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Minggu, 09 November 2008

ISLAMIC CODE OF MEDICAL ETHICS

ISLAMIC CODE OF MEDICAL ETHICS
First International Conference on Islamic Medicine
(6-10 Rabi’ul Awal 1401 in Kuwait)






dan apabila aku sakit, Dialah Yang menyembuhkan aku, (QS. As-Syu’ara:80)





Praktek kedokteran adalah perintah agama kepada masyarakat, disebut fardu kifayah yang dapat dinikmati oleh sebagian warga negara yang memerlukannya.
Untuk tujuan pengobatan, adalah diijinkannya melihat bagian-bagian tubuh yang tersembunyi dan sangat pribadi, yang diturunkan dari perundang-undangan “keadaan darurat membolehkan larangan” ... dan sesuai dengan Al-Qur’an “apabila terpaksa melakukan tanpa tujuan yang buruk”. Sejak permulaan Islam, korps wanita perawat bekerja sama dengan pasukan Nabi Muhammad turut berangkat berperang dengan tujuan mengobati luka-luka prajurit.
Rasulullah juga pernah menunjuk seorang nonmuslim bernama Abdullah bin Uraikit sebagai penunjuk jalan ketika beliau melakukan hijrah, ini memberi petunjuk bahwa seorang muslim dapat belajar dari orang nonmuslim tentang pengetahuan termasuk ilmu kedokteran.



Kami tiada mengutus rasul rasul sebelum kamu (Muhammad), melainkan beberapa orang-laki-laki yang Kami beri wahyu kepada mereka, maka tanyakanlah olehmu kepada orang-orang yang berilmu, jika kamu tiada mengetahui. (QS. Al-Anbiya:7)




Semua perbuatan dokter ditujukan untuk pengobatan dan perawatan tanpa mengenal pihak apapun, pihak kawan atau lawan, perseorangan, atau, umum.

Hai orang-orang yang beriman hendaklah kamu jadi orang-orang yang selalu menegakkan (kebenaran) karena Allah, menjadi saksi dengan adil. Dan janganlah sekali-kali kebencianmu terhadap sesuatu kaum, mendorong kamu untuk berlaku tidak adil. Berlaku adillah, karena adil itu lebih dekat kepada takwa. Dan bertakwalah kepada Allah, sesungguhnya Allah Maha Mengetahui apa yang kamu kerjakan. (Al-Maidah:8)



SUMPAH DOKTER


Saya bersumpah dengan nama Allah ... Yang Maha Besar.
Mengingat Allah dalam melaksanakan profesi saya.
Melindungi jiwa manusia dalam semua tahap dan semua keadaan, mealukan semampu mungkin untuk menyelamatkannya dari kematian, penyakit, rasa nyeri dan kecemasan.
Memelihara kemuliaan manusia, menutupi pribadinya dan menyimpan rahasianya.
Dalam segala hal, menjadi alat dan rahmat Allah memberikan perawatan kedokteran pada yang dekat dan yang jauh, yang taat dan yang berdosa serta teman maupun lawan.
Berjuang mengejar ilmu dan menggunakannya untuk keuntungan dan bukan aniaya bagi kemanusiaan
Menghormati guru saya, mengajari sejawat saya yang masih muda dan menjadikan saudara bagi setiap anggota profesi kedokteran yang bersatu dalam kesucian dan amal.
Memelihara kepercayaan saya dalam pribadi dan dalam masyarakat, mengindari dari segala yang dapat menodai saya di mata Allah, nabi-Nya dan orang yang seakidah dengan saya.
Semoga Allah menjadi saksi terhadap sumpah ini.

Sumber: Islamic Code of Medical Ethics diterjemahkan oleh Sudibyo Soepardi, Jakarta Akademika Pressindo, 2001

Disorders of Hemostasis

DISORDERS OF THE PLATELET AND VESSEL WALL - Robert I. Handin

INTRODUCTION
Patients with platelet or vessel wall disorders usually bleed into superficial sites such as the skin, mucous membranes, or genitourinary or gastrointestinal tract. Bleeding begins immediately after trauma and either responds to simple measures, such as pressure and packing, or requires systemic therapy with glucocorticoids, desmopressin, plasma fractions, or platelet concentrates. The most common platelet/vessel wall disorders are (1) various forms of thrombocytopenia, (2) von Willebrand's disease (vWD), and (3) drug-induced platelet dysfunction. This chapter reviews the diagnosis and treatment of quantitative and qualitative platelet disorders as well as vessel wall defects that cause bleeding. For further discussion of the physiology of normal hemostasis and the cardinal manifestations of bleeding arising from hemostatic disorders, see Chap. 53.

PLATELET DISORDERS
Platelets arise from the fragmentation of megakaryocytes, which are very large, polyploid bone marrow cells produced by the process of endomitosis. They undergo from three to five cycles of chromosomal duplication without cytoplasmic division. After leaving the marrow space, about one-third of the platelets are sequestered in the spleen, while the other two-thirds circulate for 7 to 10 days. Normally, only a small fraction of the platelet mass is consumed in the process of hemostasis, so most platelets circulate until they become senescent and are removed by phagocytic cells. The normal blood platelet count is 150,000 to 450,000/uL. A decrease in platelet count stimulates an increase in the number, size, and ploidy of megakaryocytes, releasing additional platelets into the circulation. This process is regulated by thrombopoietin (TPO) binding to its megakaryocyte receptor, a proto-oncogene c-mpl. TPO (c-mpl ligand) is secreted continuously at a low level and binds tightly to circulating platelets. A reduction in platelet count increases the level of free TPO and thereby stimulates megakaryocyte and platelet production.
The platelet count varies during the menstrual cycle, rising following ovulation and falling at the onset of menses. It is also influenced by the patient's nutritional state and can be decreased in severe iron, folic acid, or vitamin B12 deficiency. Platelets are acute-phase reactants, and patients with systemic inflammation, tumors, bleeding, and mild iron deficiency may have an increased platelet count, a benign condition called secondary, or reactive, thrombocytosis. The cytokines interleukin (IL) 3, IL-6, and IL-11 may stimulate platelet production in acute inflammation. In these conditions, the platelet count is usually <>

THROMBOCYTOPENIA
Thrombocytopenia is caused by one of three mechanisms — decreased bone marrow production, increased splenic sequestration, or accelerated destruction of platelets. In order to determine the etiology of thrombocytopenia, each patient should have a careful examination of the peripheral blood film, an assessment of marrow morphology by examination of an aspirate or biopsy, and an estimate of splenic size by bedside palpation supplemented, if necessary, by ultrasonography or computed tomography (CT). Occasional patients have "pseudothrombocytopenia," a benign condition in which platelets agglutinate or adhere to leukocytes when blood is collected with EDTA as anticoagulant. This is a laboratory artifact, and the actual platelet count in vivo is normal. A scheme for classifying patients with thrombocytopenia based on these clinical observations and laboratory tests is outlined in Fig. 101-1.
Impaired Production Disorders that injure stem cells or prevent their proliferation frequently cause thrombocytopenia. They usually affect multiple hematopoietic cell lines so that thrombocytopenia is accompanied by varying degrees of anemia and leukopenia. Diagnosis of a platelet production defect is readily established by examination of a bone marrow aspirate or biopsy, which should show a reduced number of megakaryocytes. The most common causes of decreased platelet production are marrow aplasia, fibrosis, or infiltration with malignant cells, all of which produce highly characteristic marrow abnormalities. Occasionally, thrombocytopenia is the presenting laboratory abnormality in these disorders. Cytotoxic drugs impair megakaryocyte proliferation and maturation and frequently cause thrombocytopenia. Rare marrow disorders, such as congenital amegakaryocytic hypoplasia and thrombocytopenia with absent radii (TAR syndrome), produce a selective decrease in megakaryocyte production.
Splenic Sequestration Since one-third of the platelet mass is normally sequestered in the spleen, splenectomy will increase the platelet count by 30%. Postsplenectomy thrombocytosis is a benign self-limited condition that does not require specific therapy. In contrast, when the spleen enlarges, the fraction of sequestered platelets increases, lowering the platelet count. The most common causes of splenomegaly are portal hypertension secondary to liver disease and splenic infiltration with tumor cells in myeloproliferative or lymphoproliferative disorders (Chap. 54). Isolated splenomegaly is rare, and in most patients it is accompanied by other clinical manifestations of an underlying disease. Many patients with leukemia, lymphoma, or a myeloproliferative syndrome have both marrow infiltration and splenomegaly and develop thrombocytopenia from a combination of impaired marrow production and splenic sequestration of platelets.
Accelerated Destruction Abnormal vessels, fibrin thrombi, and intravascular prostheses can all shorten platelet survival and cause nonimmunologic thrombocytopenia. Thrombocytopenia is common in patients with vasculitis, the hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), or as a manifestation of disseminated intravascular coagulation (DIC). In addition, platelets coated with antibody, immune complexes, or complement are rapidly cleared by mononuclear phagocytes in the spleen or other tissues, inducing immunologic thrombocytopenia. The most common causes of immunologic thrombocytopenia are viral or bacterial infections, drugs (often heparin), and a chronic autoimmune disorder referred to as idiopathic thrombocytopenic purpura (ITP). Patients with immunologic thrombocytopenia do not usually have splenomegaly and have an increased number of bone marrow megakaryocytes.

DRUG-INDUCED THROMBOCYTOPENIA
Many common drugs can cause thrombocytopenia (Table 101-1). Cancer chemotherapeutic agents may depress megakaryocyte production. Ingestion of large quantities of alcohol has a marrow-depressing effect leading to transient thrombocytopenia, particularly in binge drinkers. Thiazide diuretics, used to treat hypertension or congestive heart failure, impair megakaryocyte production and can produce mild thrombocytopenia (50,000 to 100,000/uL), which may persist for several months after the drug is discontinued.
Most drugs induce thrombocytopenia by eliciting an immune response in which the platelet is an innocent bystander. The platelet is damaged by complement activation following the formation of drug-antibody complexes. Current laboratory tests can identify the causative agent in 10% of patients with clinical evidence of drug-induced thrombocytopenia. The best proof of a drug-induced etiology is a prompt rise in the platelet count when the suspected drug is discontinued. Patients with drug-induced platelet destruction may also have a secondary increase in megakaryocyte number without other marrow abnormalities.
Although most patients recover within 7 to 10 days and do not require therapy, occasional patients with platelet counts <10,000>

IDIOPATHIC THROMBOCYTOPENIC PURPURA
The immunologic thrombocytopenias can be classified on the basis of the pathologic mechanism, the inciting agent, or the duration of the illness. The explosive onset of severe thrombocytopenia following recovery from a viral exanthem or upper respiratory illness (acute ITP1) is common in children and accounts for 90% of the pediatric cases of immunologic thrombocytopenia. Of these patients, 60% recover in 4 to 6 weeks and >90% recover within 3 to 6 months. Transient immunologic thrombocytopenia also complicates some cases of infectious mononucleosis, acute toxoplasmosis, or cytomegalovirus infection and can be part of the prodromal phase of viral hepatitis and initial infection with HIV. Acute ITP is rare in adults and accounts for <10%>

TREATMENT
Treatment of patients with ITP1 must take into account the age of the patient, the severity of the illness, and the anticipated natural history. Although adults have a higher incidence of intracranial bleeding than children, specific therapy may not be necessary unless the platelet count is <20,000/ul>20,000/uL, consideration should be given to withholding therapy. Patients with severe chronic thrombocytopenia may live with their disease for two or three decades.
Rituximab, an anti-CD20 monoclonal antibody used to treat lymphoma, has also proven an effective approach to ITP1 and is probably preferable to long-term glucocorticoid therapy. Rituximab eliminates normal B cells, including those producing the antiplatelet antibody. This B cell depletion is transient (lasting 12 to 18 months, normally) and has surprisingly few side effects or toxicities.

FUNCTIONAL PLATELET DISORDERS
As described in Chap. 53, normal hemostasis requires three critical platelet reactions — adhesion, aggregation, and granule release. Clinical bleeding can result from a failure of any of these important functions. Table 101-2 lists the major functional platelet disorders. Table 101-3 lists methods to assess platelet function.
von Willebrand's Disease vWD4 is the most common inherited bleeding disorder, occurring in 1 in 100 to 500 individuals. The von Willebrand factor (vWF) is a heterogeneous multimeric plasma glycoprotein with two major functions: (1) It facilitates platelet adhesion under conditions of high shear stress by linking platelet membrane receptors to vascular subendothelium; and (2) it serves as the plasma carrier for factor VIII, the antihemophilic factor, a critical blood coagulation protein. Discrete domains in each vWF subunit mediate each of these important functions. The normal plasma vWF level is 10 mg/L. The vWF activity is distributed among a series of plasma multimers with estimated molecular weights ranging from 400,000 to >20 million. A single large vWF precursor subunit is synthesized in endothelial cells and megakaryocytes, where it is cleaved and assembled into the disulfide-linked multimers present in plasma, platelets, and vascular subendothelium. A modest reduction in plasma vWF concentration or a selective loss in the high-molecular-weight multimers decreases platelet adhesion and causes clinical bleeding.
Although vWD4 is heterogeneous, certain clinical features are common to all the syndromes. With one exception (type III disease), all forms are inherited as autosomal dominant traits, and affected patients are heterozygous with one normal and one abnormal vWF5 allele. In mild cases, bleeding occurs only after surgery or trauma. More severely affected patients have spontaneous epistaxis or oral mucosal, gastrointestinal, or genitourinary bleeding. The laboratory findings are variable. The most diagnostic pattern is the combination of (1) a prolonged bleeding time, (2) a reduction in plasma vWF concentration, (3) a parallel reduction in biologic activity as measured with the ristocetin cofactor assay, and (4) reduced factor VIII activity. The variability in laboratory tests is related to both the heterogeneous nature of the defects in vWD and the fact that plasma levels are influenced by ABO blood group type, central nervous system disorders, systemic inflammation, and pregnancy. Since vWD is an autosomal dominant disorder, some vWF is produced by the remaining normal allele. Thus patients with mild defects may have laboratory values that fluctuate over time and may occasionally be within the normal range.
There are three major types of vWD4. Their mode of inheritance and laboratory findings are shown in Fig. 101-2. Patients with type I disease, the most common abnormality, have a mild to moderate decrease in plasma vWF6. In the milder cases, although hemostasis is impaired, the vWF level is just below normal (50% activity, or 5 mg/L). In type I disease, vWF antigen, factor VIII activity, and ristocetin cofactor activity are decreased with a normal spectrum of multimers detected by sodium dodecyl sulfate (SDS)-agarose gel electrophoresis.
The variant forms of vWD4 (type II disease) are much less common and characterized by normal or near-normal levels of a dysfunctional protein. Patients with the type IIa variant of vWD have a deficiency in the high- and medium-molecular-weight forms of vWF7 multimer detected by SDS8-agarose electrophoresis. This is due either to an inability to secrete the high-molecular-weight vWF multimers or to proteolysis of the multimers soon after they leave the endothelial cell and enter the circulation. Mutations in a localized region of the vWF A-2 domain have been identified in families with type IIa vWD (Fig. 101-3). The quantity of vWF antigen and the amount of associated factor VIII are usually normal. In the type IIb variant, high-molecular-weight multimers are also decreased; however, the decrease is due to the inappropriate binding of vWF to platelets. Intravascular platelet aggregates form that are rapidly cleared from the circulation, causing mild, variable thrombocytopenia. Mutations in a disulfide-bonded loop in the A-1 domain that binds to Gp9 Ib/IX are the cause of the type IIb defect (Fig. 101-3). A few patients have a platelet membrane disorder that mimics type IIb vWD — platelet-type vWD. It is due to mutations in the portion of Gp Ib/IX that interacts with vWF. Levels of total vWF antigen and factor VIII are normal.
Approximately 1 in 1 million individuals has a very severe form of vWD4 that is phenotypically recessive (type III disease). Type III patients are usually the offspring of two parents (usually asymptomatic) with mild type I disease. Type III patients may inherit a different abnormality from each parent (a doubly heterozygous or compound heterozygous state) or be homozygous for a single defect. Type III patients have severe mucosal bleeding and no detectable vWF10 antigen or activity and, like patients with mild hemophilia, may have sufficiently low factor VIII that they have occasional hemarthroses. Major deletions in the vWF gene have been found in some type III families. Families with nonsense mutations and the combination of a deleted and nonsense mutant allele have also been described.
Type IIn disease is due to a defect in the factor VIII binding site of vWF11. Patients resemble those with mild hemophilia and have low levels of factor VIII. The presence of disease in both males and females in a family is a clue to the role of vWF in this disease.

TREATMENT
There are two therapeutic options. Factor VIII concentrates retain high-molecular-weight vWF12 multimers (Humate-P, Alfanate), are highly purified and heat-treated to destroy HIV2, and are appropriate treatments for all the inherited forms of vWD4. During surgery or after major trauma, patients should receive factor VIII concentrates twice daily for 2 to 3 days to assure optimal hemostasis. Minor bleeding episodes such as prolonged epistaxis or severe menorrhagia may respond to a single infusion. Recurrent menorrhagia, a major problem for women with severe vWD, can be treated effectively with oral contraceptive agents that suppress menses.
A second therapeutic option, which avoids the use of plasma, is the use of desmopressin, a vasopressin analogue that has minimal blood pressure-elevating and fluid-retaining properties and raises the plasma vWF13 level in both normal individuals and patients with mild vWD4. Patients with type I disease are the best candidates for desmopressin therapy. However, they must be tested for an adequate response before anticipated surgery, and vWF levels must be monitored closely during therapy, since the patient may develop tachyphylaxis when therapy is continued for >48 h. Desmopressin should not be given to patients with variant forms of vWD without prior testing, since it may not improve multimer pattern or hemostasis in type IIa patients and may actually worsen the defect by depleting high-molecular-weight multimers, inducing intravascular platelet aggregation, and lowering the platelet count in type IIb patients. It is ineffective therapy for the severe (type III) form of vWD.
ACQUIRED VWD Although most cases of vWD4 are inherited, acquired vWD may be caused by antibodies that inhibit vWF14 function or by lymphoid or other tumors that selectively adsorb vWF multimers onto their surfaces. Anti-vWF antibodies have developed in patients with severe vWD following multiple transfusions, as well as in patients with autoimmune and lymphoproliferative disorders. Adsorption of vWF to tumor surfaces has been documented in patients with Waldenstrom's macroglobulinemia and Wilms' tumor and inferred in other patients with lymphoma. Treatment of acquired vWD should focus on the underlying disease, since plasma derivatives and desmopressin are often not effective and the disorder can be fatal.
Platelet Membrane Defects Receptors that modulate platelet adhesion and aggregation are located on the two major platelet surface glycoproteins. vWF15 facilitates platelet adhesion by binding to Gp16 Ib/IX, while fibrinogen links platelets into aggregates via sites on the Gp IIb/IIIa complex. Two rare platelet defects are characterized by a loss of or a defect in these Gp receptors. Patients with the Bernard-Soulier syndrome have markedly reduced platelet adhesion and cannot bind vWF to their platelets due to deficiency or dysfunction of the Gp Ib/IX complex. They also have reduced levels of another membrane protein (GpV that associates with Gp Ib/II), mild thrombocytopenia, and extremely large, lymphocytoid platelets. Platelets from patients with Glanzmann's disease, or thrombasthenia, are deficient or defective in the Gp IIb/IIIa complex. Their platelets do not bind fibrinogen and cannot form aggregates, although the platelets undergo shape change and secretion and are of normal size.
Both these disorders are autosomal recessive traits and markedly impair hemostasis, leading to recurrent episodes of severe mucosal hemorrhage. Bernard-Soulier platelets react normally to all stimuli except ristocetin. In contrast, thrombasthenic platelets adhere normally and will agglutinate with ristocetin but will not aggregate with any of the agonists that require fibrinogen binding, such as adenosine diphosphate (ADP), thrombin, or epinephrine.
The only effective therapy for hemorrhagic episodes in these two disorders is transfusion with normal platelets. Alloimmunization will eventually limit the life span of infused platelets. In addition, a few patients have developed inhibitor antibodies with specificity for the missing protein. These antibodies bind to the protein that is expressed on the transfused normal platelets and impair their function.
Platelet Release Defects The most common mild bleeding disorders arise from the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit platelet production of thromboxane A2, an important mediator of platelet secretion and aggregation (Figs. 53-3 and 53-4). These drugs inhibit cyclooxygenase (COX), which converts arachidonic acid to a labile endoperoxide intermediate that is critical for thromboxane formation. Aspirin is the most potent of these agents; it irreversibly acetylates the platelet enzyme so that a single dose impairs hemostasis for 5 to 7 days. The other agents are competitive and reversible inhibitors with more transient effects. Blocking thromboxane A2 synthesis partially inhibits platelet release and aggregation with weak agonists, such as ADP17 and epinephrine, and produces a mild hemostatic defect. Cyclooxygenase exists in two isoforms, COX-1, which is constitutively expressed and active in the normal platelet, and COX-2, which is induced, especially in inflamed tissue. The selective COX-2 inhibitors, such as celecoxib, are increasingly being used to control arthritis pain and in other settings where NSAIDs are clinically useful. The COX-2 inhibitors are long-acting reversible inhibitors that have no adverse effects on platelet function. Their chronic use may be associated with high blood pressure and risk of thrombosis. The administration of high doses of certain antibiotics, particularly penicillin, can coat the platelet surface, block platelet release, and impair hemostasis.
Patients with release defects generally have minimal symptoms such as easy bruising, and bleeding is usually confined to the skin. Occasional patients will have prolonged oozing after surgery, particularly with procedures involving mucous membranes such as periodontal, oral, or reconstructive plastic surgery. The antiplatelet effect of drugs such as aspirin is more dramatic when they are administered to patients with underlying defects such as vWD4 or hemophilia. Patients with drug-induced COX18 deficiency often have a mildly prolonged bleeding time, and their platelets fail to aggregate when incubated with arachidonic acid, epinephrine, or low doses of ADP19. Patients who have taken aspirin should be treated as if they have a mild hemostatic defect for the next 5 to 7 days. Platelet responses to collagen and thrombin are impaired at low doses but normal at higher doses. Symptomatic patients should be encouraged to use drugs such as acetaminophen that do not impair platelet function. Although most cases of COX deficiency are drug-induced, occasional patients have inherited disorders in platelet COX activity that impair thromboxane production or receptor level defects that prevent platelets from responding to thromboxane A2.
Of the metabolic disorders that can perturb hemostasis, uremic platelet dysfunction is clinically the most important. The mechanism by which uremia impairs platelet function is not well understood, and retention of phenolic and guanidinosuccinic acids, excess prostacyclin production, or impaired vWF20-platelet interactions have all been implicated. The degree of uremia correlates with bleeding symptoms and anemia. Bleeding can usually be reversed by dialysis and often improves after red cell transfusion or treatment with erythropoietin. In addition, factor VIII concentrate or desmopressin, both of which raise plasma vWF levels, can also improve hemostasis. Conjugated estrogens improve hemostasis and can be used as long-term therapy.
Storage Pool Defects Platelet granules have considerable amounts of adenine nucleotides, calcium, and adhesive glycoproteins such as thrombospondin, fibronectin, and vWF21, all of which promote platelet adhesion and aggregation. Patients with defective platelet granules have a mild bleeding disorder. Platelet storage pool defects may be inherited as an isolated disorder or be part of systemic granule packaging defects such as oculocutaneous albinism or the Hermansky-Pudlak or Chediak-Higashi syndromes. Clinically, these patients cannot be distinguished from those with other functional platelet disorders, since they all have easy bruising, mucosal bleeding, and a prolonged bleeding time. They can be differentiated from patients with the COX22 defects because their platelets will usually aggregate in response to arachidonic acid. In addition, their platelets have decreased levels of specific granule constituents such as ADP23 and serotonin and abnormalities in granule morphology that are best visualized by electron microscopy.
Occasionally, patients with acute or chronic leukemia or one of the myeloproliferative disorders develop an acquired storage pool disorder due to dysplastic megakaryocyte development. In addition, patients with liver disease and some patients with SLE24 or other immune complex-mediated disorders may have circulating platelets that have degranulated prematurely. Platelet degranulation and a transient storage pool disorder may occur after prolonged cardiopulmonary bypass. Fortunately, most patients with storage pool defects have only mildly impaired hemostasis. They can be treated with platelet transfusions. Occasional patients have responded to desmopressin.

VESSEL WALL DISORDERS
Bleeding from vascular disorders (nonthrombocytopenic purpura) is usually mild and confined to the skin and mucous membranes. The pathogenesis of bleeding is poorly defined in many of the syndromes, and classic tests of hemostasis, including the bleeding time and tests of platelet function, are usually normal. Vascular purpura arises from damage to capillary endothelium, abnormalities in the vascular subendothelial matrix or extravascular connective tissues that support blood vessels, or from the formation of abnormal blood vessels. Several idiopathic disorders involve the vessel wall and can cause more severe bleeding and organ dysfunction.

THROMBOTIC THROMBOCYTOPENIC PURPURA
TTP25 is a fulminant, often lethal disorder that may be initiated by endothelial injury and subsequent release of vWF26 and other procoagulant materials from the endothelial cell. Causes include pregnancy, metastatic cancer, mitomycin C, high-dose chemotherapy, HIV2 infection, and certain drugs, such as the antiplatelet agent ticlopidine. Characteristic findings include the microvascular deposition of hyaline fibrin thrombi, thrombocytopenia, microangiopathic hemolytic anemia, fever, renal failure, fluctuating levels of consciousness, and evanescent focal neurologic deficits. The presence of hyaline thrombi in arterioles, capillaries, and venules without any inflammatory changes in the vessel wall is diagnostic. The presence of a severe Coombs-negative hemolytic anemia with schistocytes or fragmented red blood cells in the peripheral blood smear, coupled with thrombocytopenia, and minimal activation of the coagulation system help to confirm the clinical suspicion of TTP. This disorder should be distinguished from vasculitis and SLE27, which can predispose patients to TTP. Platelet-associated IgG and complement levels are usually normal in TTP.
Clinical Manifestations The classic pentad of TTP28 consists of hemolytic anemia with fragmentation of erythrocytes and signs of intravascular hemolysis, thrombocytopenia, diffuse and nonfocal neurologic findings, decreased renal function, and fever. These signs and symptoms occur variably, depending on the number and sites of the arteriolar lesions. The anemia may be very mild to very severe, and the thrombocytopenia often parallels it. The neurologic and renal symptoms are usually seen only when the platelet count is markedly diminished (<20>90% of patients whose disease terminates in death. Initially, changes in mental status such as confusion, delirium, or altered states of consciousness may occur. Focal findings include seizures, hemiparesis, aphasia, and visual field defects. These neurologic symptoms may fluctuate and terminate in coma. Involvement of myocardial blood vessels may be a cause of sudden death. The severity of the disorder can be estimated from the degree of anemia and thrombocytopenia and the serum lactic dehydrogenase level. Prothrombin time, partial thromboplastin time, fibrinogen concentration, and the level of fibrin split products are usually normal or only mildly abnormal. If the coagulation tests indicate a major consumption of clotting factors, the diagnosis of TTP is doubtful. A positive antinuclear antibody (ANA) determination is obtained in ~20% of patients.
Pathogenesis TTP29 is due to a deficiency in the activity of a specific metalloproteinase called ADAMTS 13, a normal plasma constituent that cleaves the ultra-high-molecular-weight (UHMW) forms of vWF30 secreted by endothelial cells to yield the heterogeneous set of multimers normally present in plasma (Fig. 101-4). A small number of patients have recurrent episodes of a TTP-like illness (Upshaw-Schulman syndrome) and are deficient in ADAMTS 13; the syndrome is inherited as an autosomal recessive trait. The more common acquired form of TTP is due to an inhibitory antibody that blocks ADAMTS 13 activity. These findings have led to more reliable diagnostic tests based on ADAMTS 13 enzyme activity and may have implications beyond TTP. Studies are underway to see if asymptomatic carriers with 50% levels of ADAMTS 13 are at increased risk of thromboembolism.

TREATMENT
The treatment of acute TTP31 has focused on the use of exchange transfusion or intensive plasmapheresis coupled with infusion of fresh-frozen plasma. Therapy may remove abnormal forms of vWF32, lower the concentration of ADAMTS 13 inhibitor, and replenish the deficient enzyme. Overall mortality has been markedly reduced, and the majority of patients with TTP recover from this formerly fatal disorder. Most patients surviving the acute illness recover completely, with no residual renal or neurologic disease. Occasional patients with a chronic, relapsing form of TTP require maintenance plasmapheresis and plasma infusion, and a few patients are controlled only with glucocorticoids. They presumably have persistence of the ADAMTS 13 inhibitor. In the future, TTP patients may be treated with some combination of enzyme replacement and immunosuppression to block inhibitor production.

HEMOLYTIC-UREMIC SYNDROME
HUS33 is a disease of infancy and early childhood that closely resembles TTP34. Patients present with fever, thrombocytopenia, microangiopathic hemolytic anemia, hypertension, and varying degrees of acute renal failure. In many cases, onset is preceded by a minor febrile or viral illness, and an infectious or immune complex-mediated cause has been proposed. Epidemics related to infection with a specific strain of Escherichia coli (O157:H7) have been documented. The bacteria contain a Shigella-like toxin that damages endothelial cells. As in TTP, DIC35 is not found. In contrast to TTP, the disorder remains localized to the kidney, where hyaline thrombi are seen in the afferent arterioles and glomerular capillaries. Thrombi are not present in other vessels, and neurologic symptoms, other than those associated with uremia, are uncommon. No therapy is proven effective; however, with dialysis for acute renal failure, the initial mortality is only 5% in children but may be higher in adults. Between 10 and 50% of patients have some chronic renal impairment. ADAMTS 13 levels are normal, and no inhibitors of the enzyme are present in this disorder.

HENOCH-SCHONLEIN PURPURA
Henoch-Schonlein, or anaphylactoid, purpura is a distinct, self-limited type of vasculitis that occurs in children and young adults. Patients have an acute inflammatory reaction in capillaries, mesangial tissues, and small arterioles that leads to increased vascular permeability, exudation, and hemorrhage. Vessel lesions contain IgA and complement components. The syndrome may be preceded by an upper respiratory infection or streptococcal pharyngitis or be associated with food or drug allergies. Patients develop a purpuric or urticarial rash on the extensor surfaces of the arms and legs and on the buttocks as well as polyarthralgias or arthritis, colicky abdominal pain, and hematuria from focal glomerulonephritis. Despite the hemorrhagic features, all coagulation tests are normal. A small number of patients may develop fatal acute renal failure, and 5 to 10% develop chronic nephritis. Glucocorticoids provide symptomatic relief of the joint and abdominal pains but do not alter the course of the illness.

METABOLIC AND INFLAMMATORY DISORDERS
Acute febrile illnesses may cause capillary fragility and skin bleeding. Immune complexes containing viral antigens or the viruses themselves may damage endothelial cells. In addition, certain pathogens such as the rickettsiae that cause Rocky Mountain spotted fever replicate in endothelial cells and damage them. Thrombocytopenia is also a frequent finding in acute infectious disorders and may contribute to skin bleeding. In addition, whenever the platelet count is <10,000/ul,>

FURTHER READING
ALVING BM : How I treat heparin-induced thrombocytopenia and thrombosis. Blood 101:31, 2003
Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children, and pregnancy. Br J Haematol 120:574, 2003
HANDIN RI, EWENSTEIN BM : von Willebrand's disease, in Blood: Principles and Practice of Hematology, 2d ed, RI Handin et al (eds). Philadelphia, Lippincott Williams & Wilkins, 2003, pp 1103-1130
VESELY SK et al: ADAMTS 13 activity in thrombotic thrombocytopenic purpura — hemolytic uremic syndrome: Relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 102:60, 2003
— — — : Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: A systematic review. Ann Intern Med 140:112, 2004
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BOYCE TG et al: Current concepts: Escherichia coli O157:H7 and the hemolytic uremic syndrome. N Engl J Med 333:364, 1995
MARCHUK DA et al: Vascular morphogenesis: Tales of two syndromes. Hum Mol Genet 2 (Suppl): 12097, 2003
HARRISON'S PRINCIPLES OF INTERNAL MEDICINE - 16th Ed. (2005)
PART FIVE - ONCOLOGY AND HEMATOLOGY
Section 3 - Disorders of Hemostasis
101. DISORDERS OF THE PLATELET AND VESSEL WALL - Robert I. Handin
INTRODUCTION

SKIN GRAFTS

INTRODUCTION
Plastic surgery, although thought of as a technique-oriented specialty, is in fact a problem-solving field. The training of a plastic surgeon allows him or her to see surgical problems in a different light and select from a variety of options to solve surgical problems. Plastic surgeons have received broad training, and most have completed residencies in other fields such as general surgery, ENT surgery, orthopedics, urology, or neurosurgery.
The basic principles of plastic surgery are careful analysis of the surgical problem, careful planning of procedures, precise technique, and atraumatic handling of tissues. Alteration, coverage, and transfer of skin and associated tissues are the most common procedures performed. Plastic surgery may deal with closure of surgical wounds—particularly recalcitrant wounds such as those occurring post radiation or poorly healing wounds in immunocompromised patients—removal of skin tumors, repair of soft tissue injuries or burns, correction of acquired or congenital deformities of the breast, or repair of cosmetic defects. Operations on the head and neck and the hand may require special surgical training.
In the past 2 decades, increased knowledge of anatomy and the development of many new techniques have brought about important changes in plastic surgery. It is now known that in many areas the blood supply of the skin is derived principally from vessels arising from underlying muscles and larger perforating blood vessels rather than solely from vessels of the subcutaneous tissue, as was formerly thought. One-stage transfer of large areas of skin and muscle tissue can be accomplished if the axial pedicle of the underlying muscle is included in the transfer. With the use of microsurgical techniques, musculocutaneous units or combinations of bone, muscle, and skin can be successfully transferred and vessels and nerves less than 1 mm in size can be repaired. These so-called free-flap transplantations are a major advance in the treatment of defects that were previously untreatable or required lengthy or multistaged procedures. More sophisticated knowledge of the blood supply to the skin has introduced a concept of perforator flaps whereby one perforating vessel is identified that may supply a large segment of overlying skin. Similarly, the concept of neurocutaneous arteries and flaps has given rise to the design of additional flap territories such as the so-called sural flap in the lower leg.
The plastic surgeon, as a member of the craniofacial surgical team, is able to dramatically improve the appearance and function of children with severe congenital deformities. Children of normal intelligence who previously had been social outcasts are now able to lead relatively normal lives. Improved understanding of facial growth and abnormal development and diagnostic techniques such as the CT scan, MRI, and three-dimensional computer-assisted imaging enable the reconstructive surgeon to develop a complex strategy for remodeling the deformed craniofacial skeleton. This may involve remodeling or repositioning part or all of the cranial vault, the orbits, the mid face, and the mandible. These complex and at times formidable reconstructions, which were performed by moving both units and adding bone grafts from the ileum, have more recently been somewhat simplified with the introduction of the miniplate method of fixation as well as of bone substitutes that may serve as a scaffold upon which normal bone can regrow.
A recent notable advance in craniofacial surgery has been the introduction of distraction osteogenesis, which borrows from the Ilizarov principle of distraction where one makes a cortical cut in the bone and then applies a distraction apparatus so that in measured amounts (usually 1 mm per day) the bone is transported to bridge a gap. In craniofacial surgery it is more commonly brought to bear to enlarge or cause overgrowth of areas such as an underdeveloped mandible.
Additional areas of involvement for the plastic surgeon entail allotransplantation, particularly with the increasing number of clinical limb allotransplants, which unfortunately at present still require immunosuppression. It is hoped that immunotolerance will some day become a reality, thus allowing transplantation of nonessential organs.
Tissue engineering of bone, cartilage, and nerve is an area of ongoing research for plastic surgeons. Although encouraging experimental results have been reported in anatomic areas difficult to reconstruct such as the external ear, there are as yet no clinical applications.
Fetal surgery—an area pioneered by a number of plastic surgeons—appears to be in a quiescent stage, particularly because of advances in the treatment of cleft lip and cleft palate in the newborn.
Jones JW et al: Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team. N Engl J Med 2000;343:468.

SKIN GRAFTS
A graft of skin detaches epidermis and varying amounts of dermis from its blood supply in the donor area and is placed in a new bed of blood supply from the base of the wound, or recipient area. Although the technique is relatively simple to perform and generally reliable, definite considerations about the donor area and adequacy of the recipient area are important. Skin grafting is a quick, effective way to cover a wound if vascularity is adequate, infection is not present, and hemostasis is assured. Color match, contour, durability of the graft, and donor morbidity must be considered.

Types of Skin Grafts
Skin grafts can be either split-thickness or full-thickness grafts (Figure 44-1). Each type has advantages and disadvantages and is indicated or contraindicated for different kinds of wounds (Table 44-1).

A. Split-Thickness Grafts
Thinner split-thickness grafts (0.01-0.015 inch) become vascularized more rapidly and survive transplantation more reliably. This is important in grafting on less than ideal recipient sites, such as contaminated wounds, burn surfaces, and poorly vascularized surfaces (eg, irradiated sites). A second advantage is that donor sites heal more rapidly and can be reused within a relatively short time (7-10 days) in critical cases such as major burns.
In general, however, the disadvantages of thin split-thickness grafts outweigh the advantages. Thin grafts exhibit the highest degree of postgraft contraction, offer the least amount of resistance to surface trauma, and are least like normal skin in texture, suppleness, pore pattern, hair growth, and other characteristics. Hence, they are usually aesthetically unacceptable.
Thicker split-thickness skin grafts (> 0.015 inch) contract less, are more resistant to surface trauma, and are more similar to normal skin than are thin split-thickness grafts. They are also aesthetically more acceptable but not as acceptable as full-thickness grafts.
The disadvantages of thick split-thickness grafts are relatively few but can be significant. They are less easily vascularized than thin grafts and thus result in fewer successful takes when used on less than ideal surfaces. Their donor sites are slower to heal (requiring 10-18 days) and heal with more scarring than donor sites for thin split-thickness grafts—a factor that may prevent reuse of the area.
Meshed grafts are usually thin or intermediate split-thickness grafts that have been rolled under a special cutting machine to create a mesh pattern. Although grafts with these perforations can be expanded from one and one-half to nine times their original size, expansion to one and one-half times the unmeshed size is the most useful. Meshed grafts are advantageous because they can be placed on an irregular, possibly contaminated wound bed and will usually take. Also, complications of hemostasis are fewer, because blood and serum exude through the mesh pattern. The disadvantage is poor appearance following healing (alligator hide).
Donor sites for split-thickness grafts heal spontaneously by epithelialization. During this process, epithelial cells from the sweat glands, sebaceous glands, or hair follicles proliferate upward and spread across the wound surface. If these three structures are not present, epithelialization will not occur.

B. Full-Thickness Grafts
Full-thickness skin grafts include the epidermis and all the dermis. They are the most aesthetically desirable of the free grafts since they include the highest number of skin appendage elements, undergo the least amount of contracture, and have a greater ability to withstand trauma. There are several limiting factors in the use of full-thickness grafts. Since no epidermal elements remain to produce epithelialization in the donor site, it must be closed primarily, and a scar will result. The size and number of available donor sites is therefore limited. Furthermore, conditions at the recipient site must be optimal in order for transplantation to be successful.
Areas of thin skin are the best donor sites for full-thickness grafts (eg, the eyelids and the skin of the postauricular, supraclavicular, antecubital, inguinal, and genital areas). Submammary and subgluteal skin is thicker but allows camouflage of donor area scars. In grafts thicker than approximately 0.015 inch, the results of transplantation are often poor except on the face, where vascularity is so good.

C. Composite Grafts
A composite graft is also a free graft that must reestablish its blood supply in the recipient area. It consists of a unit with several tissue planes that may include skin, subcutaneous tissue, cartilage, or other tissue. Dermal fat grafts, hair transplant grafts, and skin and cartilage grafts from the ear fall into this category. Obviously, composite grafts must be small or at least relatively thin and will require recipient sites with excellent vascularity. These grafts are generally used in the face.

D. Cultured Epithelial and Dermal Grafts
Epithelial cells were first to be cultured in vitro and made to coalesce into sheets that could be used to cover full-thickness wounds. Although these culture epithelial sheets were used in the treatment of burns, the result was unsatisfactory because the coverage was very fragile and unsatisfactory. More recently, success has been obtained with artificial dermis which when placed in an appropriate bed will revascularize and can then be covered by a very thin (0.05 cm) split-thickness skin graft. This artificial dermis is increasingly being used in the treatment of burns. Modifications of this concept have also been applied to the care of chronic ulcers, particularly in the leg. The artificial dermis is made out of a collagen matrix and has very low or no antigenicity.

Obtaining Skin Grafts
Instruments used for obtaining skin grafts include razor blades, skin grafting knives (Blair, Ferris Smith, Humby, Goulian), manual drum dermatomes (Padgett, Reese), and electric or air-powered dermatomes (Brown, Padgett, Hall). The electric and air-powered dermatomes are the most widely used because of their reliability and ease of operation. A surgeon, even with only limited experience, can successfully obtain sheets of split-thickness skin grafts, using the electric dermatomes.

The Skin Graft Recipient Area
To ensure survival of the graft, there must be (1) adequate vascularity of the recipient bed, (2) complete contact between the graft and the bed, (3) adequate immobilization of the graft-bed unit, and (4) relatively few bacteria in the recipient area.

Since survival of the graft is dependent upon growth of capillary buds into the raw undersurface of the graft, vascularity of the recipient area is of prime importance. Avascular surfaces that will not generally accept free grafts are tissues with severe radiation damage, chronically scarred ulcer beds, bone or cartilage denuded of periosteum or perichondrium, and tendon or nerve without their paratenon or perineurium, respectively. For these surfaces, a bed capable of producing capillary buds must be provided; in some cases, excision of the deficient bed down to healthy tissue is possible. All unhealthy granulation tissue must be removed, since bacterial counts in granulation tissue are often very high. If bone is exposed, it can be decorticated down to healthy cancellous bone with the use of a chisel or power-driven burr, and a meshed split-thickness skin graft can be applied. If an adequate vascular bed cannot be provided or if the presence of essential structures such as tendons or nerves precludes further debridement, skin or muscle flaps are generally indicated for coverage.
Inadequate contact between the graft and the recipient bed can be caused by collection of blood, serum, or lymph fluid in the bed; formation of pus between the graft and the bed; or movement of the graft on the bed.
After the graft has been applied directly to the prepared recipient surface, it may or may not be sutured in place and may or may not be dressed. Whenever the maximum aesthetic result is desired, the graft should be cut exactly to fit the recipient area and precisely sutured into position without any overlapping of edges. Very large or thick split-thickness grafts and full-thickness grafts will usually not survive without a pressure dressing. In areas such as the forehead, scalp and extremities, adequate immobilization and pressure can be provided by circular dressings. Tie-over pressure stent dressings are advisable for areas of the face, where constant pressure cannot be provided by simple wraparound dressings, or areas where movement cannot be avoided, such as the anterior neck, where swallowing causes constant motion; and areas of irregular contour, such as the axilla. The ends of the fixation sutures are left long and tied over a bolus of gauze fluffs, cotton, a sponge, or other suitable material (Figure 44-2).
Grafts applied to freshly prepared or relatively clean surfaces are generally sutured or stapled into place and dressed with pressure. A single layer of damp or other nonadherent fine-mesh gauze is applied directly over the graft. Immediately over this are placed several thicknesses of flat gauze cut in the exact pattern of the graft. On top of these is placed a bulky dry dressing of gauze fluffs, cotton, a sponge, or other material. Pressure is then applied by wraparound dressings, adhesive tape, or a tie-over pressure stent dressing.
In many cases, it is permissible—and sometimes even preferable—to leave a skin graft site open with no dressing. This is particularly true in slightly infected wounds, where the grafts tend to float off in the purulent discharge produced by the wound. These wounds are best treated with meshed grafts, so that liquid forming between the graft and the wound bed can exude and be removed without disturbing the graft. This treatment can also be used for noninfected wounds that produce an unusual amount of serous or lymphatic drainage, as occurs following radical groin dissections.
In severely ill patients, such as those with major burns, where time under anesthesia must be kept to a minimum, large sheets of meshed split-thickness skin grafts are rapidly applied but not sutured. Skin staples may be used to fix the graft rapidly. Grafts need not be dressed if the area is small, but if the area is large or circumferential, a dressing should be applied. Meshed grafts should generally be covered for 24-48 hours to prevent dryness, since their dermal barrier has been partly disrupted.
Various biologic adhesives, in particular autologous fibrin glue, is being used to immobilize skin grafts. This is especially useful in the face or hands, or areas where bandaging is difficult or cumbersome.
Skin graft dressings may be left undisturbed for 5-7 days after grafting if the grafted wound was free of infection, if complete hemostasis was obtained, if fluid collection is not expected, and if immobilization is adequate. If any one of these conditions is not met, the dressing should be changed within 24-48 hours and the graft inspected. If blood, serum, or purulent fluid collection is present, the collection should be evacuated—usually by making a small incision through the graft with a scalpel blade and applying pressure with cotton-tipped applicators. The pressure dressing is then reapplied and changed daily so that the graft can be examined and fluid expressed as it collects.

The Skin Graft Donor Area
The ideal donor site would provide a graft identical to the skin surrounding the area to be grafted. Since skin varies greatly from one area to another as far as color, thickness, hair-bearing qualities, and texture are concerned, the ideal donor site (such as upper eyelid skin to replace skin loss from the opposite upper eyelid) is usually not found. However, there are definite principles that should be followed in choosing the donor area.

A. Color Match
In general, the best possible color match is obtained when the donor area is located close to the recipient area. Color and texture match in facial grafts will be much better if the grafts are obtained from above the region of the clavicles. However, the amount of skin obtainable from the supraclavicular areas is limited. If larger grafts for the face are required, the immediate subclavicular regions of the thorax will provide a better color match than areas on the lower trunk or the buttocks and thighs. When these more distant regions are used, the grafts will usually be lighter in color than the facial skin in whites. In people with dark skin, hyperpigmentation occurs, producing a graft that is much darker than the surrounding facial skin.

B. Thickness of the Graft and Donor Site Healing
Donor sites of split-thickness grafts heal by epithelialization from the epithelial elements remaining in the donor bed. The ability of the donor area to heal and the speed with which it does depends upon the number of these elements present. Donor areas for very thin grafts will heal in 7-10 days, whereas donor areas for intermediate-thickness grafts may require 10-18 days and those for thick grafts 18-21 days or longer.
Since there is a normal anatomic variation in the thickness of skin, donor sites for thicker grafts must be chosen with the potential for healing in mind and should be limited to regions on the body where the skin is thick. Infants, debilitated adults, and elderly people have thinner skin than healthy younger adults. Grafts that would be split-thickness in the normal adult may be full-thickness in these patients, resulting in a donor site that has been deprived of the epithelial elements necessary for healing.

C. Management of the Donor Site
The donor site itself can be considered a clean open wound that will heal spontaneously. After initial hemostasis, the wound will continue to ooze serum for 1-4 days, depending on the thickness of the skin taken. The serum should be collected and the wound kept clean so that healing can proceed at a maximal rate. The wound should be cared for as described above for clean open wounds in either of two ways.
The more common method is the open (dry) technique. The donor site is dressed with porous sterile fine-mesh or nonadherent gauze. After 24 hours, the dry gauze is changed but the nonadherent gauze is left on the wound and exposed to the air, a heat lamp, or a blow dryer. A scab will form on the gauze and will peel off from the edges as epithelialization is completed underneath. This method has the advantage of simple maintenance once the wound is dry.
The second method is the closed (moist) technique. Studies have demonstrated that the rate of epithelialization is enhanced in a moist environment. In contrast to the dry technique, pain can be reduced or virtually eliminated. Moist-to-moist gauze dressings that require frequent wetting have been replaced by newer synthetic materials. A gas-permeable membrane (OpSite) that sticks to the surrounding skin provides an artificial blister over the wound. Occasionally there is a break in the protective seal covering leakage of serum collected under the membrane. This increases the risk of infection, especially in a contaminated zone. Newer hygroscopic dressings actually absorb and retain many times their weight in water. They are permeable to oxygen yet impervious to bacteria. Infection is still a concern, however, because of occasional exposure of the wound during healing.
(Plastic & Reconstructive Surgery - Luis O. Vasconez, MD, & Henry C. Vasconez, MD )

Kishi K, Nakajima H, Tajima S: Differential responses of collagen and glycosaminoglycan syntheses and cell proliferation to exogenous transforming growth factor beta 1 in the developing mouse skin fibroblasts in culture. Br J Plast Surg 1999;52:579.
van Zuijlen PP et al: Graft survival and effectiveness of dermal substitution in burns and reconstructive surgery in a one-stage grafting model. Plast Reconstr Surg 2000;106:615.
Wang JC, To EW: Application of dermal substitute (Integra) to donor site defect of forehead flap. Br J Plast Surg 2000;53:70.
Current Surgical Diagnosis and Treatment, 11th Ed 2003: Lawrence W. Way, Gerard M. Doherty By McGraw-Hill/Appleton & Lange

Mood Disorders seen in Children

Major depressive disorder, dysthymic disorder, and bipolar disorder are the three major types of affective or mood disorders seen in children and adolescents.

1 Major Depression
Although in the past there was some doubt as to whether prepubertal children experience depression similar to that seen in adults, this view has been dispelled through the use of structured interviews and rating scales. Major depression is characterized by dysphoria (which in children may present as irritability) and an obvious loss of interest and pleasure in usual activities. Diagnostic symptoms also include a significant weight change secondary to decreased or increased food intake, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy on most days, feelings of worthlessness and excessive guilt, diminished ability to concentrate, and recurrent thoughts of death. A melancholic subtype of depression, characterized by marked anhedonia and early morning awakening, has been described in adolescents.
Epidemiology.

The prevalence of depression varies based on sampling and measurement: Studies in childhood report rates of 0.4–2.5% and in adolescence, 0.4–8.3%. The lifetime prevalence of depression starting in adolescence is 15–20%, underscoring the fact that depression is a common disorder. At least twice as many girls as boys meet criteria for depression during adolescence; prepubertal depression is equally common among the sexes. Depression is undertreated across the life span, despite available and effective treatments shown to counter the high cost of lost productivity (e.g., school failure in adolescence) associated with ongoing depression.

Etiology.
Many factors contribute to causing depression. However, there is strong evidence of a genetic basis for major depressive disorders across the life span. Individuals at high genetic risk appear to be more sensitive to the effects of adverse environmental conditions. Twin studies have shown a 76% concordance for depression among monozygotic twins reared together and 67% for monozygotic twins reared apart compared with 19% for dizygotic twins reared together. There is also an increased rate of depression (3–6 times greater) in first-degree relatives of patients suffering from a major affective disorder. Low functional levels of norepinephrine and serotonin are thought to be important genetic markers for depression and low urinary levels of 3-methoxyhydroxyphenylglycol and 5-hydroxyindoleacetic acid have been described in depressed patients. Positron emission tomography scans reveal altered metabolic activity in specific brain regions associated with mood, sleep, and appetite regulation. Neuroimaging data are reinforced by the fact that antidepressants that block presynaptic reuptake of serotonin are highly effective in treating depression. The development of hopelessness and helplessness secondary to an actual loss or the perception of loss suggests that cognitive factors play a role in the onset and maintenance of depression. Numerous studies confirm that adverse life events clearly play a role in causing depression, and there is even research on the pathophysiology linking experience and mood.

Clinical Manifestations.
Depressive symptoms vary according to age and developmental level. Spitz described the anaclitic depression of infancy, and Bowlby observed that separation from a primary caregiver after 6–7 mo of age first leads to strong protest (e.g., crying and searching). Eventually, abandoned infants become withdrawn and apathetic, exhibiting hypotonia, lethargy, and an obviously sad facial expression. These infants often cry silently and, when picked up, may cling to a stranger, though they are usually inconsolable.
The clinical picture of depression in children somewhat parallels that of adults, except that children are more likely to present with separation anxiety, phobias, somatic complaints, and behavioral problems. Instead of reporting sadness, children may behave irritably. The hallmark of psychotic depression in children is the occurrence of hallucinations; delusions are more common in adolescents and adults.
The symptoms of a major depressive episode usually develop over a period of many days or weeks. The duration of each episode of depression is variable, though symptoms often persist for 7–9 mo without treatment; 6–10% of episodes are more protracted. Several longitudinal studies show that children and adolescents who are depressed are at risk for the development of later episodes of depression. Other studies have shown that, within 2 yr of the first depressive episode, 40% of children who have had a major depressive disorder experience a relapse. For children, like adults, depression should be considered a chronic disease marked by periods of normal mood. However, 20–40% of teenagers hospitalized with major depression develop a manic episode within 3–4 yr of discharge. Three predictors of later mania in depressed adolescents are (1) a depressive symptom cluster characterized by rapid onset, psychomotor retardation, and mood-congruent psychotic features; (2) a family history of bipolar illness or other affective illness; and (3) induction of hypomania by antidepressant medication. The picture of depression is further complicated by the fact that co-morbidity commonly occurs: 20–50% of depressed children have two or more diagnoses, including an anxiety disorder (30–80%), a disruptive behavior disorder (10–80%), dysthymic disorder (30–80%), or substance abuse disorder (20–30%).

Diagnosis.
The Children's Depression Inventory, Children's Depression Scale, Depression Self-Rating Scale, and the Center for Epidemiological Studies Depression Scale for Children have all been shown to be helpful to clinicians in diagnosing depression in children and adolescents. However, clinical interview with the child and multiple adults familiar with the child
85
remains the gold standard. There are no biologic tests specific for depression, though various biologic markers have been studied. For instance, during major depressive episodes, some children have been shown to hyposecrete growth hormone in response to insulin-induced hypoglycemia, whereas others produce higher growth hormone peaks during sleep. However, no test has sufficient sensitivity or specificity to assist in diagnostic assessment.

Treatment.
Both psychotherapy and pharmacotherapy are effective in treating depression in childhood and adolescence. Psychotherapy is especially important for patients with multiple diagnoses or precipitants related to family disruption or conflict. Cognitive behavioral therapy (12–16 wk) has been most well studied and is effective in about 70% of cases of adolescent depression. Rigorous studies have also shown that selective serotonin reuptake inhibitors (SSRIs) reduce depressive symptoms in about 70% of cases. However, only 1 of 12 controlled studies of tricyclic antidepressants (TCAs) have demonstrated efficacy, and these agents, which have a narrow therapeutic window and serious side effects, are rarely indicated for depression in childhood. Furthermore, because depression is strongly associated with suicidal ideation and attempts and TCAs are deadly in overdose, the pediatrician should avoid using these drugs for depression.
Mood Disorders(Nelson Textbook of Pediatrics 17th edition (May 2003): by Richard E., Md. Behrman (Editor), Robert M., Md. Kliegman (Editor), Hal B., Md. Jenson (Editor) By W B Saunders)
Neil W. Boris
Richard Dalton
Marc A. Forman

KAWASAKI SYNDROME

Kawasaki syndrome is a worldwide multisystemic disease initially described by Tomisaku Kawasaki in 1967. It is also known as the "mucocutaneous lymph node syndrome." It occurs mainly in children under age 5 but occasionally in adults, at times in epidemic fashion. Asian children are at higher risk. The epidemiology suggests an infectious origin, though no agent has been identified. While disease is probably not mediated by a bacterial toxin, a staphylococcal toxin may serve as a "superantigen" that interacts with T cells. IgA plasma cell infiltration is noted in the visceral organs, lungs, and coronary arteries of Kawasaki syndrome patients.

The disease is characterized by fever and four of the following for at least 5 days: bilateral nonexudative conjunctivitis, mucous membrane changes of at least one type (injected pharynx, cracked lips, strawberry tongue), extremity changes of at least one type (edema, desquamation, erythema), a polymorphous rash, and cervical lymphadenopathy greater than 1.5 cm.

A major complication is arteritis of the coronary vessels, occurring in about 25% of untreated cases and on occasion causing myocardial infarction. Noninvasive diagnosis can be made with magnetic resonance angiography or transthoracic ultrasound. Factors associated with the development of coronary artery aneurysms are leukocytosis and elevated C-reactive protein. Arteritis of extremity vessels and peripheral gangrene are also reported. Cerebrospinal fluid pleocytosis is reported in one-third of cases. The cause of these complications is also unknown. Differentiation from disseminated adenovirus infection is important and may be facilitated in the future with rapid adenovirus assays.

Management is with aspirin (80-100 mg/kg/d in divided doses with subsequent tapering) and intravenous immune globulin, 2 g/kg over 10 hours. Plasmapheresis may be useful in the up to 10% of cases that are unresponsive to immune globulin. Corticosteroids are used by some in refractory disease. Their role in increasing the likelihood of the development of coronary aneurysms is controversial. Aspirin is used for patients with persisting coronary artery aneurysms, while warfarin is indicated for aneurysms larger than 8 mm in diameter. Regular follow-up by a cardiologist is recommended for patients with coronary artery disease or aneurysms. Success is reported with interventional catheter treatment, including stent implantation in patients with long-term cardiac complications.


Barron KS: Kawasaki disease: etiology, pathogenesis, and treatment. Cleve Clin J Med 2002;69 (Suppl 2):SII69. [PMID: 12086269]
Blanchard JN et al: Recurrent Kawasaki disease-like syndrome in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2003;36:105. [PMID: 12491210]
Brogan PA et al: Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research. Arch Dis Child. 2002;86:286. [PMID: 11919108]
Chang RK: Hospitalizations for Kawasaki disease among children in the United States, 1988-1997. Pediatrics 2002;109:e87. [PMID: 12042581]
Mason WH et al: Kawasaki syndrome. Clin Infect Dis 1999;28:169. [PMID: 10064222]
Document Bibliographic Information:
Location In Book:
CURRENT MEDICAL DIAGNOSIS & TREATMENT - 43rd Ed. (2004)
Infectious Diseases: Viral & Rickettsial - Samuel Shelburne III, MD, & Wayne X. Shandera, MD
VIRAL DISEASES

Clinical features of burn injuries

  1. Pain
    Pain is immediate, acute and intense with superficial burns. It is likely to persist until strong analgesia is administered. With deep burns there may be surprisingly little pain.
  2. Acute anxiety
    The patient is often severely distressed at the time of injury. It is frequent for patients to run about in pain or in an attempt to escape, and secondary injury may result.
  3. Fluid loss and dehydration
    Fluid loss commences immediately and, if replacement is delayed or inadequate, the patient may be clinically dehydrated. There may initially be tachycardia from anxiety and later a tachycardia from fluid loss.
  4. Local tissue oedema
    Superficial burns will blister and deeper burns develop oedema in the subcutaneous spaces. This may be marked in the head and neck, with severe swelling which may obstruct the airway. Limb oedema may compromise the circulation.
  5. Special sites
    Burns of the eyes are uncommon in house fires as the eyes are tightly shut and relatively protected. The eyes, however, may be involved in explosion injuries or chemical burns. Burns of the nasal airways, the mouth and upper airway may occur in inhalation injuries.
  6. Coma
    Following house fires, the patient may be unconscious and the reason for this must be ascertained. Asphyxiation or head injury must be excluded. Burning furniture is particularly toxic and the patient may suffer from carbon monoxide or cyanide poisoning.

    (DAVID J. COLEMAN, Bailey Surgical Textbook)

PREVENTING CHILDHOOD POISONINGS

Each year, children are accidentally poisoned by medicines, polishes, insecticides, drain cleaners, bleaches, household chemicals, and garage products. It is the responsibility of adults to make sure that children are not exposed to potentially toxic substances.


Here are some suggestions for parents:

  1. Insist on packages with safety closures and learn how to use them properly.
  2. Keep household cleaning supplies, medicines, garage products, and insecticides out of the reach and sight of your child. Lock them up whenever possible.
  3. Never store food and cleaning products together. Store medicine and chemicals in original containers and never in food or beverage containers.
  4. Avoid taking medicine in your child's presence. Children love to imitate. Never suggest that medicine is candy—especially aspirin and children's vitamins.
  5. Read the label on all products and heed warnings and cautions. Never use medicine from an unlabeled or unreadable container. Never pour medicine in a darkened area where the label cannot be seen clearly.
  6. If you are interrupted while using a product, take it with you—it takes only a few seconds for your child to get into it.
  7. Know what your child can do physically. For example, if you have a crawling infant, keep household products stored above floor level, not beneath the kitchen sink.
  8. Keep the phone numbers of your doctor, poison center, hospital, police department, and emergency medical system (EMS) near the phone.

CHAPTER REFERENCES
Baselt RC, Cravey RH: Disposition of Toxic Drugs and Chemicals in Man, 4th ed. Year Book, 1995.
Bresinsky A, Besl H: A Colour Atlas of Poisonous Fungi: A Handbook for Pharmacists, Doctors, and Biologists. Wolfe, 1990.
Clayton GD, Clayton FE: Patty's Industrial Hygiene and Toxicology, Vol 2, 4th ed. Wiley-Interscience, 1993.
Dart RC et al: The 5 Minute Toxicology Consult. Lippincott Williams & Wilkins, 2000.
Finkel AJ (editor): Hamilton & Hardy's Industrial Toxicology, 4th ed. Publishing Sciences Group, 1983.
Goldfrank LR et al: Goldfrank's Toxicologic Emergencies, 6th ed. Appleton & Lange, 1998.
Grant WM: Toxicology of the Eye, 4th ed. Thomas, 1993.
Haddad LM, Shannon MW, Winchester JF: Clinical Management of Poisoning and Drug Overdose, 3rd ed. Saunders, 1998.
Koren G: Maternal-Fetal Toxicology: A Clinician's Guide, 2nd ed. Dekker, 1994.
Lampe KF, McCann MA: AMA Handbook of Poisonous and Injurious Plants. American Medical Association, 1985.
Olson KR (editor): Poisoning and Drug Overdose, 3rd ed. Appleton & Lange, 1999.
Rumack BH, Spoerke DG, Smolinske SC (editors): POISINDEX Information System. Micromedex, Inc., Denver, CO. [Published quarterly.]

(By textbook of
Current Pediatric Diagnosis & Treatment 16th Ed: William W. Hay Jr, et al By McGraw-Hill Education - Europe 2002)