with widespread metastasis medicine news purchase methotrexate 2.5mg on-line. Staging includes examination of the surgically resected specimen treatment room generic methotrexate 5mg on line, including a lymph node dissection 5 medications order methotrexate 10 mg on line, along with imaging studies and lab tests treatment bladder infection 2.5mg methotrexate fast delivery. It is characteristically sensitive to both chemotherapy and radiation medicine 6 year methotrexate 5 mg without prescription, and has an excellent prognosis (early stage seminoma has 95% cure rate). A variant is spermatocytic seminoma, a disease of older men, also with an excellent prognosis. Microscopic exam shows sheets of monotonous cells (with clear cytoplasm and round nuclei) separated by fibrous septae. Yolk sac tumor (endodermal sinus tumor) is the most common germ cell tumor in children; in pediatric cases, the prognosis is good. In adults, the prognosis may depend on the other histologic types that are admixed. Microscopically, mature teratoma usually contains ectodermal, endodermal, and mesodermal tissue in a haphazard arrangement. Prepubertal cases are benign regardless of immature elements; teratomas in adults have malignant potential. When both teratoma and embryonal carcinoma are present, the name teratocarcinoma is used. Androgens (dihydrotestosterone) play an important role in the pathogenesis, and the lesion is not premalignant. Microscopically, the lesion shows glandular and stromal hyperplasia resulting in the characteristic prostate enlargement. Prostate adenocarcinoma is the most common cancer in men in the United States and the second most common cause of cancer death in men. Pathologically, an ill-defined, firm, yellow mass commonly arises in the posterior aspect of the peripheral zone. Microscopically, adenocarcinoma is graded with the Gleason system, which scores glandular differentiation. Chronic nonbacterial prostatitis (chronic pelvic pain syndrome) is more common than bacterial prostatitis. Plummer syndrome is the development of hyperthyroidism (toxic multinodular goiter) late in the course. Microscopically, the tissue shows nodules of varying sizes composed of colloid follicles. Multinodular goiter (nontoxic goiter) refers to an enlarged thyroid gland with Hyperthyroidism the term hyperthyroidism is used when the mean metabolic rate of all cells is increased due to increased T4 or T3. Clinical features include tachycardia and palpitations; nervousness and diaphoresis; heat intolerance; weakness and tremors; diarrhea; and weight loss despite a good appetite. Clinical features include hyperthyroidism, diffuse goiter, ophthalmopathy (exophthalmus), and dermopathy (pretibial myxedema). Other causes of hyperthyroidism include toxic multinodular goiter, toxic adenoma (functioning adenoma producing thyroid hormone), and Hashimoto and subacute thyroiditis (transient hyperthyroidism). Clinical features include fatigue and lethargy; sensitivity to cold temperatures; decreased cardiac output; myxedema (accumulation of proteoglycans and water); facial and periorbital edema; peripheral edema of the hands and feet; deep voice; macroglossia; constipation; and anovulatory cycles. Iatrogenic hypothyroidism is the most common cause of hypothyroidism in the United States, and is secondary to thyroidectomy or radioactive iodine treatment. Congenital hypothyroidism (cretinism) in endemic regions is due to iodine deficiency during intrauterine and neonatal life, and in nonendemic regions is due to thyroid dysgenesis. Patients present with failure to thrive, stunted bone growth and dwarfism, spasticity and motor incoordination, and mental retardation. Endemic goiter is due to dietary deficiency of iodine; it is uncommon in the United States. Thyroiditis Hashimoto thyroiditis is a chronic autoimmune disease characterized by immune destruction of the thyroid gland and hypothyroidism. Hashimoto thyroiditis is the most common cause of hypothyroidism (due to destruction of thyroid tissue), though the initial inflammation may cause transient hyperthyroidism (hashitoxicosis). Thyroid Neoplasia Thyroglossal duct cyst presents as a midline neck mass in a young patient. Clinically, adenomas are usually painless, solitary, encapsulated nodules that appear "cold" on thyroid scans. Follicular Adenoma (left), Separated from Normal Thyroid Parenchyma (right), by the Capsule (center) Papillary carcinoma accounts for 80% of malignant thyroid tumors. The prognosis is excellent, with 20-year survival 90% due to slow growth and metastasis to regional cervical lymph nodes. Characteristic nuclear features include clear "Orphan Annie eye" nuclei, nuclear grooves, and intranuclear cytoplasmic inclusions. These cancers are microscopically distinguished from follicular adenoma by the presence of capsular invasion. It can present with a firm, enlarging, and bulky mass, or with dyspnea and dysphagia. The tumor has a tendency for early widespread metastasis and invasion of the trachea and esophagus. Microscopically, the tumor is composed of undifferentiated, anaplastic, and pleomorphic cells. Note Osteitis fibrosa cystica (von Recklinghausen disease) is seen when excessive parathyroid hormone (hyperparathyroidism) causes osteoclast activation and generalized bone resorption (causing possible bone pain, deformities, and fractures). Clinical features include galactorrhea, amenorrhea, and infertility, or decreased libido and impotence. Clinical Correlate Any pituitary tumor that destroys >75% of the pituitary may result in panhypopituitarism, which is characterized by abnormalities of the thyroid, adrenal gland, and reproductive organs. Coarse Facial Features and Protruding Jaw Seen with Acromegaly Sheehan syndrome is ischemic necrosis of the pituitary secondary to hypotension from postpartum hemorrhage resulting in panhypopituitarism. Craniopharyngioma is a benign pituitary tumor derived from Rathke pouch rem- nants that are usually located above the sella turcica, but can extend downward to destroy the pituitary. Cushing Syndrome and Its Effects Hyperaldosteronism may cause hypertension and hypokalemia. They are caused either by adrenocortical adenoma/carcinoma, which produces androgens, or by congenital adrenal hyperplasia, a cluster of autosomal recessive enzyme defects (most common is 21-hydroxylase deficiency). Patients present with gradual onset of weakness, skin hyperpigmentation, hypotension, hypoglycemia, poor response to stress, and loss of libido. It can present with sustained or episodic hypertension and associated severe headache, tachycardia, palpitations, diaphoresis, and anxiety. Microscopically, the tumor shows nests of cells (Zellballen) with abundant cytoplasm. Microscopically, lymphocytic inflammation involves the islets of Langerhans (insulitis), leading to loss of cells and fibrosis of the islets. T2D is often asymptomatic, but it can present with either polydipsia, polyuria, and polyphagia, or with hyperosmolar nonketotic diabetic coma. Microscopically, the changes are nonspecific, and can include focal atrophy and amyloid deposition in islets (hyalinization). Treatment is diet/weight loss, oral antidiabetic drugs, and insulin as needed (more common in long-standing cases). The vascular disease can lead to atrophy of skin and loss of hair of the lower extremities, claudication, nonhealing ulcers, and gangrene of lower extremities. Diabetic nephropathy includes glomerular lesions, arteriolosclerosis, and pyelonephritis (see Renal chapter). Nonproliferative retinopathy is characterized by microaneurysms, retinal hemorrhages, and retinal exudates. Diabetic neuropathy can cause peripheral neuropathy, neurogenic bladder, and sexual impotence. Bone remodeling occurs throughout life and is necessary to maintain healthy bones. Bone resorption by osteoclasts is tightly balanced with bone formation by osteoblasts. Long bones may have broadened metaphyses, causing an "Erlenmeyer flask"-shaped deformity. Cranial nerve compression due to narrowing of cranial foramina may result in blindness, deafness, and facial nerve palsies. Lab studies show highly elevated serum alkaline phosphatase and increased levels of urinary hydroxyproline. Complications include arteriovenous shunts within marrow, which may result in high-output cardiac failure and an increased incidence of osteosarcoma and other sarcomas. Microscopically, there is a haphazard arrangement of cement lines, creating a "mosaic pattern" of lamellar bone. Skull involvement leads to increased head size and foraminal narrowing that can impinge on cranial nerves, often leading to deafness. Lab studies may show normal serum calcium, phosphorus, and alkaline phosphatase, but the diagnosis is not based on labs. Treatment can include estrogen replacement therapy (controversial; not recommended currently); weight-bearing exercise; calcium and vitamin D; bisphosphonate (alendronate); and calcitonin. Specific causes include dietary deficiency of vitamin D, intestinal malabsorption, lack of sunlight, and renal and liver disease. Note Rickets and osteomalacia are disorders of osteoid mineralization; osteoid is produced in normal amounts but is not calcified properly. The patient may present clinically with bone pain or fractures (vertebrae, hips, and wrist). Lab studies show low serum calcium, low serum phosphorus, and high alkaline phosphatase. Osteomalacia (adults) is due to impaired mineralization of the osteoid matrix Rickets (children) occurs in children prior to closure of the epiphyses. Both remodeled bone and bone formed at the epiphyseal growth plate are undermineralized. Skull deformities include craniotabes (softening, seen in early infancy) and frontal bossing (hardening, later in childhood). The "rachitic rosary" is a deformity of the chest wall as a result of an overgrowth of cartilage at the costochondral junction. Clinical Correlate Lab findings help to distinguish osteomalacia from osteoporosis. Clinically, osteomyelitis is characterized by fever and leukocytosis; and localized pain, erythema, and swelling. X-ray studies may be normal for up to 2 weeks, and then initially show periosteal elevation followed by a possible lytic focus with surrounding sclerosis. Vascular insufficiency can lead to ischemic necrosis of bone; a sequestrum is an area of necrotic bone, while an involucrum is the new bone formation that surrounds the sequestrum. Complications include fracture, intraosseous (Brodie) abscess, secondary amyloidosis, sinus tract formation, squamous cell carcinoma of the skin at the site of a persistent draining sinus tract, and, rarely, osteogenic sarcoma. Common sites of involvement include thoracic and lumbar vertebrae ("Pott disease"). Complications include vertebral compression fracture, psoas abscesses, and secondary amyloidosis. Causes include trauma and/or fracture (most common); idiopathic; steroid use; sickle cell anemia; Gaucher disease; and caisson disease. It develops when stress from the quadriceps during rapid growth causes inflammation of the proximal tibial apophysis at the insertion of the patellar tendon. Fibrous dysplasia presents with painful swelling, deformity, or pathologic frac- ture of involved bone (typically ribs, femur, or cranial bones), usually in children and young adults. Osteoid osteoma is a benign, painful growth of the diaphysis of a long bone, often the tibia or femur. Osteoblastoma is similar to an osteoid osteoma but larger (>2 cm) and often involves vertebrae.
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Therefore medicine overdose purchase methotrexate 2.5mg otc, this Quality Attribute was evaluated in conjunction with upstream process development since oligosaccharide heterogeneity is dependent on mode of production and culture conditions treatment that works generic 2.5 mg methotrexate with mastercard. Specific analytical assays were developed to support upstream process development and to evaluate product quality for batches used in nonclinical and clinical studies medicine rocks state park buy 2.5mg methotrexate fast delivery. This assay is capable of resolving and quantifying a broad spectrum of glycan structures symptoms 2dpo generic methotrexate 2.5mg. A risk assessment was performed to evaluate the impact of glycosylation on the safety and efficacy of the product jnc 8 medications buy methotrexate 5 mg low price. Process performance and capability were not taken into consideration for this assessment treatment gout methotrexate 2.5 mg generic. The outcome of this risk assessment resulted in a designation of High` criticality for certain oligosaccharide structures. The ranges for other glycan structures are supported by nonclinical and clinical experience. Since the production bioreactor has the greatest potential to influence the oligosaccharide profile and consequently impact safety and efficacy, a risk assessment was performed to evaluate the impact of each process parameter associated with this unit operation. The process parameters identified by this risk assessment as having the greatest impact on the oligosaccharide profile were further examined in upstream process characterization studies. Following completion of these studies, a final risk assessment was conducted to categorize input parameters. The design space limits for each of these parameters are discussed in the Upstream Process Development section. A process capability risk assessment was conducted for the production bioreactor and the results are shown in Table 6. These include: the ranges for afucosylated and galactosylated structures are supported by nonclinical and clinical experience. Prior knowledge obtained with other monoclonal antibodies manufactured using the platform upstream process show similar consistency of oligosaccharide profile over multiple commercial lots. Even though the criticality of afucosylated glycans is rated high, there is only one unit operation that impacts this quality attribute and the process capability risk is low. The extensive upstream development studies have identified the process parameters that influence the oligosaccharide profile and all of these are well controlled. To ensure consistency, testing for these specific glycan structures will be included as part of process monitoring. Process monitoring at the production bioreactor may include collection of complete oligosaccharide profiling data to support lifecycle verification of consistent operations. Oligosaccharide profiling will also be included as part of characterization and comparability testing to verify movement within the design space or of process changes outside of the defined design space. A summary of the integrated control strategy for the oligosaccharide profile is presented in Table 6. A quality system is in place for raw materials management and maintenance of the cell line. Process monitoring of the drug substance oligosaccharide profile will be conducted to support lifecycle verification of consistent operations. The frequency of monitoring will be reviewed periodically and adjusted based on trends. Development of the strategy to control aggregate level utilized iterative risk assessments based on platform knowledge and product-specific data. Aggregation may generally be viewed as a symptom of some type of stress to the protein. Individual proteins vary from one another in their sensitivity to specific stresses. Typically, extremes of temperature, pH, osmolality, mechanical shear, covalent degradation, exposure to hydrophobic surfaces or interfaces have the potential to encourage protein aggregation (Manning et al. Further, risk is greater as protein concentration is increased and the level of aggregate tends to increase on storage of solutions, whether that solution is a process intermediate or a formulated product. Measurable characteristics of a protein are closely associated with specific risks of aggregation. Thus, before selection of the A-Mab primary amino acid sequence as a clinical candidate, the propensity for aggregation under a variety of buffer matrices and stressed environments was evaluated and used as a candidate selection criterion and to inform initial risk assessments. Manufacturing process risk has been minimized by a combination of process design, to minimize aggregate formation, inclusion of an operation capable of aggregate removal following the steps with the highest risk of generating aggregates, plus analytical controls to assure consistent process performance and assure patient safety. The process used to manufacture A-Mab is a platform process designed to minimize aggregates and other risks that was refined during development of several prior IgG drug candidates. That prior platform knowledge informed process design and early product-specific process risk assessments, and was supported by product-specific experimental designs. In summary, there is risk of aggregate formation at multiple steps in the process and aggregates are removed/cleared effectively at the cation exchange step. Aggregation occurs on storage as a solution, especially when the mAb is concentrated and aggregation rate is affected by the buffer pH, matrix and temperature. This understanding guided development of the control strategy for operations, development of the drug product formulation and analytical control. The conclusion of the product-specific risk assessment was that the highest risks of aggregation are in the bioreactor, the low pH viral inactivation step, pumping of formulated drug product and during the shelf life of the drug product. A process capability risk assessment was conducted for the unit operations that pose the highest risk to aggregate formation and the results are summarized in Table 6. Severity of impact was rated as 10 unless there are downstream steps that can clear aggregate. Thus, while the process delivers appropriate aggregation control when operated well within the process design space/limits, release testing is necessary to assure that an undetected process deviation does not compromise product quality. An integrated control strategy has been developed based on the process risks and mitigations, above, and is summarized in Table 6. Detailed descriptions of process capability can be found in the respective sections describing the upstream, downstream and drug product processes. Details of these risk assessments and characterization studies can be found in the Upstream and Downstream process sections. During its development, the method was qualified against 2-D gels and Western blots as providing a response to a broad range of host cell proteins; therefore the method can be considered to provide an accurate assessment of overall mass levels of host cell protein residuals in the product. The assay has been validated for linearity, precision, accuracy, and robustness to enable its use in process characterization and validation studies. To address the dependency between the Protein A and Cation Exchange design spaces, the option has been taken to constrain one or the other design space to avoid the need to perform in-process testing. This monitoring may be discontinued once robustness of column performance over the resin lifetime is demonstrated. This knowledge, in conjunction with the low criticality of the quality attribute, has eliminated the need for in-process testing or extraordinary process control. To fully understand the process and determine the appropriate process control strategy, levels of deamidation observed in designed process characterization experiments were assessed. Based on the body of process data as a whole, it was determined that the level of control on the process for other more critical attributes far exceeded the level of control needed to maintain deamidation. Due to the evidence of very low criticality of this attribute, acceptable levels of deamidation is not limited by levels seen in material used in clinical trials. Process capability results indicate that the A-Mab downstream process is robust and that it consistently reduces viral loads to levels that are well below safety concerns. Working within the design space of each step provides a high degree of assurance that viral clearance targets are met. In addition, the potential presence of adventitious virus is checked by testing cell culture samples at the end of each production bioreactor step. Stability of protein pharmaceuticals, Part A, Chemical and Physical Pathways of Protein Degradation. The regulatory section is provided to stimulate discussion about how the knowledge and data exemplified in this case study can be used to create risk-based regulatory strategies for product licensure, and management of changes to the manufacturing process. An enhanced understanding of product attributes based on prior knowledge, preclinical and clinical data, linked to demonstrated understanding of the process can result in a more rational basis for design of the overall control strategy. The design space is based on development data generated from small scale lots up to commercial scale lots. This data in its entirety can form the basis for process qualification and validation when coupled with a program of continued process verification. An iterative, risk based approach for managing changes to the manufacturing process can be implemented by leveraging the original approach for creating a design space by linking process parameters to critical quality attributes. Movement within a design space, based on the documented lack of effect on critical quality attributes, can be managed within the quality system. For movement outside of a design space, the outcome of the risk assessment exercise will facilitate determination of the data required to support the change. The level of regulatory oversight required for the change should be proportional to the level of risk identified Some examples of specific application of these principles with regard to managing changes outside of a design space are provided as a stimulus to discussion in an appendix to the section. Thus, the QbD approach provides a rational and science based approach to linking product specifications to clinical relevance. This differs greatly from the current practice of setting numerical acceptance limits based solely on clinical trial experience and/or process capability and assay performance considerations Likewise, in the QbD paradigm, adjustments to the product`s specifications throughout the lifecycle should be based on the same rational evaluation of clinical relevance rather than on the traditional approach of basing adjustments on statistical analysis of manufacturing performance at target process conditions. In the traditional approach as process control capabilities increase and sources of variability are eliminated, the quality outputs and thus specification limits become even tighter. This traditional approach ensures that process performance and quality outputs are consistent, but fails to consider clinical relevance and the linkage of the specifications to the approved design space. In QbD applications, approved product specifications should not change unless significant new data related to clinical outcomes became available. However, continued assurance of consistent process performance and identification of any potential out-of-trend results would be assured by applying process-capability analysis as part of the continued process verification approach managed through the quality system. Regulatory commitments are the elements of the file that will not change without health authority agreement. The health authority interaction can range from annual notification to approval prior to implementation. The design space may also require regulatory control of critical raw materials; however, this was not explored in the case study. An understanding of the overall process development history incorporating risk assessments and process design decisions is important in the overall evaluation and justification of the product and process controls with regard to a regulatory submission. In order to understand the basis for the overall process and product control strategy the following information would be provided: A summary of the process development history and understanding that is the basis for selection of the routine operating parameters for each unit operation and their classification as critical, key or general for each unit operation. This is exemplified in the case study by the thaw, seed-train and N-2 and N-1 steps presented in the upstream section. An important consideration is the amount of data that is required in order to understand the process development and risk assessment summaries. The data presented in this case study includes detailed information that exemplifies the types of logic that must be built into risk assessments used to identify areas of high risk to product and patient, as well as the rigor required of the tools used to perform the data analysis. This may represent an extreme level of data and detail not required or useful with regard to a regulatory submission. A design space is justified based on process-specific and historical (platform) data collected over a wide range of scales. The majority of the data will result from small scale experimentation with the balance being supported by clinical and commercial production scales. The approach to process qualification lots differs in this case study from the traditional 3 or more pre-filing validation lots by allowing commercial scale lots produced at any time during development to be used to assure that the process, when operated within the proposed commercial design space meets all in-process controls and release test limits intended for the commercial scale process. Are accepted as suitable based on a Quality approved protocol that specifies the required process conditions, analytical testing and criteria to be met for lots to be considered representative of the commercial production. The number of lots required is risk-based and dependent on the amount of process understanding available and an assessment of the information needed to appropriately augment the development data. They can be run using various target set points, provided the targets are contained within the proposed design space. In this case study, since no commercial scale production was performed during clinical development, two commercial scale lots were manufactured prior to the license application to gather additional data to support the design space. However, if a sponsor had already produced commercial scale lots during clinical development using a documented process that met all the requirements of the commercial process, no additional commercial lots would be needed prior to the filing. For example robustness of process design and independence from thaw to thaw variation, are judged through the robustness and inclusiveness of the development data with regard to these issues, rather than on including > 2 thaws in the traditional demonstration campaign of 3-5 consecutive runs. Confidence in the small scale models is sufficient to allow direct application and approval of the design space based on a combination of the following: 1. Collection of development data at scale using various targets for parameters within the design space may be particularly useful. Data collected as a result of investigation of manufacturing deviations also enhances process understanding and increases confidence in the design space model. Process monitoring data will be collected at pre-defined intervals to review process performance and to assess if a change in the process control is warranted. In regulatory submissions employing a QbD approach, it is important to distinguish between the information provided to demonstrate product and process knowledge vs. The overall risk assessment as outlined in the control strategy section (Figure 5-2) is used to support lifecycle management. The key element to consider when the risk assessment is repeated is to analyze proposed movements within or changes to the design space, is whether the proposed change falls within criteria and limits defined by the previous assessment. Categorization of reporting requirements would be commensurate with potential risk. A discussion on our approach to assessments and categorization of change, within and beyond an approved design space, is provided in the following sections. Planned movement within a design space does require a prospective assessment of the risks associated with the particular move to be performed within the quality system and a conclusion that the proposed change is supported by the existing product and process knowledge. Movement within the design space is managed without a regulatory notification requirement because the space has already been assessed and approved. The level of regulatory oversight required for the change should be proportional to the level of risk identified Change outside the design space must be evaluated on a case-by-case basis to determine the appropriate data package and regulatory approval pathways. We envision that the systematic process risk assessments described for the approval of the original process provide the roadmap to assess the impact of changes outside the design space. The proposed change would be evaluated for its impact on the originally defined design space, and the outputs for the specific unit operation.
Samples/ day1 1 2 3 4 If at any time the residual disinfectant concentration falls below 0 symptoms 5 weeks pregnant cheap methotrexate 2.5 mg amex. For systems serving 500 or fewer persons symptoms 5 days past ovulation methotrexate 2.5 mg amex, the State may reduce the turbidity sampling frequency to once per day treatment medical abbreviation generic methotrexate 2.5mg on line, regardless of the type of filtration treatment used symptoms adhd buy methotrexate 2.5mg without a prescription, if the State determines that less frequent monitoring is sufficient to indicate effective filtration performance treatment 20 initiative methotrexate 5 mg with mastercard. Information that must be reported includes: (i) the cumulative number of months for which results are reported treatment quincke edema cheap 2.5 mg methotrexate overnight delivery. Information that must be reported includes: (i) For each day, the lowest measurement of residual disinfectant concentration in mg/l in water entering the distribution system. If the inspection was conducted by the State, the State must provide a copy of its report to the public water system. The system also must notify the State by the end of the next business day whether or not the residual was restored to at least 0. Information that must be reported includes: (i) the total number of filtered water turbidity measurements taken during the month. All subpart H systems that employ conventional filtration or direct filtration treatment and that recycle spent filter backwash water, thickener supernatant, or liquids from dewatering processes must meet the requirements in paragraphs (b) through (d) of this section. A system must notify the State in writing by Decemeber 8, 2003, if the system recycles spent filter backwash water, thickener supernatant, or liquids from dewatering processes. If capital improvements are required to modify the recycle location to meet this requirement, all capital improvements must be completed no later than June 8, 2006. The system must collect and retain on file recycle flow information specified in paragraphs (d)(1) through (6) of this section for review and evaluation by the State beginning June 8, 2004. Unless otherwise indicated, each of the provisions of this subpart applies to community water systems and nontransient, non-community water systems (hereinafter referred to as ``water systems' or ``systems'). These regulations establish a treatment technique that includes requirements for corrosion control treatment, source water treatment, lead service line replacement, and public education. Each sampling result shall be assigned a number, ascending by single integers beginning with the number 1 for the sample with the lowest contaminant level. The number assigned to the sample with the highest contaminant level shall be equal to the total number of samples taken. The State may require any such system to conduct additional monitoring or to take other action the State deems appropriate to ensure that such systems maintain minimal levels of corrosion in the distribution system. Any such large system shall adhere to the schedule specified in that paragraph for medium-size systems, with the time periods for completing each step being triggered by the date the system is no longer deemed to have optimized corrosion control under this paragraph. If any such water system thereafter exceeds the lead or copper action level during any monitoring period, the system (or the State, as the case may be) shall recommence completion of the applicable treatment steps, beginning with the first treatment step which was not previously completed in its entirety. The State may require a system to repeat treatment steps previously completed by the system where the State determines that this is necessary to implement properly the treatment requirements of this section. The State shall notify the system in writing of such a determination and explain the basis for its decision. The requirement for any small- or medium-size system to implement corrosion control treatment steps in accordance with paragraph (e) of this section (including systems deemed to have optimized corrosion control under paragraph (b)(1) of this section) is triggered whenever any small- or medium-size system exceeds the lead or copper action level. The State may require any small or medium-size system that exceeds the lead or copper action level to perform corrosion control studies under paragraph (c) of this section to identify optimal corrosion control treatment for the system. Based upon the results of lead and copper tap monitoring and water quality parameter monitoring, small and medium-size water systems exceeding the lead or copper action level shall recommend installation of one or more of the corrosion control treatments listed in paragraph (c)(1) of this section which the system believes constitutes optimal corrosion control for that system. The water system shall provide a rationale for its recommendation along with all supporting documentation specified in paragraphs (c) (1) through (5) of this section. When designating optimal treatment the State shall consider the effects that additional corrosion control treatment will have on water quality parameters and on other water quality treatment processes. If the State requests additional information to aid its review, the water system shall provide the information. The State shall evaluate the results of all lead and copper tap samples and water quality parameter samples submitted by the water system and determine whether the system has properly installed and operated the optimal corrosion control treatment designated by the State in paragraph (d) of this section. Upon reviewing the results of tap water and water quality parameter monitoring by the system, both before and after the system installs optimal corrosion control treatment, the State shall designate: (1) A minimum value or a range of values for pH measured at each entry point to the distribution system; (2) A minimum pH value, measured in all tap samples. The values for the applicable water quality control parameters listed above shall be those that the State determines to reflect optimal corrosion control treatment for the system. The State shall notify the system in writing of these determinations and explain the basis for its decisions. A water system is out of compliance with the requirements of this paragraph for a six-month period if it has excursions for any State-specified parameter on more than nine days during the period. An excursion occurs whenever the daily value for one or more of the water quality parameters measured at a sampling location is below the minimum value or outside the range designated by the State. Upon its own initiative or in response to a request by a water system or other interested party, a State may modify its determination of the optimal corrosion control treatment under paragraph (d) of this section or optimal water quality control parameters under paragraph (f) of this section. A request for modification by a system or other interested party shall be in writing, explain why the modification is appropriate, and provide supporting documentation. The State may modify its determination where it concludes that such change is necessary to ensure that the system continues to optimize corrosion control treatment. Any system which exceeds the lead or copper action level shall recommend in writing to the State the installation and operation of one of the source water treatments listed in paragraph (b)(2) of this section. If the State requests additional information to aid in its review, the water system shall provide the information by the date specified by the State in its request. The State shall notify the system in writing of its determination and set forth the basis for its decision. Each system shall properly install and operate the source water treatment designated by the State under paragraph (b)(2) of this section. The State shall review the source water samples taken by the water system both before and after the system installs source water treatment, and determine whether the system has properly installed and operated the source water treatment designated by the State. Based upon its review, the State shall designate the maximum permissible lead and copper concentrations for finished water entering the distribution system. Such levels shall reflect the contaminant removal capability of the treatment properly operated and maintained. The State shall notify the system in writing and explain the basis for its decision. The system is out of compliance with this paragraph if the level of lead or copper at any sampling point is greater than the maximum permissible concentration designated by the State. The State may modify its determination where it concludes that such change is necessary to ensure that the system continues to minimize lead and copper concentrations in source water. The initial number of lead service lines is the number of lead lines in place at the time the replacement program begins. The first year of lead service line replacement shall begin on the date the action level was exceeded in tap sampling referenced in paragraph (a) of this section. A system is not required to bear the cost of replacing the privately-owned portion of the line, nor is it required to replace the privatelyowned portion where the owner chooses not to pay the cost of replacing the privately-owned portion of the line, or where replacing the privately-owned portion would be precluded by State, local or common law. A water system that does not replace the entire length of the service line also shall complete the following tasks. The system shall collect the sample and report the results of the analysis to the owner and the resident(s) served by the line within three business days of receiving the results. Mailed notices post-marked within three business days of receiving the results shall be considered ``on time. In instances where multi-family dwellings are served by the line, the water system shall have the option to post the information at a conspicuous location. The State shall make this determination in writing and notify the system of its finding within 6 months after the system is triggered into lead service line replacement based on monitoring referenced in paragraph (a) of this section. A community water system shall include the following text in all of the printed materials it distributes through its lead public education program. Systems may delete information pertaining to lead service lines, upon approval by the State, if no lead service lines exist anywhere in the water system service area. Public education language at paragraphs (a)(1)(iv)(B)(5) and (a)(1)(iv)(D)(2) of this section may be modified regarding building permit record availability and consumer access to these records, if approved by the State. This brochure explains the simple steps you can take to protect you and your family by reducing your exposure to lead in drinking water. Lead is a common metal found throughout the environment in lead-based paint, air, soil, household dust, food, certain types of pottery porcelain and pewter, and water. Lead builds up in the body over many years and can cause damage to the brain, red blood cells and kidneys. In addition, a child at play often comes into contact with sources of lead contamination-like dirt and dust- that rarely affect an adult. These materials include lead-based solder used to join copper pipe, brass and chrome plated brass faucets, and in some cases, pipes made of lead that connect your house to the water main (service lines). This means the first water drawn from the tap in the morning, or later in the afternoon after returning from work or school, can contain fairly high levels of lead. To find out whether you need to take action in your own home, have your drinking water tested to determine if it contains excessive concentrations of lead. Testing the water is essential because you cannot see, taste, or smell lead in drinking water. Some local laboratories that can provide this service are listed at the end of this booklet. For more information on having your water tested, please call [insert phone number of water system]. If your house has a lead service line to the water main, you may have to flush the water for a longer time, perhaps one minute, before drinking. It usually uses less than one or two gallons of water and costs less than [insert a cost estimate based on flushing two times a day for 30 days] per month.
Corticosteroids also induce the enzyme involved in transformation of norepinephrine to epinephrine and increase the responsiveness of the receptors for endogenous and exogenous catecholamines medicine 5e safe 2.5mg methotrexate. Some observational studies have reported a statistical association between hypotension and serum cortisol levels < 15 mcg/dl ("relative adrenal insufficiency") in preterm infants treatment with chemicals or drugs order 5 mg methotrexate overnight delivery. However these levels are poor predictors for actual occurrence of hypotension or response to treatment with hydrocortisone medications like zoloft discount methotrexate 10 mg visa. Use of corticosteroids in premature infants has been associated with adverse neurologic outcome and increased risk of intestinal perforation treatment tinea versicolor order 5mg methotrexate mastercard, especially if used in conjunction with indomethacin medicine zalim lotion methotrexate 5 mg discount. Therefore medications over the counter buy methotrexate 10mg without prescription, we do not recommend concurrent administration of hydrocortisone and indomethacin. Hyperglycemia and impaired bone mineralization have also been associated with corticosteroid use. Patent Ductus Arteriosus Adrenal Insufficiency Adrenal insufficiency most likely contributes to or plays a complicating role in the development of hypotension in certain at-risk neonates like premature infants or those with an underlying endocrine abnormality. In these at-risk patient groups, consider hydrocortisone to support the blood pressure, particularly when the hypotension is refractory to pressors. Although it also stimulates both -2 and -1 receptors in the vasculature, the cumulative result is some vasodilation in addition to the inotropic and chronotropic effects. The use of dobutamine may be considered for inotropic support when left ventricular function is impaired based on clinical or echocardiographic evidence (weak recommendation, low quality evidence). Dopamine-is the most frequently prescribed medication for Dobutamine-stimulates myocardial -1 and -1 receptors failure. In the neonatal population, it is used in patients with low cardiac output associated with congenital heart disease or myocardial dysfunction. Milrinone can cause hypotension and should be considered only when blood pressure is adequate. It should be avoided in patients with oliguria or anuria due to increased risk of toxicity. Vasopressin- induces vasoconstriction via multiple nonspecific hypotension, though its overall use has declined in the last decade. It is no longer the preferred agent in pediatric and adult patients due to its effect on heart rate and its arrhythmogenic potential. In adults, it has been shown to have variable dose-related activation of receptors, but it is unclear if similar receptor activation occurs in neonates. Moreover, it appears that neonates have activation of receptors at lower doses with variable results. When used, it should be started at 5 mcg/kg/min and titrated to effect (strong recommendation, low quality evidence). If no effect is seen with doses of 10-15 mcg/kg/min, addition of another agent should be considered. Epinephrine may be considered in patients when improvement of systolic performance is desired and may be a better option than dopamine when concern for hypoxic respiratory failure is present (strong recommendation, low quality evidence). Its effects on the cardiovascular system are not fully understood, but vasoconstrictive effects are preserved during hypoxia and severe acidosis. It should also be considered a viable option in hypotension when tachycardia or increased inotropy would be contraindicated. It can be used for the purpose of "rescue" in select premature infants with severe pulmonary hypertension. Inhaled nitric oxide is administered via the ventilator circuit at an initial dose of 20 ppm. Response to therapy is defined as an improvement in PaO2 of at least 10 mmHg or increase in oxygen saturations of at least 5%. At 5 ppm, we recommend to wean by increments of 1ppm every 1-2 hours until discontinued. It has an inotropic effect on the heart and a dilating effect on veins and arterioles, and does not depend on neurotransmitter stores or receptors. Carvedilol, a non-selective antagonist with -1 adrenergic blocking activity, is commonly used in pediatric heart failure patients. It has vasodilatory, anti-oxidant, anti-proliferative, and anti-apoptotic properties. Although carvedilol has not been directly compared with other -blockers, the broad suppression of adrenoceptors is believed to contribute to improved outcomes in patients with chronic heart failure. Propranolol and carvedilol are available as a liquid formulation, allowing for ease of administration in infants and young children. Adverse effects of -blockers include hypotension and mild worsening of heart failure symptoms, especially at onset of treatment. Contraindications include symptomatic bradycardia/heart block and significant hypotension. Despite the lack of long term efficacy and mortality data from pediatric clinical trials, diuretics are routinely used for symptom relief in the acute management of symptomatic heart failure. If diuresis with loop diuretic is inadequate, addition of a thiazide diuretic may be considered. Most serious and life threatening lesions that require urgent intervention usually present within the first several days of life. Timing and mode of presentation depend upon the type of lesion or ductus arteriosus closure, and fall in pulmonary vascular resistance. A differential for congenital heart diseases based on symptoms is presented in Table 3-8. Other differential diagnoses to consider when working up a patient for congenital heart disease include sepsis, primary pulmonary disease, anemia, and metabolic disorders. Because of its short half-life, captopril requires frequent dosing, from 2-4 times daily. Enalapril has a longer duration of action due to the long half-life of its active metabolite enalaprilat and can be administered once to twice daily. Studies have shown that pulse oximetry is an effective, though not infallible, screening measure. In addition to pulse oximetry screening, careful review of the history and physical examination of the infant remain imperative. Basic Physiology & Management of Neonatal Cardiac Disease Presentation in newborn period: Cyanosis- bluish discoloration of the tissues results when the -blockers-In adults, -blockers have been shown to decrease mortality and morbidity through reversal of adrenergic myocardial dysfunction, attenuation of neuro hormonal systems, antiarrhythmic effect, and negative chronotropic effect. It is unclear if beta blockers exert the same effects and benefits for pediatric patients with heart failure. Propranolol is 50 absolute level of reduced hemoglobin in the capillary bed exceeds 5 g/dL. The appearance of cyanosis depends upon the total amount of reduced hemoglobin rather than the ratio of reduced to oxyhemoglobin. Acidosis- increased lactate production due to anaerobic metabolism Differential Cyanosis- difference of >5% in the oxygen saturation measured in the right hand (preductal) and either foot (postductal) identifies infants with differential cyanosis. Surgical interventions may include the single ventricle pathway, eventual biventricular repair, or orthotopic cardiac transplantation. Surgical interventions depend on the physiology and may include aortopulmonary shunts, pulmonary banding, and eventual Fontan palliation. The right ventricular cavity size is reduced, the tricuspid valve is regurgitant (often severely), and right ventricular outflow is obstructed. This increases right atrial size producing the characteristic chest radiograph where the cardiac silhouette fills the thoracic cavity. There may be functional pulmonary atresia if right ventricular function is insufficient to generate enough force to open the pulmonary valve. Surgical interventions depend upon right ventricular size and function and the ability to repair the tricuspid valve. Differential cyanosis also occurs in infants with structurally normal hearts who have persistent pulmonary hypertension of the newborn. In these lesions, pulmonary blood flow may be ductal-dependent and PgE may be required to maintain ductal patency. Depending upon the degree of obstruction, balloon valvuloplasty of the pulmonary valve or surgical valvuloplasty may be considered. Imaging and cardiac catheterization is necessary to delineate anatomy to determine interventional strategy. In a similar fashion, PgE is usually not helpful and may lead to worsened systemic perfusion (unless coarctation or interrupted aortic arch is present). In utero, this may cause dilation of the normally-connected pulmonary arteries, often severe, which postnatally results in bronchial compression and respiratory failure. Neonatal repair is typical with respiratory failure continuing post-operatively due to severe malacia. Acyanotic Lesions with Left to Right Shunt Parallel Circulations with Poor Mixing Patients with defects involving a large left to right shunt typically become symptomatic over time due to increased pulmonary blood flow (Qp:Qs >1) and present with respiratory distress, pulmonary congestion, and eventually congestive heart failure. Palliation with pulmonary artery banding may be appropriate in symptomatic infants who have not reached an adequate size or age for definitive repair. With the two circulations in parallel, communication is required at the atrial, ventricular, and/or ductal levels. Management in the neonatal period includes PgE and balloon atrial septostomy, if needed. Surgical repair, the arterial switch procedure, is usually performed in the first 2 weeks of life. Depending upon the amount of conal muscle, these arteries may be normally-related, malposed (side-by-side), or transposed (aorta rightward of the pulmonary artery). Cyanosis is generally progressive and these infants may have hypercyanotic spells. Balloon atrial septostomy may be required and surgical repair is generally during the neonatal period. Diuretics are the mainstay of medical therapy with surgical intervention usually in early infancy. Cardiac output is dependent upon right to left shunting through an atrial septal defect. If pulmonary venous return is unobstructed, there is increased pulmonary blood flow leading to tachypnea and respiratory distress with mild cyanosis. Surgical repair is emergent and may be complicated by postoperative pulmonary artery hypertension. Truncus Arteriosus- a failure of septation of the great vessels resulting in complete mixing of the circulations in a single truncal vessel. In the absence of obstruction to pulmonary blood flow, as pulmonary vascular resistance decreases after birth, partitioning of the cardiac output favors the pulmonary circulation. The infant may present with mild tachypnea and saturations of approximately 85% (or lower if there is branch pulmonary stenosis or pulmonary edema). The infant may also have a wide pulse pressure due to diastolic runoff from the aorta to the low-resistance pulmonary circuit or incompetence of the truncal valve, resulting in poor coronary and systemic perfusion. Workup should include serum ionized calcium due to the 52 Single ventricle Single ventricle physiology involves complete mixing of systemic and venous blood, which may occur at various levels. The oxygen saturation in the ventricle and great arteries depend on the relative systemic and pulmonary blood flow which is dictated by pulmonary and systemic vascular resistance. One of the great arteries typically originates from the hypoplastic outlet chamber. At the time of ductal closure, these infants present with signs of poor systemic perfusion characterized by weak or absent peripheral pulses, metabolic acidosis, and shock. Sedatives and/or narcotics should be judiciously provided in cases of pain or agitation not alleviated by non-pharmacologic measures. Therefore, normothermia should be ensured by maintaining servocontrolled temperature regulation or frequent measurement of body temperature if the infant is dressed and bundled. Overall appearance, skin color, and perfusion should be assessed regularly under appropriate lighting. Monitoring perfusion to distal tissues due to narrowing or obstruction of the aorta. Management in the preoperative period includes PgE administration and careful prevention of excessive pulmonary blood flow. Continuous blood pressure monitoring should be considered during periods of clinical instability and during periods of changing physiology. Upper extremity cuff blood pressure monitoring may be employed during periods of stability and should be performed every 3 hrs. Four-extremity blood pressure monitoring should be performed upon admission for all patients and regularly in those with suspicion for aortic arch hypoplasia. Laboratory investigations may include regular monitoring of blood gas and lactate levels, particularly when there is concern for inadequacy of systemic blood flow or cardiac output. Optimal measurement of lactate is obtained by arterial puncture or indwelling line. Capillary lactate specimens may be used as a method for trending lactate levels, but should not be considered diagnostic or be interpreted without consideration of the overall clinical picture. Balloon dilation is the procedure of choice if left-sided structures are amenable to biventricular repair. A Norwood approach may be needed if there is marked annular hypoplasia, unicuspid aortic valve, ventricular hypoplasia/dysfunction, or associated subaortic obstruction. Classically, this includes parachute mitral valve, supravalvar ring, coarctation of the aorta, and subaortic obstruction with multiple levels of resistance leading to decreased cardiac output and left-atrial hypertension. For those with unclear physiology or expected to have surgery in the first week of life, it is recommended to establish umbilical artery and umbilical venous access at the time of delivery or admission.
Dewald GW, Kayle RA, Hicks GA, et al. The clinical significance of cytogenetic studies in 100 patients with MM, plasma cell leukemia or amyloidosis. Blood 66:380-390, 1985.
Lepor H, Kaci L: The impact of open radical retropubic prostatectomy on tontinence and lower urinary tract symptoms: a prospective assessment using validated self-administered outcome instruments, J Urol 171:1216n 1219, 2004.
Albrich, S., Naumann, G., Skala, C. et al. TVT Secur- First experiences after a follow-up of 17 months [abstract]. Neurourol Urodyn 2008;27.
