THERAPEUTICS

treatment and care of a patient for the purpose of both preventing and combating disease or alleviating pain or injury. The term comes from the Greek therapeutikos, which means inclined to serve. In a broad sense therapeutics means serving and caring for the patient in a comprehensive manner, preventing disease as well as managing specific problems. Exercise, diet, and mental factors are therefore integral to the prevention, as well as the management, of disease processes. More specific measures that are employed to treat specific symptoms include the use of drugs to relieve pain or treat infection, surgery to remove diseased tissue or replace poorly functioning or nonfunctioning organs with fully operating ones, and counseling or psychotherapy to relieve emotional distress. Confidence in the physician and in the method selected enhances effectiveness. treatment and care of a patient for the purpose of both preventing and combating disease or alleviating pain or injury. The therapeutic aim of preventive medicine is either to obviate the opportunity for a disease to take hold, as by childhood immunizations or adhering to a healthy diet and exercise program, or to detect a disease in its earliest stages, as screening for colon cancer or mammograms for breast cancer are intended to do. Therapeutics involves a wide variety of techniques, including the use of drugs, surgery, radiation, mechanical devices, and psychiatry. In conventional modern medicine, therapeutic concepts and techniques are incorporated into such therapeutic specialties as pharmacology, immunology, preventive medicine, psychiatry, psychotherapy, and radiology. The scope of therapeutics is broad, as indicated by the many types of therapy. Included are surgical therapy, the correction or removal of diseased tissues by surgical operation; biological therapy, which involves the use of biological products, such as serums, vaccines, and antitoxins; drug therapy, including chemotherapy, the use of pure chemicals to attack specific diseases; radiation therapy, the use of X rays and radioactive isotopes to destroy diseased tissues; and psychotherapy, the use of counseling or behavioral modification to treat emotional disorders. Other forms of therapy make use of gold, heat, high-frequency sound (ultrasound), oxygen at normal pressure or at high pressure, infrared rays, ultraviolet rays, hypnosis, water baths (hydrotherapy), and vitamins. Still other forms include acupuncture, physical therapy, and occupational therapy. The application of measures to prevent and cure disease goes back to early human history. The ancient Greeks believed in the healthy effects of proper diet and exercise, and through trial and error people found much of therapeutic value in plants, animals, and minerals. Accidental discoveries, keen observations, and careful study resulted in useful findings. For example, the value of digitalis for heart diseases was learned by a physician in England investigating a brew made from foxglove. Many techniques, such as cupping (applying a cup to the body's surface in order to create a vacuum with which to draw up the skin), were tried widely and ultimately discarded. Following basic chemical and physical research in the 19th century, modern chemotherapy and therapeutics were born. Major contributions were made by Louis Pasteur, Robert Koch, and Paul Ehrlich, among others. Drugs were purified, specific measures against disease were developed, diseases were identified and their causes determined, and techniques for diagnosis, treatment, and prevention of disease were found. The development of more effective and purer drugs was an important factor, as was an understanding of the specificity of drug action. Formerly, a shotgun approach to therapy was often used. Today the physician can choose the type of anesthetic agent that is best for a certain type of operation, the best type of drug for pain, and the type of drug best suited to control muscle spasm, high blood pressure, allergy, or infection. In addition to advances ensuing from improved technology and increased understanding of drugs and the human organism, much of the development of modern therapeutics was a result of the work of individuals such as Florence Nightingale and Joseph Lister who brought attention to bear on hygiene, health education, hospital facilities, surgical techniques, transportation of the sick and injured, and other related factors. Additional reading Ralph H. Major, A History of Medicine, 2 vol. (1954), covers medical history from its beginnings to modern times; unlike many history books, it is easy reading. An unusual reference containing technical information not found in standard medical dictionaries is James L. Bennington, Dictionary & Encyclopedia of Laboratory Medicine and Technology (1984). Robert E. Rakel, Textbook of Family Practice, 4th ed. (1990), is the standard textbook for family physicians covering the breadth of the discipline and emphasizing clinical diagnosis and treatment. Annually an issue of JAMA, the journal of the American Medical Association, is devoted to recent discoveries in every medical discipline and is an excellent source of up-to-date information on new developments in medicine; one such development is treated in Richard C. Reba, Nuclear Medicine, JAMA, 270(2):230232 (July 14, 1993). An expert panel reviewed the scientific literature and developed recommendations for prevention in 60 conditions that represent the leading causes of death and disability in the United States; these recommendations are found in U.S. Preventive Services Task Force, Guide to Clinical Preventive Services (1989). Manual of Clinical Dietetics, 4th ed. (1992), published by the American Dietetic Association, is an excellent reference for diets and nutritional contents of foods. Drug Facts and Comparisons (annual), contains detailed information about all prescription drugs. Drug Evaluations Annual is a well-written evaluation of the clinical use of specific drugs, including comparative evaluations. Conn's Current Therapy (annual), provides a concise reference for the treatment of most medical and surgical diseases. Scientific American Medicine (monthly), published in loose-leaf format, covers all major areas of internal medicine. Douglas Wilmore (ed.), Care of the Surgical Patient, 2 vol. (1989), is a regularly updated loose-leaf publication from the Committee on Pre and Postoperative Care of the American College of Surgeons; vol. 1 is devoted to critical care and vol. 2 to elective surgery. Current Medical Diagnosis & Treatment (annual), contains concise diagnostic information and treatment for a large number of medical diseases. James B. Wyngaarden, Lloyd J. Smith, Jr., and J. Claude Bennett, Cecil Textbook of Medicine, 19th ed. (1992), is one of the best standard textbooks of medicine, compiled by leading authorities and containing thorough information on common and rare diseases. Richard D. DeShazo and David L. Smith (eds.), Primer of Allergic and Immunologic Diseases, JAMA, 268(20):27852996 (Nov. 25, 1992), is an entire issue devoted to allergy and immunology, containing articles ranging from the basics of the immune response to autoimmune diseases and immunization; prepared by the American Academy of Allergy and Immunology, it provides complete coverage of the subject. Robert Edwin Rakel Biological therapy Blood and blood cells Blood transfusions were not clinically useful until about 1900 when the blood types A, B, and O were identified and cross-matching of the donor's blood against that of the recipient to prove compatibility became possible. When blood with the A antigen (type A or AB) is given to someone with anti-A antibodies (type B or O blood), lysis of the red blood cells occurs, which can be fatal. Persons with blood type O are universal donors because this blood type does not contain antigen A or B; however, because type O blood contains antibodies against both A and B, patients with this blood type can receive only type O blood. Fortunately, type O is the most common blood type, occurring in 40 to 60 percent of people, depending on the selected population (e.g., 40 percent of the white population has blood type O, while 60 percent of Native Americans have it). Conversely, persons with type AB blood are universal recipients. Having no antibodies against A or B, they can receive type O, A, or B red blood cells. Most individuals are Rh-positive, which means they have the D antigen; less than 15 percent of the population lack this antigen and are Rh-negative. Although anti-D antibodies are not naturally present, the antigen is so highly immunogenic (able to provoke an immune response) that anti-D antibodies will develop if an Rh-negative person is transfused with Rh-positive blood. Severe lysis of red blood cells will occur at any subsequent transfusion. The condition erythroblastosis fetalis, or hemolytic disease of the newborn, occurs when Rh-positive babies are born to Rh-negative mothers who have developed anti-D antibodies either from a previous transfusion or by maternal-fetal exchange during a previous pregnancy. Whole blood transfusions are infrequently used because most transfusions only require one or more specific blood components. Whole blood, which contains red blood cells, plasma, platelets, and coagulation factors, is used mainly during cardiac surgery and when there is moderate or massive hemorrhage. It can be used only up to 35 days after it has been drawn and is not always available, because most units of collected blood are used for obtaining components. Packed red blood cells are what remains of whole blood after the plasma and platelets have been removed. A 450-millilitre unit of whole blood is reduced to a 220-millilitre volume. Packed red blood cells are used most often to raise a low hemoglobin or hematocrit level in patients with chronic anemia or mild hemorrhage. Leukocyte-poor red blood cells are obtained by employing a filter to remove white blood cells (leukocytes) from a unit of packed red blood cells. This type of transfusion is used to prevent febrile reactions in patients who have had multiple febrile transfusion reactions in the past, presumably to white blood cell antigens. Platelet transfusions are used to prevent bleeding in patients with very low platelet counts, usually less than 20,000 cells per microlitre, and in those undergoing surgery whose counts are less than 50,000 cells per microlitre. Autologous transfusion is the reinfusion of one's own blood. The blood is obtained before surgery and its use avoids transfusion reactions and transfusion-transmitted diseases. Donation can begin one month before surgery and be repeated weekly, depending on the number of units likely to be needed. Plasma Plasma, the liquid portion of the blood, is more than 90 percent water. It contains all the noncellular components of whole blood including the coagulation factors, immunoglobulins, electrolytes, and proteins. When frozen, the coagulation factors remain stable for up to one year but must be used within 24 hours when thawed. Fresh frozen plasma is used in patients with multiple clotting factor deficiencies, such as in those with severe liver disease or massive hemorrhage. Cryoprecipitate is prepared from fresh frozen plasma and contains about half the coagulation factors in 1/15 the volume. It is used to treat patients with deficiencies of factor VIII, von Willebrand factor, factor XIII, and fibrinogen. Specific clotting factor concentrates are prepared from pooled plasma or pooled cryoprecipitate. Factor VIII concentrate, the antihemophilic factor, is the preferred treatment for hemophilia A. A monoclonal antibodypurified human factor VIII is also available. Factor IX complex, the prothrombin complex, is also available for treating hemophilia B (factor IX deficiency). Drug therapy General features Principles of drug uptake and distribution Study of the factors that influence the movement of drugs throughout the body is called pharmacokinetics, which includes the absorption, distribution, localization in tissues, biotransformation, and excretion of drugs. The study of the actions of the drugs and their effects is called pharmacodynamics. Before a drug can be effective, it must be absorbed and distributed throughout the body. Drugs taken orally may be absorbed by the intestines at different rates, some being absorbed rapidly, some more slowly. Even rapidly absorbed drugs can be prepared in ways that slow the degree of absorption and permit them to remain effective for 12 hours or longer. Drugs administered either intravenously or intramuscularly bypass problems of absorption, but dosage calculation is more critical. Individuals respond differently to the same drug. Elderly persons, because of reduced kidney and liver function, may metabolize and excrete drugs more slowly. Because of this and other factors, the elderly usually require lower doses of medication than do younger people. Other factors that affect the individual's response to drugs are the presence of disease, degree of nutrition or malnutrition, genetics, and the presence of other drugs in the system. Furthermore, just as the pain threshold varies among individuals, so does the response to drugs. Some people need higher-than-average doses; some, being very sensitive to drugs, cannot tolerate even average doses, and they experience side effects when others do not. Infants and children may have different rates of absorption than adults because bowel motility is irregular or gastric acidity is decreased. Drug distribution may be different in some people, such as premature infants who have little fatty tissue and a greater proportion of body water. Metabolic rates, which affect pharmacokinetics, are much higher during childhood, as anyone with a two-year-old can attest. The dosages of drugs for children are usually calculated on the basis of weight (milligrams per kilogram) or on the basis of body surface area (milligrams per square metre). If a drug has a wide margin of safety, it may be given as a fraction of the adult dose based on age, but the great variation in size among children of the same age complicates this computation. Children are not small adults, and drug dosages may be quite different than they are for adults. The elderly are particularly susceptible to adverse drug effects because they often have multiple illnesses that require their taking various medications, some of which may be incompatible with others. In addition to decreased renal and hepatic function, gastric acid secretion decreases with age, and arteriosclerosis narrows the arteries, decreasing blood flow to the intestines and other organs. The precautions followed in prescribing medication for the elderly are an excellent example of the principle that should govern all drug therapydrugs should be used in the lowest effective dose, especially because side effects increase with concentration. Because of illness or frailty, elderly people often have less reserve and may not be able to tolerate minor side effects that younger adults might not even notice. When drugs are given in repeated doses, a steady state is achieved: the amount being administered equals the amount being excreted or metabolized. With some drugs, however, it may be difficult to determine the proper dose because of individual variations. In these cases, determining the plasma level of the drug may be useful, especially if the therapeutic window (i.e., the concentration above which the drug is toxic and below which it is ineffective) is relatively small. Plasma levels of phenytoin, used to control epilepsy; digitalis, prescribed to combat heart failure; and lithium, used to moderate bipolar disorder (traditionally called manic-depressive disorder), should be monitored. Indications for use The purpose of using drugs is to relieve symptoms, treat infection, reduce the risk of future disease, and destroy selected cells such as in the chemotherapeutic treatment of cancer. The best treatment, however, may not require a drug at all. Recognizing that no effective medication exists is just as important as knowing which one to select. When more than one drug is useful, physicians should select the one that is most effective, least hazardous, and least expensive. A recently developed drug may promise better results, yet it will be less predictable and possibly more expensive. Every drug has multiple actions: it will affect organs and systems beyond those to which it is specifically targeted. Some patients may also experience idiosyncratic effects (abnormal reactions peculiar to that individual) as well as allergic reactions to certain drugsadditional reasons to select drugs carefully and avoid their use altogether when simpler measures will work just as well. A case in point is the belief that penicillin or other antibiotics will cure viral infectionsthey will not. While new antiviral drugs are under development, using antibiotics unnecessarily is unwise and potentially dangerous. The number of drug-resistant organisms is growing and must be counteracted by the judicious prescribing of these chemicals. Unnecessary drug use also increases the possibility of drug interactions that may interfere with drug effectiveness. Interaction can occur in the stomach or intestinal tract where the presence of one drug may interfere with the absorption of another. Antacids, for example, reduce the absorption of the popular antibiotic tetracycline by forming insoluble complexes. Of greater importance is the interference of one drug with another. Some drugs can inhibit metabolism, which allows the amount of the drug to accumulate in the system, leading to potential toxicity if the dose is not decreased. Cimetidine, a drug used to treat peptic ulcers, causes few side effects by itself, but it does inhibit drug-metabolizing microsomal enzymes in the liver, increasing concentrations of many drugs that depend on these enzymes to be metabolized. This inhibition can be serious if the other drug is the anticoagulant warfarin. Bleeding can result if the dose is not reduced. Many other drugs are affected, such as antihypertensives (calcium channel blockers), antiarrhythmics (quinidine), and anticonvulsants (phenytoin). One drug can also decrease the renal excretion of another. Sometimes this effect is used to advantage, as, for example, when probenecid is given with penicillin to decrease its removal and thereby increase its concentration in the blood. But this type of interaction can be deadly: quinidine, for instance, can reduce the clearance of digoxin, a drug used to treat heart failure, potentially increasing its concentration to dangerous levels. Two drugs can also have additive effects, leading to toxicity, though either one alone would be therapeutic. Problems with drug interactions can occur when a patient is being treated by different physicians, and one physician is not aware of the drug(s) that another has prescribed. Sometimes a physician may prescribe a drug to treat a symptom that actually is a side effect of another drug. Of course, discontinuing the first drug is preferable to adding another that may have side effects of its own. When a new symptom occurs, a recently initiated drug should be suspected before other causes are investigated. Patients should inform their physicians of any new drugs they are taking, as well as consult with the pharmacist about possible interactions that a nonprescription drug might have with a prescription drug already being taken. Having a personal physician who monitors all the drugs, both prescription and nonprescription, that the patient is taking is a wise course to follow. In the United States, responsibility for assuring the safety and efficacy of prescription drugs is delegated to the Food and Drug Administration (FDA). This includes the approval of new drugs, identification of new indications, official labeling (to prevent unwarranted claims), surveillance of adverse drug reactions, and approval of methods of manufacture. Before an investigational new drug (IND) can be tested in humans, it must be submitted to and approved by the FDA. If clinical trials are successful, a new drug application (NDA) must be approved before it can be licensed and sold. This process usually takes years, but if the drug provides benefit to patients with life-threatening illnesses when existing treatments do not, then accelerated approval is possible. Physicians can receive permission to use an unapproved drug for a single patient. This consent, called emergency use and sometimes referred to as single-patient compassionate use, is granted if the situation is desperate and no other treatment is available. The FDA also sometimes grants approval to acquire drugs from other countries that are not available in the United States if a life-threatening situation seems to warrant this action. Another way to gain access to an investigational drug is to participate in a clinical trial. If it is a well-controlled, randomized, double-blind trial rather than an open trialin which the investigator is not blinded and knows who is the subject and who is the controlthe patient runs the risk of being given a placebo rather than the active drug. The Federal Trade Commission (FTC) has responsibility for truth in advertising to assure that false or misleading claims are not made about foods, over-the-counter drugs, or cosmetics. A rare disease presents a unique problem in treatment because the number of patients with the disease is so small (fewer than 200,000 in the United States) that it is not worthwhile for companies to go through the lengthy and expensive process required for approval and marketing. Drugs produced for such cases are made available under the Orphan Drug Act of 1983, which was intended to stimulate the development of drugs for rare diseases. More than 400 orphan drugs have been designated, but there are about 5,000 rare diseases that remain without treatment. Controlled substances are drugs that foster dependence and have the potential for abuse. The Drug Enforcement Administration (DEA) regulates their manufacture, prescribing, and dispensing. Controlled substances are divided into five classes, or schedules, based on their potential for abuse or physical and psychological dependence. Schedule I encompasses heroin and other drugs with a high potential for abuse and no accepted medical use in the United States. Schedule II drugs, including narcotics such as opium and cocaine and stimulants such as amphetamines, have a high potential for abuse and dependence. Schedule III includes those drugs such as certain stimulants, depressants, barbiturates, and preparations containing limited amounts of codeine that cause moderate dependence. Schedule IV contains drugs that have limited potential for abuse or dependence, and includes some sedatives, antianxiety agents, and nonnarcotic analgesics. Schedule V drugs have an even lower potential for abuse than do schedule IV substances. Some, such as cough medicines and antidiarrheal agents containing limited amounts of codeine, can be purchased without a prescription. Physicians must have a DEA registration number to prescribe any controlled substance. Special triplicate prescription forms are required in certain states for schedule II drugs, and a patient's supply of these drugs cannot be replenished without a new prescription. Psychotherapy Drug therapy The use of drugs to treat emotional disorders has expanded dramatically with the development of new and more effective medications for a variety of disorders that formerly were not treatable. Drugs that affect the mind are called psychotropic and can be divided into three categories: antipsychotic drugs, antianxiety agents, and antidepressant drugs. Antipsychotic agents The advent of antipsychotic, or neuroleptic, drugs such as Thorazine (trademark) enabled many patients to leave mental hospitals and function in society. The primary indication for the use of antipsychotics is schizophrenia, erroneously called split personality. This is a severe mental disorder characterized by delusions, hallucinations, and sometimes bizarre behaviour. One form, paranoid schizophrenia, is marked by delusions that are centred around a single theme, often accompanied by hallucinations. The most effective drug to use may depend on an individual patient's metabolism of the drug or the severity and nature of the side effects. Radiation and other nonsurgical therapies Radiation therapy Ionizing radiation is the transmission of energy by electromagnetic waves (e.g., X rays) or by particles such as electrons, neutrons, or protons. Interaction with tissue produces free radicals and oxidants that damage or break cellular DNA, leading to cell death. When used properly, radiation may cause less damage than surgery and can often preserve organ structure and function. The type of radiation used depends on the radiosensitivity of the tumour and which healthy organs are within the radiation field. High-energy sources, such as linear accelerators, deposit their energy at a greater depth, sparing the skin but treating the deep-seated tumour. The radiation beam can also come from multiple directions, each beam being focused on the deep tumour, delivering a smaller dose to surrounding organs and tissues. Electron-beam radiation has low penetration and is useful in treating some skin cancers. The basic unit of absorbed radiation is the gray (Gy): one gray equals 100 rads. Healthy organs have varying tolerance thresholds to radiation, bone marrow being the most sensitive and skin the least. The nervous system can tolerate much more radiation than the lungs or kidneys. Total body irradiation with approximately 10 Gy causes complete cessation of development of the bone marrow, and physicians use it to destroy defective tissue before performing a bone marrow transplant. Radiation therapy can also be palliative if a cure is not possible; the size of the tumour can be reduced, thereby relieving pain or pressure on adjacent vital structures. It also can shrink a tumour to allow better drainage of an area, such as the lung, which can help to prevent infection and decrease the chance of bleeding. Radioactive implants in the form of metal needles or seeds are used to treat some cancers, such as those of the prostate and uterine cervix. They can deliver high doses of radiation directly into the tumour with less effect on distant tissues. An organ can also be irradiated by the ingestion of a radioactive substance. Hyperthyroidism can be treated with iodine-131, which collects in the thyroid gland and destroys a percentage of glandular tissue, thereby reducing function to normal. The drawback to this procedure is the difficulty in calculating the correct dose. Irradiation is less effective in treating tissues that are poorly oxygenated (hypoxic) because of inadequate blood supply than it is in treating those that are well oxygenated. Some drugs enhance the toxic effect of radiation on tumour cells, especially those that are hypoxic. Other noninvasive therapies Hyperthermia Some tumours are more sensitive than the surrounding healthy tissue to temperatures around 43 C (109.4 F). Sensitivity to heat is increased in the centre of tumours, where the blood supply is poor and radiation is less effective. A tumour may be heated using microwaves or ultrasound. Hyperthermia may enhance the effect of both radiation and chemotherapy; it is one form of nonionizing radiation therapy. Surgical therapy Major categories of surgery Wound treatment Wounds, whether caused by accidental injury or a surgical scalpel, heal in three ways: (1) primary intention (wound edges are brought together, as in a clean surgical wound), (2) secondary intention (the wound is left open and heals by epithelization), or (3) third intention, or delayed closure (the wound is identified as potentially infected, is left open until contamination is minimized, and is then closed). Choosing which method is best depends on whether excessive bacterial contamination is present, whether all necrotic material and foreign bodies can be identified and removed, and whether bleeding can be adequately controlled. Normal healing can occur only if the wound edges are clean and can be closely opposed without undue stress on the tissue. An adequate blood supply to the wound is essential. If the tissue is tight and the edges cannot be closed without tension, the blood supply will be compromised. Cutting under the skin to free it from the underlying subcutaneous tissue may allow the edges to be brought together without tension. If direct approximation is still not possible, then skin grafts or flaps are used for closure. Wound closure begins with a thorough cleansing of the wound and the installation of a local anesthetic, usually lidocaine, which takes effect quickly and lasts for one to two hours. If the wound is contaminated, further cleansing is performed after instilling the local anesthetic, especially if foreign material is present. If the injury resulted from a fall on gravel or asphalt as in some motorcycle accidents, then aggressive scrubbing is needed to remove the many small pieces imbedded beneath the skin. High-pressure irrigation with saline solution will remove most foreign material and reduce the risk of subsequent infection. Contaminated wounds must be considered to be prone to infection with Clostridium tetani, which causes tetanus, and appropriate immunization should be given. Sutures are the most commonly used means of wound closure, although staples and adhesive tissue tape may be more appropriate in certain circumstances. Silk sutures were originally used to close skin wounds, but nylon is stronger and causes less tissue reaction. Ideally, sutures are of the smallest possible diameter that will still maintain approximation of the wound edges. Absorbable sutures made of catgut (made not from cat but from sheep intestines) or a synthetic material such as polyglycolic acid are used to approximate the deeper layers of tissue beneath the skin so that tissue reaction will be lessened. The objective is to eliminate any unfilled space that could delay healing or allow fluid to accumulate. Drains connected to closed suction are used to prevent the collection of fluid when it is likely to accumulate, but drains serve as a source of contamination and are used infrequently. Staples permit faster closure of the skin but are less precise than sutures. When the edges can be brought together easily and without tension, tape is very useful. Although it is comfortable, easy to apply, and avoids the marks left by sutures, tape may come loose or be removed by the patient and is less successful if much wound edema occurs. Sutures are removed after 3 to 14 days depending on the area involved, the cosmetic result desired, the blood supply to the area, and the amount of reaction that occurs around the sutures. Sutures on the face should be removed in three to five days to avoid suture marks. Tape is often used to provide support for the remainder of the time the wound needs to heal. Sutures on the trunk or leg will be removed after 7 to 10 days or longer if there is much tension on the wound. Tension and scarring are minimized in surgical procedures by making an incision parallel to normal skin lines, as in the horizontal neck incision for thyroidectomy. Dressings protect the wound from external contamination and facilitate absorption of drainage. Because a surgical wound is most susceptible to surface contamination during the first 24 hours, an occlusive dressing is applied, consisting of gauze held in place by tape. Materials like transparent semipermeable membranes permit the wound to be observed without removal of the dressing and exposure of the wound to contamination. Dressings support the wound and, by adding compression, aid healing, as skin grafts do. The healing of a wound results in scar formation; a strong yet minimally apparent scar is desirable. In some individuals a keloid, or thick overgrowth of scar, occurs no matter how carefully the wound was closed. The four phases of wound healing are inflammatory, migratory, proliferative, and late. The first, or inflammatory, phase occurs in the first 24 hours when platelets form a plug by adhering to the collagen exposed by damage to blood vessels. Fibrin joins the platelets to form a clot, and white blood cells invade the area to remove contamination by foreign material. Local blood vessels dilate to increase blood supply to the area, which hastens healing. In the second, or migratory, phase, fibroblasts and macrophages infiltrate the wound to initiate reconstruction. Capillaries grow in from the periphery, and epithelial cells advance across the clot to form a scab. In the proliferative phase, the fibroblasts produce collagen that increases wound strength, new epithelial cells cover the wound area, and capillaries join to form new blood vessels. In the late phase, the production of new and stronger collagen remodels the scar, blood vessels enlarge, and the epithelium at the surface heals. Many factors, including diabetes mellitus or medications, can affect wound healing. In a patient whose diabetes is well controlled, wound healing is essentially normal, but, if the blood glucose level is elevated, it can impair healing and predispose the wound to infection. Kidney or liver failure and malnutrition also will delay wound healing, as will poor circulation owing to arteriosclerosis. Having steroids or anticancer or other drugs in the system can adversely affect the normal healing process. Surgical extirpation Extirpation is the complete removal or eradication of an organ or tissue and is a term usually used in cancer treatment or in the treatment of otherwise diseased or infected organs. The aim is to completely remove all cancerous tissue, which usually involves removing the visible tumour plus adjacent tissue that may contain microscopic extensions of the tumour. Excising a rim of adjacent, seemingly normal tissue ensures a complete cure unless there has been extension through the lymphatic system, which is the primary route for cancer to spread. For this reason, local lymph nodes are often removed with the tumour. Pathological examination of the nodes will show whether the cancer has spread. This indicates the likelihood of cure and whether additional treatment such as radiation or chemotherapy is needed. If complete removal of a tumour is not possible, palliative surgery, which provides relief but is not a cure, may be useful to relieve pain or pressure on adjacent structures. Radical surgery may not always be best, as in the early stages of breast cancer. Removal of the entire breast and surrounding structures, including the axillary lymph nodes, has been shown to provide no greater benefit than a lumpectomy (removal of the tumour only) followed by radiation to the area in early stages of breast cancer, while it often causes the patient increased psychological distress. However, because of improvements in breast reconstruction techniques, the trauma of a radical mastectomy is becoming less severe.