Lymphoma is a cancer that occurs in lymphatic system. Lymphoma represents many different cancers of lymphocytes-about 35 different subtypes. It is the sixth most common cancer in adults and the third most common in children

Lymphatic system
• The lymphatic system is composed mainly of lymphoid tissue, lymph vessels, and lymph.
• Lymphoid tissue includes the lymph nodes and related organs that are part of the body’s immune and blood-forming systems, such as the spleen and bone marrow.8
• Lymphoid tissue is made up of cells called lymphocytes, which are a type of infection-fighting white blood cell. There are 2 types of lymphocytes.
 B lymphocytes (B cells)
B lymphocytes or B cells help protect the body from invading germs. They do this by maturing into plasma cells, which make antibodies (immune proteins). These antibodies attach to germs, such as bacteria, marking them for destruction.
 T lymphocytes(T cells)
T lymphocytes or T cells can directly destroy certain kinds of bacteria or cells infected with viruses or fungi, or they can help other immune system cells do their job better. 1, 2
• Lymph nodes: Lymph nodes are small, bean-shaped organs found under the skin in the neck, under the arms, the groin & inside the chest, abdomen, and pelvis. 7
• The lymph nodes are connected by a system of lymphatic vessels. These vessels are like veins, except that instead of carrying blood, they carry lymph and immune system cells traveling between lymph nodes and other tissues.
• Lymph nodes increase in size when they fight an infection. Lymph nodes that grow in reaction to infection are called reactive nodes or hyper plastic nodes and are often tender to the touch.

Cancer occurs when normal cells undergo a transformation whereby they grow and multiply uncontrollably.
Lymphoma is a malignant transformation of either lymphocytes B or T cells or their subtypes. As the abnormal cells multiply, they may collect in 1 or more lymph nodes or in other lymph tissues such as the spleen. As the cells continue to multiply, they form a mass often referred to as a tumor.7
Tumors often overwhelm surrounding tissues by invading their space, thereby depriving them of the necessary oxygen and nutrients needed to survive and function normally. Because of their uncontrolled growth, lymphomas can encroach on and/or invade neighboring tissues or distant organs.
In lymphoma, abnormal lymphocytes travel from one lymph node to the next, and sometimes to remote organs, via the lymphatic system. While lymphomas are often confined to lymph nodes and other lymphatic tissue, they can spread to other types of tissue almost anywhere in the body. Lymphoma development outside of lymphatic tissue is called extra nodal disease.8
Lymphomas are currently classified on the basis of histological appearance into
 Hodgkin’s lymphoma
 Non- Hodgkin’s lymphoma
Lymphoma Causes
The exact causes of lymphoma are not known. Several factors have been linked to an increased risk of developing lymphoma, but it is unclear what role they play in the actual development of lymphoma. These risk factors include the following:
• Age: Generally the risk of NHL increases with advancing age. HL in the elderly is associated with a poorer prognosis than that observed in younger patients.
• Infections
o Infection with HIV
o Infection with human T-lymphocytic virus type 1 (HTLV-1)
o Infection with Epstein-Barr virus (EBV), one of the etiologic factors in mononucleosis
o Infection with Helicobacter pylori, a bacterium that lives in the digestive tract
o Infection with hepatitis B or hepatitis C virus 8
• Medical conditions that compromise the immune system
o HIV
o Autoimmune disease
o Diseases requiring immune suppressive therapy, often used following organ transplant
o Inherited immunodeficiency diseases (severe combined immunodeficiency, ataxia telangiectasia, among a host of others)
• Exposure to toxic chemicals
o Farm work or an occupation with exposure to certain toxic chemicals such as pesticides, herbicides, or benzene and/or other solvents
o Black hair dye, which for more than 20 years has been linked to higher rates of NHL 2
• Genetics: Family history of lymphoma
Staging of lymphoma
Staging is the classification of a cancer type by its size and whether and how much it has spread around the body. Determining a cancer’s stage is very important because it tells the oncologist which treatment is most likely to work and what are the chances of remission or a cure (prognosis).9
Staging of lymphomas, as in all cancers, is based on the microscopic examination and on the results of imaging studies and related tests that reveal the extent of the cancer involvement.1
HL is often described as being “bulky” or “nonbulky.” Nonbulky means the tumor is small; bulky means the tumor is large. Nonbulky disease has a better prognosis than bulky disease.8
Staging of both HL and NHL, are similar.
• Stage I (early disease) – Lymphoma located in a single lymph node region or in one area or organ outside the lymph node
• Stage II (locally advanced disease) – Lymphoma located in two or more lymph node regions all located on the same side of the diaphragm or in one lymph node region and a nearby tissue or organ. (The diaphragm is a flat muscle that separates the chest from the abdomen.)
• Stage III (advanced disease) – Lymphoma affecting two or more lymph node regions, or one lymph node region and one organ, on opposite sides of the diaphragm
• Stage IV (widespread or disseminated disease) – Lymphoma outside the lymph nodes and spleen that has spread to another area or organ such as the bone marrow, bone, or central nervous system
Both HL and NHL are further classified with letters.
• An “A” or “B” designation indicates whether the person with lymphoma had symptoms such as fevers and/or weight loss at the time of diagnosis. “A” indicates no such symptoms, and “B” indicates symptoms.9
• An “E” designation indicates that the tumor spread directly from a lymph node into an organ or that a single organ outside the lymphatic system is affected with no apparent lymphatic involvement.
Hodgkin’s lymphoma (HL)
• Hodgkin’s lymphoma (also known as Hodgkin’s disease) tends to affect younger people, most commonly those who are in their mid-teens to early 30s.1
• The hallmark of HL is the Reed-Sternberg cells which are usually derived from germinal centre B cells or rarely, peripheral T cell.
• There are different types of Hodgkin disease. These types are classified by their appearance under the microscope. This is important because types of Hodgkin disease may grow and spread differently and may be treated differently. The 2 main types are
o classical Hodgkin disease
o Nodular lymphocyte predominance Hodgkin disease.
Classical Hodgkin Disease
• Classical Hodgkin disease (HD) accounts for about 95% of all cases of Hodgkin disease in developed countries. It has 4 subtypes, all of which have classical appearing Reed-Sternberg cells.
• Nodular sclerosis Hodgkin disease: This is the most common type of Hodgkin disease in developed countries, accounting for about 70% to 80% of cases. It occurs mainly in younger people, with equal occurrence in men and women. It tends to start in lymph nodes in the neck or chest (mediastinum). Under the microscope, the lymph nodes contain fibrous bands that crises-cross the node and encircle abnormal nodules of lymph tissue.
• Mixed cellularity Hodgkin disease: This is the second most common type (15% to 30%) and is seen mostly in older adults. It can occur in any lymph node but most often occurs in the upper half of the body. Under the microscope, many different kinds of cells can be seen on the biopsy specimen, including Reed-Sternberg cells and normal immune system cells (lymphocytes, eosinophils, and plasma cells).
• Lymphocyte-rich Hodgkin disease: This subtype accounts for about 5% of Hodgkin disease cases. It usually occurs in the upper half of the body and is rarely found in more than a few lymph nodes. Under the microscope it looks very much like mixed cellularity, except that most of the cells are small lymphocytes.
• Lymphocyte-depleted Hodgkin disease: This is the least common form of Hodgkin disease, making up only about 1% of cases. It is seen mainly in older people. The disease is more likely to involve lymph nodes in the abdomen as well as the spleen, liver, and bone marrow. When looking at the cells under the microscope, there are few normal lymphocytes or other immune system cells, and many Reed-Sternberg cells.
Nodular Lymphocyte Predominant Hodgkin Disease
• Nodular lymphocyte predominant Hodgkin disease (NLPHD) accounts for about 5% of Hodgkin disease. This type mostly involves lymph nodes in the neck and under the arm. It can occur at any age. It contains large cells, often called “popcorn” cells (because they look like popcorn), which are variants of Reed-Sternberg cells. Under the microscope, there is a pattern of sheets of lymphocytes arranged in nodules.
All types of Hodgkin disease are malignant because as they grow they may compress, invade, and destroy normal tissue and spread to other tissues. There is no benign (non-cancerous) form of Hodgkin disease.
Signs and Symptoms of Hodgkin Disease
Lump(s) Under the Skin
• May notice a lump in the neck, under the arm, or in the groin, which is an enlarged lymph node. Sometimes this may go away, only to come back, But Hodgkin disease is not the most common cause of lymph node swelling. Other cancers can also cause lymph node swelling.
Generalized (non-specific) Symptoms
• Fever, drenching night sweats, or weight loss.
• The fever can come and go over several days or weeks.
• Itching, tiredness, and decreased appetite are other symptoms that may occur.
• Sometimes the only symptom may be being tired all the time.
• However, infections, other types of cancer, or other conditions can also produce these symptoms.
Cough or Trouble Breathing
• When Hodgkin disease affects lymph nodes inside the chest, the swelling of these nodes may compress the windpipe (trachea) and make you cough or even have trouble breathing, especially when lying down.
Treatments for Hodgkin disease
Treatments are based on many factors, including:
• The kind of Hodgkin disease
• The extent of the Hodgkin disease in the body
• Results of blood and other lab tests
• General health of patient
• Age of patient
• Medical history of patient

Stage IA and IIA, Non-bulky Disease
This group includes Hodgkin disease that is confined to one side of the diaphragm (above or below), is not bulky, and that doesn’t cause any of the “B” symptoms.
The preferred treatment option for most patients is chemotherapy (usually 2 or 4 cycles of ABVD), followed by involved field radiation to the initial site of the disease. Less commonly used options may include either radiation therapy alone (often given over more extensive area) or chemotherapy alone (usually for 4 or 6 cycles) in selected patients.
In children and adolescents with Hodgkin disease, treatment generally starts with chemotherapy alone, used at the lowest dose that is likely to result in a cure. If the disease doesn’t completely go away with initial treatment, radiation therapy or more chemotherapy might be added. If radiation is used, the dose and field would be kept as small as possible.
Stage IA and IIA, Bulky Disease
This group includes Hodgkin disease that is confined to one side of the diaphragm (above or below) and that doesn’t cause any of the “B” symptoms, but is bulky in terms of tumor mass.
Treatment is generally more intense than with non-bulky disease. The most common option is chemotherapy (usually ABVD for 4 to 6 cycles or other regimens such as Stanford V or BEACOPP), followed by involved-field radiation therapy to the sites of the tumor. For those who don’t respond to treatment, high-dose chemotherapy (and possibly radiation) followed by a stem cell transplant may be recommended.
In children and adolescents, treatment is likely to consist of chemotherapy combined with radiation therapy, although the dose and field of radiation would be kept as small as possible.
Stage IB or IIB (Non-bulky), or Stage III or IV (Bulky or Non-bulky)
Generally treat these stages with chemotherapy at full doses. Although ABVD (for at least 6 cycles) can be used As long as the cancer is still shrinking, chemotherapy will be continued. Any remaining areas of enlarged lymph nodes are then treated with radiation, if needed. PET scans might be used during treatment to assess how much treatment you need. For those who don’t respond to treatment, high-dose chemotherapy (and possibly radiation) followed by a stem cell transplant may be recommended.
In children, treatment includes chemotherapy, either alone or in combination with low-dose radiation therapy to areas with bulky disease (areas that contain a lot of Hodgkin disease).
Non-Hodgkin’s Lymphomas
This form of lymphoma is more common than Hodgkin’s disease. In fact, over 85 per cent of all people with lymphoma have the non-Hodgkin’s form of the disease. The risk of developing non-Hodgkin’s lymphoma increases with age, and the disease is most common in people aged over 50 years.
Types of Non-Hodgkin Lymphoma
Types of Non-Hodgkin Lymphoma have been classified.The most recent classification is the World Health Organization (WHO) classification. The WHO system uses the appearance of the lymphoma cells, the chromosome features of the cells, and the presence of certain chemicals on the surface of the cells.4, 8

World Health Organization (WHO) classification
B-Cell Neoplasm
I. Precursor B-cell neoplasm:
a. Precursor B-lymphoblastic leukemia/lymphoma
II. Mature (peripheral) B-cell neoplasm
a. B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma
b. B-cell prolymphocytic leukemia
c. Lymphoplasmacytic lymphoma
d. Splenic marginal zone B-cell lymphoma
e. Hairy cell leukemia
f. Plasma cell myeloma/plasmacytoma
g. Extra nodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type
h. Nodal marginal zone lymphoma
i. Follicle center lymphoma, follicular,
j. Mantle cell lymphoma
k. Diffuse large cell B-cell lymphoma
l. Mediastinal large B-cell lymphoma
m. Primary effusion lymphoma
n. Burkett’s lymphoma/Burkett’s cell leukemia 6,8

T-Cell and Natural Killer Cell Neoplasm
I. Precursor T cell neoplasm:
a. Precursor T-lymphoblastic lymphoma/leukemia
II. Mature (peripheral) T cell and NK-cell neoplasm
a. T cell prolymphocytic leukemia
b. T-cell granular lymphocytic leukemia
c. Aggressive NK-Cell leukemia
d. Adult T cell lymphoma/leukemia
e. Extra nodal NK/T-cell lymphoma, nasal type
f. Enteropathy-type T-cell lymphoma
g. Hepatosplenic gamma-delta T-cell lymphoma
h. Subcutaneous panniculitis-like T-cell lymphoma
i. Mycosis fungoides/ Sézary’s syndrome
j. Ana plastic large cell lymphoma, T/null cell, primary cutaneous type
k. Peripheral T cell lymphoma, not otherwise characterized
l. Angioimmunoblastic T cell lymphoma
m. Ana plastic large cell lymphoma, T/null cell, primary systemic type 10,8,11
Signs and Symptoms of Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma may cause many different signs and symptoms, depending on its location in the body
Lymph nodes near the skin: can be easily seen or felt as lumps under the skin. Enlarged lymph nodes are more often caused by infections than by non-Hodgkin lymphoma.
Abdomen: When the lymphoid tissue inside the abdomen is involved, the abdomen can become tender, painful, and/or swollen. This may be due to either a tumor or to large collections of fluid. When lymphoma causes swelling near the intestines, the passage of feces may be blocked, which may lead to discomfort or abdominal pain. The pressure or blockage can also cause nausea or vomiting.
Chest: When lymphoma starts in the thymus or lymph nodes in the chest, it may irritate or compress the nearby trachea (windpipe), which can cause coughing or trouble breathing.11
Lymphomas in heart area may affect to the SVC. .It can cause the blood to back up in the veins. This is known as SVC syndrome. 10 It can cause swelling in the face and arms and a bluish-red coloration of the head, arms, and upper chest. It can also cause trouble breathing and a change in consciousness if it affects the brain. The SVC syndrome can be life-threatening, and requires treatment right away.
Brain: Lymphomas of the brain, called primary brain lymphomas, can cause headache, trouble thinking and moving parts of the body, personality changes, and sometimes seizures.
General symptoms: Along with symptoms and signs resulting from local effects of cancer growth, non-Hodgkin lymphoma can produce generalized symptoms, such as:
• unexplained weight loss
• fever
• drenching night sweats
• severe itchiness
Sometimes these generalized effects are called B symptoms. The presence of B symptoms is often related to the presence of more rapidly growing lymphoma cells.
Types of Non-Hodgkin Lymphoma
B-Cell Lymphomas
a) Diffuse Large B-cell Lymphoma.
b) Diffuse large B-cell lymphoma (DLBCL) can affect any age group but occurs mostly in older people (the average age of most patients is mid-60s). 3, 5. The usual symptoms are a quickly growing mass in an internal lymph node, such as in the chest or abdomen or in a lymph node that you can feel, for example, in the neck or armpit. Although this lymphoma usually starts in lymph nodes, it can grow in other areas such as the intestines, bone, and even the brain or spinal cord.
This is a fast growing lymphoma, but it often responds well to treatment with chemotherapy. Overall, about 3 out of 4 people will have no signs of disease after initial treatment, and about half of all people with this lymphoma are cured with therapy.
c) Follicular Lymphoma
The term follicular is used because the cells tend to grow in a circular, or nodular, pattern in lymph nodes.
The average age for people with this lymphoma is about 60.8. It is rare in very young people. Most of the time, this lymphoma occurs in many lymph node sites in the body, as well as in the bone marrow. In about 10% of cases, it only involves lymph nodes in one part of the body.

d) Chronic Lymphocytic Leukemia /Small Lymphocytic Lymphoma
These related diseases account for about 1 out of 4 lymphomas. The same type of cell (known as a small lymphocyte) is involved in both chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). The only difference is where the cancer occurs. In CLL it is mostly in the blood and bone marrow; in SLL, it is mainly in the lymph nodes.
Both are slow-growing diseases, although CLL, which is much more common, tends to grow slower.
e) Mantle Cell Lymphoma
Only about 5% of lymphomas are of this type. The cells are small to medium.
Men are affected most often. The average age of patients is in the early 60s. The lymphoma is usually widespread when it is diagnosed, involving lymph nodes, bone marrow, and, very often, the spleen.
f) Marginal Zone B-cell Lymphomas
This type account for about 4% of lymphomas. The cells in these lymphomas look small under the microscope. There are 3 main types of marginal zone lymphomas.
I. Extra nodal marginal zone B-cell lymphomas (also known as mucosa-associated lymphoid tissue
II. Nodal marginal zone B-cell lymphoma
III. Splenic marginal zone B-cell lymphoma.

g) Primary Mediastinal B-cell Lymphoma
This type accounts for about 2% of all lymphomas. The cells are large and resemble those of diffuse large B-cell lymphomas.
This lymphoma starts in the mediastinum. It usually is localized at the beginning and rarely involves the bone marrow. It can cause trouble breathing because it often presses on the windpipe (trachea) leading into the lungs. It can also block the superior vena cava. It is a fast growing lymphoma but it is treatable.
h) Burkett Lymphoma
This is a very fast-growing lymphoma. In the African variety, it often starts as tumors of the jaws or other facial bones.4. The lymphoma usually starts in the abdomen. Close to 90% of patients are male, and the average age is about 30.
i) Hairy Cell Leukemia
Despite the name, this is sometimes considered to be a type of lymphoma. The cells are small B lymphocytes with projections around them that give them a “hairy” appearance. They are typically found in the bone marrow and spleen and circulating in the blood.
Patients tend to be older in general. An enlarging spleen or dropping blood counts (due to cancer cells invading the bone marrow) are the usual reasons to begin treatment, which is highly effective.
j) Primary Central Nervous System Lymphoma
This lymphoma usually involves the brain (called primary brain lymphoma), but it may also be found in the spinal cord and in tissues around the spinal cord and the eye. Over time, it tends to become widespread in the central nervous system. Most people develop headache and confusion.
The outlook for people with this condition has always been thought to be fairly poor, but about 30% to 50% of people can live at least 5 years with today’s treatments.
T-Cell Lymphomas
a) Precursor T-lymphoblastic Lymphoma/Leukemia
This disease accounts for about 1% of all lymphomas. It can be considered either a lymphoma or leukemia, depending on how much of the bone marrow is involved. The cancer cells are small-to-medium immature T-cells.
It often starts in the thymus gland (where many T cells are made) and can develop into a large tumor in the mediastinum. Patients are most often young adults, with males being affected more often than females. Once it is in the bone marrow, only about 40% to 50% of patients can be cured.
b) Peripheral T-cell Lymphomas
These lymphomas develop from more mature forms of T cells. There are several kinds of peripheral T-cell lymphomas,
• Cutaneous T-cell lymphomas
• Extra nodal natural killer/T-cell lymphoma, nasal type:
• Enteropathy type T-cell lymphoma:
• Subcutaneous panniculitis-like T-cell lymphoma:
• Ana plastic large cell lymphoma:
Treatments
The main types of treatment are:
 Radiation therapy
 Chemotherapy
 Immunotherapy
 Bone marrow and peripheral blood transplants.6,7
Radiation therapy is the use of high-energy x-rays to kill cancer cells and shrink tumors. Radiation for NHL usually comes from a machine outside the body (external-beam radiation therapy). Radiation therapy given to the neck, chest, and lymph nodes under the arms is called radiation therapy to a mantle field. Radiation therapy given to the mantle field and to the lymph nodes in the upper abdomen, the Spleen and the lymph nodes in the pelvis are called total nodal irradiation. Radiation therapy may be used alone or in addition to chemotherapy
Immunotherapy/ biological response modifier (BRM) therapy tries to help body to fight cancer or infections. It uses materials made by body or made in a laboratory to boost, direct, or restore body’s natural defenses against disease Recent advances have been made in the use of Monoclonal Antibody therapy and vaccines. In Non-Hodgkin’s, T-Cell Immunotherapy is now coming out of the labs into trials which use a patient’s own immune cells.

The lymphomas are commoner than the leukaemias and are increasing incidence of reasons which are unclear. They arise as the result of abnormal proliferation of the lymphoid system, and hence occur at any site where lymphoid tissue is found. Most commonly they are manifest by the development of lymphadenopathy at single multiple sites, although primary extranodal presentations account for up to 20% of non-Hodgkin’s lymphoma. The prognosis is determined by the specific subtype of lymphoma and the anatomical extent of disease and its bulk, the clinical ranging from months to years.

The lymphatic system is part of the immune system. It consists of a network of vessels that carry fluid called lymph, similar to the way that the network of blood vessels carries blood throughout the body. Lymph contains white blood cells called lymphocytes. Lymphocytes attack a variety of infectious agents as well as many cells in the precancerous stages of development.
Lymph nodes are small collections of lymph tissue that occur throughout the body. The lymphatic system involves lymphatic channels that connect thousands of lymph nodes scattered throughout the body. Lymph flows through the lymph nodes, as well as through other lymphatic tissues including the spleen, the tonsils, the bone marrow, and the thymus gland.

WHO classification of lymphomas13
• B-cell neoplasms
o Precursor B-cell neoplasms
 Precursor B-cell acute lymphoblastic leukemia (B ALL)
 Lymphoblastic lymphoma
o Peripheral B-cell neoplasms
 B-cell CLL/small lymphocytic lymphoma
 B-cell prolymphocytic leukemia
 Lymphoplasmacytic lymphoma/immunocytoma
 Mantle cell lymphoma
 Follicular lymphoma
 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type
 Nodal marginal zone lymphoma (with or without monocytoid B-cells)
 Splenic marginal zone lymphoma (with or without villous lymphocytes)
 Hairy cell leukemia
 Plasmacytoma/plasma cell myeloma
 Diffuse large B-cell lymphoma
 Burkitt lymphoma
• T-cell and putative NK-cell neoplasms
o Precursor T-cell neoplasms
 Precursor T-cell acute lymphoblastic leukemia (T-ALL)
 Lymphoblastic lymphoma
o Peripheral T-cell and NK-cell neoplasms
 T-cell CLL/prolymphocytic lymphoma
 T-cell granular lymphocytic leukemia
 Mycosis fungoides/Sézary syndrome
 Peripheral T-cell lymphoma, not otherwise characterized
 Hepatosplenic gamma/delta T-cell lymphoma
 Subcutaneous panniculitislike T-cell lymphoma
 Angioimmunoblastic T-cell lymphoma
 Extranodal T-cell/NK-cell lymphoma, nasal type
 Enteropathy-type intestinal T-cell lymphoma
 Adult T-cell lymphoma/leukemia (with human T-cell leukemia virus type 1 [HTLV-1])
 Anaplastic large cell lymphoma, primary systemic type
 Anaplastic large cell lymphoma, primary cutaneous type
 Aggressive NK-cell leukemia

• Pathological classification of hodgkin lymphoma (Hodgkin disease)
o Nodular lymphocyte-predominant Hodgkin lymphomas
o Classic Hodgkin lymphomas
 Nodular sclerosis Hodgkin lymphoma
 Lymphocyte-rich classic Hodgkin lymphoma
 Mixed cellularity Hodgkin lymphoma
 Lymphocyte depletion Hodgkin lymphoma

Hodgkin lymphoma (HL)

This disease is characterized by progressive painless enlargement of lymphoid tissues throughout the body. It occurs in both sexes, often in adolescence and early adult life, but it may be found also in alder people. The pathogenesis is unknown and the condition is usually regarded as a form of malignant disease related to other neoplastic processes of haemopietic tissue. It is distinguished from non-Hodgkin lymphoma by the presence of Reed-Sternberg cells, now thought to be the malignant cells.

• Nodular sclerosing HL (70% of cases) where many fibrotic bands are present. This type is typically seen in young females, involving particularly lymph nodes in the mediastinum and neck.
• Lymphocyte-rich HL appears in 5% and is characterized by an infiltrate of many small lymphocytes and Reed-Sternberg cells. It often occurs in peripheral lymph nodes. It is often an indolent disease.
• Mixed cellularity HL approximately 25% of cases have mixed cellularity with lymphocytes, eosinophils, neutrophils and histiocytes. Reed-Sternberg cells are present but no fibrotic bands. It is more common in men and is associated with B symptoms.
• Lymphocyte-depleted HL is rare and there is lack of cellular infiltrate with numerous Reed-Sternberg cells. It is seen in HL associated with HIV
• Nodular lymphocyte-predominant HL (5% of cases) contains malignant lymphocytic and/or histiocytic Reed-sternberg cell variants, also called ‘popcorn cells.

Non-Hodgkin lymphoma

In this group of disorders there is a malignant monoclonal proliferation of lymphoid cells, usually identifiable as B cells. Occasionally T cells are affected. Non-hodgkin lymphomas merge with lymphoblastic and lymphocytic leukaemias with which they have many features in common.
The incidence of these tumours is approximately 15/100000 per year in developed countries, an incidence which has increase over the last 20-30 years. There is a slight male predominance. The median age of presentation is 55-75 years.

Clinical staging of Hodgkin and non-Hodgkin lymphomas (Ann Arbor classification) 6
Stage distribution of disease
I. Involvement of a single lymph-node region or
lymphoid structure ( e.g. spleen, thymus, waldeye’s ring )
or involvement of a single extralymphatic site.
II. Involvement of two more lymph-node regions on the same
Side of the diaphragm ( hilar nodes, when involved on the
both sides, constitute stage II disease ) ;localized
contiguous involvement of only one extranodal organ or
site and lymph-node region(s) on the same side of the
diaphragm (IIE). The number of anatomic regions involved
should be indicated by a subscript (e,g , II3 )
III. Involvement of lymph-node regions on both sides of
diaphragm (III), which may also be accompanied by
involvement of the spleen (IIIS) or by localized
involvement of only one extranodal organ site(IIIE)
or both (IIISE)
III1 with or without involvement of splenic, hilar, coeliac,
or portal nodes.
III2 with involvement of para-aortic, iliac, and mesenteric
nodes
IV. Diffuse or disseminated involvement of one or more
extranodal organs or tissues, with or without associated
lymph-node involvement.
Lymphoma causes
The exact causes of lymphoma are not known. Several factors have been linked to an increased risk of developing lymphoma, but it is unclear what role they play in the actual development of lymphoma. These risk factors include the following:
• Age: Generally the risk of NHL increases with advancing age. HL in the elderly is associated with a poorer prognosis than that observed in younger patients.
• Infections
• Infection with HIV
• Infection with human T-lymphocytic virus type 1 (HTLV-1)
• Infection with Epstein-Barr virus(EBV), one of the etiologic factors in mononucleosis
• Infection with Helicobacter pylori, a bacterium that lives in the digestive tract
• Infection with hepatitis B or hepatitis C virus
• Medical conditions that compromise the immune system
• HIV
• Autoimmune disease
• Diseases requiring immune suppressive therapy, often used following organ transplant
• Inherited immunodeficiency diseases (severe combined immunodeficiency, ataxia telangiectasia, among a host of others)

• Exposure to toxic chemicals
• Farm work or an occupation with exposure to certain toxic chemicals such as pesticides, herbicides, or benzene and/or other solvents
• Black hair dye, which for more than 20 years has been linked to higher rates of NHL.

• Genetics ; family history of lymphoma
The presence of these risk factors does not mean a person will actually develop lymphoma. In fact, most people with one or several of these risk factors do not develop lymphoma.

Lymphoma Symptoms

Often, the first sign of lymphoma is a painless swelling in the neck, under an arm, or in the groin.
• Lymph nodes or tissues elsewhere in the body may also swell. The spleen, for example, often becomes enlarged in lymphoma.
• The enlarged lymph node sometimes causes other symptoms by pressing against a vein or lymphatic vessel (swelling of an arm or leg), a nerve (pain, numbness, or tingling), or the stomach (early feeling of fullness).
• Enlargement of the spleen may cause abdominal pain or discomfort.
• Many people have no other symptoms.

Symptoms of lymphoma may include the following:
• Fevers
• Chills
• Unexplained weight loss
• Night sweats
• Lack of energy

These symptoms are nonspecific. This means that they could be caused by any number of conditions unrelated to cancer. For instance, they could be signs of the flu or other viral infection, but in those cases, they would not last very long. In lymphoma, the symptoms persist over time and cannot be explained by an infection or another disease.

When to Seek Medical Care
Swelling in the neck, armpit, or groin, or unexplained swelling in an arm or leg should prompt one to seek medical attention. Such swellings may have many causes or have nothing to do with lymphoma, but they should be checked.
If any of the following symptoms persist for more than a few days, seek medical attention:
• Fevers
• Chills
• Unexplained weight loss
• Night sweats
• Lack of energy
• Itchi

Medical Treatment

Standard first-line therapy (primary therapy) for lymphoma includes radiation therapy for most early-stage lymphomas, or a combination of chemotherapy and radiation. For later-stage lymphomas, chemotherapy is primarily used, with radiation therapy added for control of bulky disease. Biological therapy, or immunotherapy, is increasingly being used in addition to or as an alternative to these standard therapies.

Radiation therapy
Radiation therapy uses high-energy rays to kill cancer cells. It is considered a local therapy, meaning that it should be used to target areas of the body involved by tumor masses. A radiation oncologist will plan and supervise therapy.
The radiation is targeted at the affected lymph node region or organ. Occasionally, nearby areas are also irradiated to kill any cells that might have spread there undetected.
Depending on how and where the radiation is administered, it may cause certain side effects such as fatigue, loss of appetite, nausea, diarrhea, and skin problems. Radiation of lymph node areas may result in suppression of the immune system to varying degrees. Irradiation of the underlying bone and the marrow within the bone may result in suppression of the blood counts.
The radiation is usually administered in short bursts on 5 days a week over the course of several weeks. This keeps the dose of each treatment low and helps prevent or lessen side effects.

Chemotherapy
Chemotherapy is the use of powerful drugs to kill cancer cells. Chemotherapy is a systemic therapy, meaning that it circulates through the bloodstream and affects all parts of the body. Ideally, chemotherapy can find and kill cancer cells anywhere in the body.
Unfortunately, chemotherapy also affects healthy cells; this accounts for its well-known side effects.
The side effects of chemotherapy depend partly on the drugs used and the doses.
Some people, because of variability in metabolism of chemotherapy drugs, tolerate chemotherapy better than other people.
The most common side effects of chemotherapy include suppression of blood counts, which could result in increased susceptibility to infection (low white blood cell count), anemia (low red blood cell count), or blood clotting problems (low platelet). Other side effects may include nausea and vomiting, loss of appetite, hair loss, sores in the mouth and digestive tract, fatigue, muscle aches, and changes in fingernails and toenails. Specific drugs may confer other, specific side effects.
Medications and other treatments are available to help people tolerate these side effects, which can be severe.
It is very important to discuss and review the potential side effects of each chemotherapy drug in the treatment with the oncologist, pharmacist, or oncology nurse. Medications to lessen the side effects should also be reviewed.
Chemotherapy may be given in pill form, but it is typically a liquid infused directly into the bloodstream through a vein (intravenous).
Most people who receive intravenous chemotherapy will have a semi-permanent device placed in a large vein, usually in the chest or arm.
This device allows the medical team quick and easy access to the blood vessels, both for administering medications and for collecting blood samples.
These devices come in several types, usually referred to as a “catheter,” “port,” or “central line.”
Experience has shown that combinations of drugs are more efficient than monotherapy.
Combinations of different drugs both increase the chance that the drugs will work and lower the dose of each individual drug, reducing the chance of intolerable side effects.
Several different standard combinations are used in lymphoma. Which combination one receives depends on the type of lymphoma and the experiences of the oncologist and the medical center where a person is receiving treatment.
The combinations of drugs are usually given according to a set schedule that must be followed very strictly.
In some situations, chemotherapy can be given in the oncologist’s office. In other situations, one must stay in the hospital.
Chemotherapy is given in cycles.
One cycle includes the period of actual treatment, usually several days, followed by a period of rest for several weeks to allow recovery from side effects caused by the chemotherapy, particularly anemia and low white blood cells.
Standard treatment typically includes a set number of cycles, such as 4 or 6.
Spreading the chemotherapy out this way allows a higher cumulative dose to be given, while improving the person’s ability to tolerate the side effects.

Biological therapy
Biological therapies are sometimes referred to as immunotherapy because they take advantage of the body’s natural immunity against pathogens. These therapies are attractive because they offer anticancer effects without many of the undesirable side effects of standard therapies. There are many different types of biological therapies. The following are some of the most promising for treating lymphoma:
Monoclonal antibodies: Antibodies are substances produced by lymphocytes to fight pathogens. Every cell, organism, or pathogen within our body carries markers on its surface that antibodies may recognize. These surface markers are called antigens. A monoclonal antibody is an antibody that is made in a laboratory to find and attach itself to a specific antigen. Monoclonal antibodies can be used to help one’s own immune systems kill tumor cells and other pathogens directly, or they can deliver cancer-killing therapies (such as radiation or chemotherapy) directly to a specific antigen found on cancer cells.
Cytokines: These naturally occurring chemicals are produced by the body to stimulate the cells in the immune system and other organs. They can also be produced artificially and administered in large doses to patients with greater effect. Examples include interferon’s and interleukins, which stimulate the immune system, and colony-stimulating factors, which stimulate the growth of blood cells.
Vaccines: Unlike the more familiar vaccines for infectious diseases such as polio and flu, cancer vaccines do not prevent the disease. Rather, they are designed to stimulate the immune system to mount a specific response against the cancer. They also create a “memory” of the cancer so that the immune system activates very early in cases of recurrence, thus preventing the development of a new tumor.
The subtype and classification of a lymphoma may determine whether biologic therapy will be used to treat an individual patient’s lymphoma. Monoclonal antibodies are being increasingly used in the treatment of B cell NHLs, usually in combination with chemotherapy. Monoclonal antibodies may also be given as maintenance therapy following chemotherapy, particularly in low-grade disease.
Interferon may be used in indolent, low-grade lymphomas, or as adjunctive therapy in patients with hepatitis associated lymphomas. Colony-stimulating factors, such as growth factors for white blood cells, may be used to stimulate recovery of the white cells following chemotherapy.
Other therapies under continuing development include drugs that target cancer cells on a molecular level, various new monoclonal antibodies, and other biologic therapies.

Medications
Numerous chemotherapy and biological drug combinations may be prescribed by an oncologist. Which type and combination of therapy depends on many factors, including the type and stage of lymphoma, whether treating adolescents, young adults, or older adults, the ability to tolerate chemotherapy side effects, and if any previous treatment for the lymphoma has occurred. Oncologists often work together regionally to decide which combination of chemotherapy and biological drugs are currently working best for their patients. Because of this regional collaboration, the drug combinations often vary and are able to change rapidly when improved results occur.

Other Therapy
Watchful waiting means choosing to observe and monitor the cancer rather than treat it right away. This is strategy is sometimes used for indolent recurrent tumors. Treatment is given only if the cancer starts to grow more rapidly or to cause symptoms or other problems.
Stem cell transplantation is usually not used as a primary therapy in lymphoma.
Stem cell transplantation is usually reserved for lymphoma that has been previously treated into remission but has recurred.
Stem cell therapy as primary therapy has been used for aggressive T-cell NHL in first remission, usually as part of a clinical trial. Stem cell therapy is also considered when standard primary treatment is unable to control the lymphoma and achieve remission.
This procedure, which requires a lengthy hospital stay, involves very high doses of chemotherapy to kill the aggressive cancer cells.
The chemotherapy doses are so high that the chemotherapy also stops the patient’s bone marrow from producing healthy new blood cells.
The patient then receives a transfusion of healthy bone marrow or blood stem cells, either from previously collected stem cells from the patient himself or herself (called autologous transplantation) or from a donor (called allogeneic transplantation), to “kick start” the bone marrow into producing healthy blood cells.
This is a very intensive therapy with a lengthy recovery period.

World Lymphoma Awareness Day (WLAD)
World Lymphoma Awareness Day is held on September 15 every year and is a day dedicated to raising awareness of lymphoma. Launched in 2004 and now an established date in the health calendar, WLAD provides a focus for doctors, nurses, patient support groups, patients and their families to join forces in a united campaign to inform the public about lymphoma, its signs and symptoms and how it affects lives of thousands of people around the world.
WLAD is a global initiative hosted by the Lymphoma Coalition, a non-profit network organization of patient groups from around the world. It currently has 35 member groups from 29 countries.
Why have WLAD?
Despite the fact that one million people worldwide live with lymphoma and nearly 1,000 people are diagnosed with the disease every day, research shows:
• Less than 50 per cent of people know anything about this potentially life-threatening disease
• Almost three quarters (74 per cent) of people do not know that lymphoma is a form of cancer
Through raised awareness of lymphoma, people around the world will better recognize the signs and symptoms, which leads to earlier diagnosis and more timely treatment.
Greater awareness will also empower patients and their families to demand specialist treatment and care from qualified lymphoma physicians as well as gain access to the most up-to-date information, support and treatment.

Introduction

Warfarin (also known under the brand names Coumadin, Jantoven, Marevan, and Waran) is an anticoagulant. It was initially marketed as a pesticide against rats and mice, and is still popular for this purpose, although more potent poisons such as brodifacoum have since been developed. A few years after its introduction, warfarin was found to bepreventing effective and relatively safe for thrombosis and embolism(abnormal formation and migration of blood clots) in many disorders. It was approved for use as a medication in the early 1950s, and has remained popular ever since; warfarin is the most widely prescribed anticoagulant drug in North America.[1]
The use of anticoagulant drugs is based on the knowledge that thrombin generation and blood coagulation are important steps in pathogenesis of thrombosis and that inhibition of these processes will prevent initiation of thrombus formation and extension of formed thrombi.[2]

History of the Warfarin

The early 1920s saw the outbreak of a previously unrecognized disease of cattle in the northern United States and Canada. Cattle would die of uncontrollable bleeding from very minor injuries, or sometimes drop dead of internal hemorrhage with no external signs of injury. In 1921, Frank Schofield, a Canadian veterinarian, determined that the cattle were ingesting moldy silage made from sweet clover that functioned as a potent anticoagulant. In 1929, North Dakota veterinarian Dr L.M. Roderick demonstrated that the condition was due to a lack of functioning prothrombin.[1]
The identification of the anticoagulant substance in moldy sweet clover leads to isolate and characterize the hemorrhagic agent from the spoiled hay. It was named as the Dicumerol.
Over the next few years, numerous similar chemicals were found to have the same anticoagulant properties.
. Link continued working on developing more potent coumarone-based anticoagulants for use as rodent poisons, resulting in warfarin in 1948
Warfarin inhibits the enzyme peroxide reeducates and hence interferes with vitamin K metabolism
Warfarin is tasteless and colorless, and produces symptoms similar to those that Stalin exhibited.[3]

Pharmacokinetics

Systematic (IUPAC) name

(RS)-4-hydroxy-3-(3-oxo-1-phenylbutyl)-
2H-chromen-2-one

Warfarin consists of a racemic mixture of two active optical isomers—R- and S- forms—each of which is cleared by different pathways. S-warfarin (t1/2-35h) has five times the potency of the R-isomer (t1/2-50h) with respect to vitamin K antagonism.[4]
Warfarin is readily absorbed from the gastrointestinal tract and like all oral anticoagulants, is more than 90% bound to plasma proteins. Its action is terminated by metabolism in the liver.[5]
Coumadin and Marevan are Warfarin sodium.
Are they the same?
The answer is No.
Coumadin and Marevan are intended to have exactly the same function. However ,there are difference in there formulation.

Mechanism of Action

What is an Anticoagulant?
When cut the vessels blood leaks out from the damaged vessels and clots, sealing the wound and preventing more blood being lost. Normally blood will not clot inside the blood vessels but sometimes things go wrong and clots form in vessels. This process is called ‘Thombosis’.
Anticoagulant prevent or treat thrombosis by decreasing the clotting power of the blood.[2]

Types of Anticoagulants

Indirect acting Direct acting

• Take about 72h to become Rapidly effective
Fully effective
• Act for several day Act for only a few hours
• Given orally & can be antagonized Must be given parenterally
By vit.K

Eg: Coumarin Eg: Heparin
Indandion Hirudin
Bivalirudin

Coagulation System

Coagulation system consist of glycoprotein component that circulate in (necessarily inactive) pro-enzyme or pro- cofactor (factors ν and νш) form. The activated enzymes are serine proteases.

Physiological coagulation (the extrinsic pathway) begins when tissue factor (tissue thromboplastin) exposed by vascular injary,activates and complexes with factor νıı to activate factors ıх and х which complex with νшa and νa respectively on membrane surfaces. The хa/νa complex converts prothrombin to thrombin which converts fibrinogen to fibrin and also activates factors хı,νш,ν and хш,both accelerating coagulation and cross linking fibrin.

The intrinsic pathway refers to coagulation in vitro. It is initiated when factor хıı with the cofactor high molecular weight kininogen (HMWK) comes into contact with a foreign surface(e.g. glass, kaolin). Thus it has no physiological role (and patients lacking factor хıı do not have a bleeding disorder) . Both in vivo and vitro the systems are dependent on the presence of Calcium ions.[5]

Role of Vitamin K on Haemostasis
Vitamin K (coagulation vitamin) is essential to normal haemostatic and antithrombotic mechanism. This vitamin occurs naturally in two forms. Bile is required for the absorption of the natural vitamin K, which are fat-soluble.[6]
Leafy green vegetables are a good sours of vitamin K. The storage pool of vitamin K is modest and can be exhausted in one week,though though gut flora will maintain suboptimal production of vitamin K dependent protein.
Vitamin K is necessary for the final stage of the synthesis of six coagulation- related proteins in the liver by γ-carboxytlation of glutamic acid residuce on molecule. The γ-carboxyglutamic acid reciduce permit calcium to bind to the molecule which in turn mediates binding to negatively charged phospholipids surfaces. The vitamin K dependent proteins are coagulation factors ıı(prothrombin),νıı,ıх and х,and the anticoagulant (regulatory) proteins, proteins C and S. During γ-carboxylation of the proteins by the vitamin K dependent carboxylase, the reduced form of vitamin K is converted to an epoxide, an oxldation product, which is subsequently reduce again enzymatically to the active vitamin K again. When the vitamin is deficient or where its activity is inhibited by drugs,coagulation proteins which cannot bind calcium result their physiologically critical binding to membrane surfaces fails to occur, and this impaired the coagulation mechanism.
Blood coagulation system [7]

Intrinsic Pathway
Extrinsic Pathway
Foreign surface Damaged tissue

хıı TF + νıı TF/νııa
ıх

HMWK

хı хıa
ıхa х

νııı νıııa/ıхa

хa
Common
Pathway

PL
ν νa хa/νa

Prothrombin Thrombin

Fibrinogen Fibrin

Хııı хıııa

Mode of Action of Warfarin

Warfarin is most widely used anticoagulant. Is share a common ring structure with Vit. K.[5]
Wararin is a 4-hydroxy – coumarin derivative. Vit.K is necessary for the addition of gamma – carboxyglutamic acid residue(Gla) , to clotting factors ıı,νıı,ıх,х, (and also Proteins C& S). The Gla residue binds calcim ions and undergoes a configurational change that is necessary for the protein to bind to the cofactors on the phospholipids surface and participate in coagulation.[2] This occurs in the liver.
During the gamma- carboxylation of the coagulant factors , active vitamin K is oxidized to an epoxide and must be reduced by the enzymes vitamin Kepoxide reductase and vitamin K reductase to become active again.[5]
Warfarin is structurally similar to vitamin K and competitively inhibit vitamin K epoxide reductase , so limiting availability of the active reduced form of the vitamin to form coagulant (and anticoagulant) proteins.

Precursor forms of factors ıı,νıı,ıх,х,Protien C&S

Vit.K

WARFARIN

Vit.K epoxide

Active forms of factors ıı,νıı,ıх,х,Protein C&S

The overall result is a shift in haemostatic balance in favour of anticoagulation because of the accumulation of clotting proteins with absent or decreased gamma – carboxylation sites (PIVKAs). This shift does not take place until functional vit.K – dependent proteins made before the drug was administered are cleared from the circulation. The process occurs at different rates for individual coagulation factors ( νıı – t ½ 6h ,ıх and х –t ½ 24h ,prothrombin
T ½ 72h). Moreover , the anticoagulant proteins C and S have a shorter t ½ than the procoagulent proteins and their more rapid decline in concentration creates a transient hypercoagulable state. This can be serious in those who have inherited protein C & S deficiency who may develop skin necrosis and justifies initiating anticoagulation with heparin until the effect of warfarin is well established.

Anticoagulant Therapy
The use of anticoagulant drugs is based on the knowledge that thrombin generation and blood coagulation are important steps in pathogenesis of thrombosis and that inhibition of these processes will prevent initiation of thrombus formation , extension of formed thrombi.
The ideal control of anticoagulant therapy would be to achieve a level of anticoagulation at which there is a complete antithrobotic effect with no risk of bleeding. The ideal is not always achieved by using current drugs.
The oral anticoagulants consist of two classes. Coumarins & indanediones.Only Coumarin drugs are now recommended , because of the more frequent side effects such as hypersensitivity reactions of the other. Most widely used Coumarin is warfarin sodium.[2]

Cardiovascular disease
Anticoagulant is used to reduce the risk of venous thromboembolism , and the risk and size of emboli from mural thrombi following acute myocardial infarction.
Long – term anticoagulation with warfarin to prevent arterial thromboembolism should be considered for any patient who has a large left atrium or paroxysmal or established atrial fibrillation.[5]

Institution of therapy
It is important to confirm the diagnosis for which anticoagulant treatment is to be given. Oral anticoagulants can be commenced on day 1 in conjunction with Heparin. In a hospitalized adult patient , who has been treatment with Heparin for an acute thrombosis , Warfarin is initiated with a dose of 10 mg daily for the first two days.On the third day morning the prothrombin time and INR (international normalized ratio) are done to assess further doses. The subsequent doses are based on the INR. Modification of the oral anticoagulation loading dose may be necessary if base – line coagulation results are abnormal. The daily dose of Warfarin should be given at a fixed time of the day,usually at 6 pm. When patient are electively anticoagulated in the out patient department, Eg; for Atrial fibrillation, the loading dose of Warfarin is usually omitted. 2 to 5 mg is given daily with adjustment as needed. The monitering of Warfaring in a child is difficult because of their variable response to therapy.One approach is to give a Warfarin loading dose of 0.4 mg/ kg/ day for the first two days and then modify the subsequent doses as indicated by the INR.[8]

Laboratory Monitoring
Ideally base line Prothrombin time (PT) , Activated Partial Thromboplastin Time (APTT) , platelet count and liver function test should be done before initiation of treatment. Dosage is controlled by Prothrombin Time/(INR). The whole blood clotting time and bleeding time are not the test for control of therapy.
For rapid anticoagulation with Warfarin, daily INR should be measured for a minimum of 4 days, after which monitoring should be continued weekly until the INR is stable. Patients with protein C deficiency are at risk of developing skin necrosis during commencement of Warfarin, and therefore initiation of therapy should proceed without a loading dose.
Warfarin has no effect on established thrombus nor does it reverse ischaemic tissue damage.
The INR of a person not taking an anticoagulant , is approximately 1. When taking anticoagulants the higher INR, the longer blood take to clot. Changes in Warfarin dose will change INR; however , these changes may not happen immediately. It can take 4-5 days before patient have the full impact of a dose change on the INR. The INR levels are very important as they help to maintain the dose of Warfarin that suit for the individual.[8]
The three things to remember about INR testing are;
 Have the INR test done every it is ordered by the doctor.
 Call the doctor or laboratory as instructed or within 24 hours of the test in case the Warfarin dose need adjusting.
 Record the test results on the record sheet provided.
Therapeutic Range

INR Indication

2.0-2.5 For prophylaxis of DVT, including surgery on high risk patient ,
For Prosthetic heart valves.

2.5 Treatment of DVT and PE .
Atrial fibrillation , due to CHD, Thyrotoxicosis .
Cardiovertion
Mural Thrombus following Myocardial Infarction.
Rheumatic Heart Valve Disease(RHD).
Prosthetic heart valves
Symptomatic inherited throbophilia.
2.0 – 3.0 Hip Surgery and Fracture Femur, operations, on high risk
Patients.
Upto 3.5 Recurrent DVT and PE in patient currently on Warfarin.
Antiphospholipid syndrome with thrombotic episodes.

Taking Warfarin
Dosage
Patient must take the tablets at approximately the same time everyday as specified by the doctor.Warfarin can be taken before,during or after meals. By getting into the daily routine of marking a calendar after you have taken Warfarin and not relying on your memory, you will be unlikely to miss a dose.[8]

Missing a dose
If patient forget to take a dose and then remember within two to three hours,you can still take your tablets.
If patient forget for a longer time, do not take the tablets to catch up but take the next dose when it is due and tell the doctor or laboratory.

Do not take a double dose.
Important Instruction For Patients
Different things in your life affect how Warfarin works on your blood.

 Whether you are eating properly.
 Other medicines you may be taken.
 The amount of alcohol you drink.
 A new illness.

The most important thing to remember is that when there is a big change to any of these things you must tell your doctor. The time when a change may occur is when you leave hospital and go home and when you go away on holiday.

While taking Warfarin,
• Carry an ID card or wear a medical alert bracelet stating that you are taking warfarin, in case of emergency. Any doctor, dentist, or emergency medical care provider who treats you should know that you are taking this medication.[9]
• Warfarin interacts with many other drugs, and these interactions can be dangerous, even fatal.
Taking other medicines may interfere with the way Warfarin works. Therefore ,
- Before taking any medicines, even prescribed by a doctor , be certain to check with the doctor monitoring your warfarin dose.
- Not only mean prescription medicines but anything else you might buy (in a chemist or food store) for common colds, aches pains and so on. It is especially important to check with your doctor or pharmacist before taking common medicine such as aspirin, paracetamol, or other pain medicine, rubs and liniments, cold or cough preparation, certain stomach remedies, laxatives, multi vitamins containing K and herbal medicines.
These medicines may affect blood clotting and could cause serious bleeding in your stomach or intestines.
• Avoid sudden changes in your diet.
- Maintain a well balanced and consistent diet.
– Stabilise your intake of vitamin K.
Warfarin is affected by vitamin K. A high vitamin K intake in your diet can affect your response to Warfarin and lower your INR significantly.You should therefore keep your intake of Vitamin K – containing food relatively constant.[10]
Large amounts of vitamin K are found in foods such as liver, broccoli, brussels sprouts, spinach, Swiss chard, coriander, collards, cabbage, and other green leafy vegetables.
Do not change the amount
of these foods in your diet without first talking to your doctor.
Avoid eating cranberries, drinking cranberry juice, or taking cranberry herbal products.[10]
• Avoid drinking alcohol, which can increase some of the side effects of warfarin.
Do not take warfarin if you have:
• a bleeding disorder such as hemophilia;
• a blood cell disorder such as anemia;
• a stomach ulcer or bleeding in the stomach;
• a history of aneurysm, blood clot, or bleeding in your brain; or
• an infection of your heart, fluid or swelling around your heart.
Before taking warfarin, tell your doctor if you have:
• kidney disease;
• liver disease;
• celiac sprue (an intestinal disorder);
• a recent injury, surgery, or medical emergency;
• high blood pressure;
• severe or uncontrolled diabetes;
• polycythemia vera;
• congestive heart failure;
• cancer;
• overactive thyroid;
• a seizure disorder for which you take an anticonvulsant such as phenytoin (Dilantin) or phenobarbital (Luminal); or
• a connective tissue disorder such as Marfan Syndrome, Sjogren syndrome, scleroderma, rheumatoid arthritis, or lupus.
If you have any of these conditions, you may not be able to use warfarin, or you may need a dosage adjustment or special tests during treatment.
• Pregnancy must be avoided.
• Warfarin can seriously affect an unborn baby. All women who may become pregnant should discuss with their doctor the possible risks and available means of reducing those risks.[11] There is no ideal anticoagulant in pregnancy. Use must depend on individual assessment of risks and benefits. Warfarin has been the risk of haemorrhage at delivery means that it should be discontinued approaching term. Fetal risks are derived from the transplacental passage of Warfarin. There is a relatively high incidence of spontaneous abortion and stillbirth and use during first trimester has been associated with “coumarin embryopathy” in 5-15% of infants so exposed. This syndrome includes hypoplasia of the nasal bone and epiphyseal stipling , CNS disease, including optic atrophy and blindness, mental retardation, cerebral palsy and intracranial bleeding.[3] Warfarin administration in the second and third trimesters is much less commonly associated with birth defects, and when they do occur, are considerably different from fetal warfarin syndrome. The most common congenital abnormalities associated with warfarin use in late pregnancy are central nervous system disorders, including spasticity and seizures, and eye defects.
Warfarin may pass into breast milk and cause bleeding problems in the nursing baby. Do not use warfarin without telling your doctor if you are breast-feeding a baby.

Side effects and Complication
Obvious bleeding
Signs of obvious bleeding you may notice when you are taking Warfarin are ;
• Cuts may bleed for a long time.
• Occasional nosebleed may occur.
• Heavier bleeding during periods or other vaginal bleeding.
• Bleeding gums.

Less obvious bleeding
Sometimes this may not look like bright blood but you may notice;
• Dark red or brown urine
• Dark or black bowel movements.
Bruising

A bruise occurs when you bleed under the skin. If you notice you are bruising for unknown reasons or more than normal , tell the doctor right away.

If you do experience any problem tell the doctor immediately so the problem can be handled promptly and effectively.
Poisoning can be treated with Vitamin K.

Organisation of an oral anticoagulant clinic
The patient discharged from hospital should be referred to a Consultant Haematologist for the outpatient anticoagulation management. These patient can be thus divided into four categories.[2]

 Newly referred patient who require information and an explanation about treatment.
 Stable patient with no problem who simply require their blood taken and to receive the next dose with the minimum of inconvenience.
 Patients with intercurrent problems , Eg; bleeding or brusing , those started on new medication and those about to undergo dental procedure.
 Patient with mobility problems who have difficulties in attending hospital. Their blood can be taken at home by a phlebotomist or a nurse and the result together with the instruction can be conveyed to the patient by phone.

Dose adjustment should be made at the clinic after laboratory investigation. Capillary INR method is also useful for large out patient clinics and for patient self testing.
Other Usages

Use as Pectiside

Warning label on a tube of rat poison laid on a dike of the Scheldt river in Steendorp, Belgium. The tube contains bromadiolone, a second-generation (“super-warfarin”) anticoagulant.[12]
To this day, coumarins are used as rodenticides for controlling rats and mice in residential, industrial, and agricultural areas. Warfarin is both odorless and tasteless, and is effective when mixed with food bait, because the rodents will return to the bait and continue to feed over a period of days until a lethal dose is accumulated (considered to be 1 mg/kg/day over about six days). It may also be mixed with talc and used as a tracking powder, which accumulates on the animal’s skin and fur, and is subsequently consumed during grooming
The use of warfarin as a rat poison is now declining because many rat populations have developed resistance to it, and poisons of considerably greater potency are now available. Other coumarins used as rodenticides include coumatetralyl and brodifacoum, which is sometimes referred to as “super-warfarin”, because it is more potent, longer-acting, and effective even in rat and mouse populations that are resistant to warfarin. Unlike warfarin, which is readily excreted, newer anticoagulant poisons also accumulate in the liver and kidneys after ingestion.

Introduction
Human circulatory system contains blood inside the vessels as its circulatory fluid. Therefore blood should be in the fluid formation to achieve the optimal function of circulatory system. But they must be clotted in vessel damage to prevent further bleeding so there are highly regulated clotting & anti clotting mechanism inside the body. If any of those mechanism get impaired either excessive bleeding such as in Hemophilia or intravascular clot formation such as in distal venous thrombosis can be occurred. Both of these conditions are severe and even be motile (Distal venous thrombosis) and anti coagulation drugs are used to prevent intra vascular coagulation. Warfarin is an indirect acting anticoagulant.[1] Anticoagulant is any agent used to prevent the formation of blood clots. It is the most widely using anti coagulant.[1] It is a 4-hydroxy-caumarin derivative, the name is derived from Wisconsm Alumin Research foundation.Warfarin is the oral anticoagulant of choice, for it is reliably effective and has the lowest incidence of adverse effects.[1]Warfarin exert an antithrombic effect by blocking regeneration of vitamin K from it,s epoxide. [2]it is use in treatment for many disease condition which are related with bleeding disorders such as Distal venous thrombosis( DVT),Pulmonary embolism,Atrial embolismand so on. [2] There is much inter individual variation in dosage requirement. [3] Some side effect including bleeding in any tissue or organ,less often necrosis or gangrene of tissues can occur.[4] Therefore patients should be treated with strict dosages and they are asked to have an INR(International Normalized Ratio). [6] Some drugs such as Erythromycin, Propananol, Cimetidine (potent the effect of warfarin )and rimpinafccillin,barbifurates,cholestyramine,and food that are in high in vitamin K such as avocado (inhibit the effect of warfarin) have highest(level1)evidence for interaction with warfarin.[3]
1.History
The name Warfarin is derived from WARF(Wiscohisis Albumin Research Foundation )+Rin which indicate the connection with caumarin.
The early 1920s previously unrecognized diseases crisis occur among the chattels in United States and Canada. Cattle would die of uncontrollable bleeding from very minor injuries, or sometimes drop dead of internal hemorrhage with no external signs of injury. In 1921, Frank Schofield, a Canadian veterinarian, determined that the cattle were ingesting moldy silage made from sweet clover that functioned as a potent anticoagulant.[7] In 1929, North Dakota veterinarian Dr L.M. Roderick demonstrated that the condition was due to a lack of functioning prothrombin.[8]
1940 Karl Paul Link and his lab of chemists working at the University of Wisconsin set isolated and characterized the hemorrhagic agent from the spoiled hay. Then Link’s student Harold A. Campbell to recover 6 mg of crystalline anticoagulant. Next, Link’s student Mark A. Stahmann an initiated a large scale extraction, isolating 1.8 g of recrystallized anticoagulant in about 4 months. Then Stahmann and Charles F. Huebner check their results against Campbell’s and to thoroughly characterize the compound. Through degradation experiments they established that the anticoagulant was 3,3′-methylenebis-(4-hydroxycoumarin), which they later named dicumarol. They confirmed their results by synthesizing dicumarol and proving that it was identical to the naturally occurring product.[9]The first compound that is Chemically similar to 4-hydroxycoumarinthat widely commercialized was dicoumarol, patented in 1941. Link continued working on developing more potent coumarin-based anticoagulants for use as rodent poisons, resulting in warfarin in 1948. Warfarin was first registered for use as a rodenticide in the US in 1948. A famous early recipient of warfarin was US president Dwight Eisenhower, who was prescribed the drug after having a heart attack in 1955. [10]
A 2003 theory posits that warfarin was used by a conspiracy of Lavrenty Beria, Nikita Khrushchev and others to poison Soviet leader Joseph Stalin. Warfarin is tasteless and colorless, and produces symptoms similar to those that Stalin exhibited. [11]
2. Therapeutic uses
Warfarin is prescribed to people with an increased tendency for thrombosis or as secondary prophylaxis (prevention of further episodes) in those individuals that have already formed a blood clot (thrombus). Warfarin treatment can help prevent formation of future blood clots and help reduce the risk of embolism (migration of a thrombus to a spot where it blocks blood supply to a vital organ) Warfarin can be used for short term or long term purposes.
Short term
• Prevention of Deep Vein Thrombosis DVT after high risk surgery at least for 3 month
• Prevention of stroke in atrial fibrillation
• Prevention of recurrent of DVT and pulmonary embolism following DVT at least for 6 month after the first episode.
• Prevention of embolic complications in procedure like coronary angioplasty and stents in high risk patients(Aspirin considered as first line therapy)
Long term
• Recurrent DVT and Pulmonary Embolism PE
• Embolic complications of Rheumatic and Congenital Heart Diseases (CHD)
• Atrial fibrillation due to Cardiac disease and thyrotoxicosis
• Cardiac Prosthesis,Mural thrombus,Cadiomyopathy
• Sympathtic inherited Thrombophilia
Antiphspholipid syndrome with thrombotic events.[5]But warfarin has no effect on established thrombus nor does it reverse ischemic damage.[5] In established venous thromboembolism as anticoagulant is used to prevent extension of as existing thrombous while its size is reduced by natural thrombolitic activity.[1]Anticoagulant should be commenced immediately in patient with higher or intermediate probability of (PE) but can usually be withheld from patient with low clinical probability pending further investigations.[2]Anticoagulants are used to prevent embolisms and thrombosis not only because they prevent formation of clots inside the vessels, but also clear the vessel walls. It also help to reanalyze veins and to clear vein valves of thrombus and should thus prevent long-term consequences such as swelling of the leg and stasis ulceration.[1] Antiphospholipid syndrome is another condition warfarin therapy is used. But when a pregnant woman is having antiphospholipid syndrome although warfarin is given aspirin is often prescribed. Heparin and aspirin are given early in the pregnancy because warfarin is toxic to fetus.[4]Another therapeutic use of warfarin is to prevent acute myocardial infarction.long-trem anticoagulation with warfarin to prevent atrial thromboembolism should be considered for any patient who has a large left atrium or a low cardiac output or paroxysmal or established atrial fibrillation(with or without cardiovascular disease.[1] Other than those conditions warfarin is prescribed to patient who are having Atrial fibrillation Warfarin reduces the risk of ischemic stroke in non rheumatic atrial fibrillation by about 62% (absolute risk reduction 2.7% for primary prevention and 8.4% for secondary prevention.).[2]
Dosing of warfarin is complicated by the fact that it is known to interact with many commonly-used medications and even with chemicals that may be present in certain foods.[13] These interactions may enhance or reduce warfarin’s anticoagulation effect. In order to optimize the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is recquired.Usually the test is carried out with a standardized thromboplastin an d result is expressed as the international Normalized Ratio(INR),which is the ratio of the prothrombin time in the patient to that in abnormal person(non-anticoagulated) taking account of the sensitivity of the thromboplastin used.[1]During the initial stage of treatment, checking may be required daily; intervals between tests can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose.[14] Othrethan warfarin, anticoagulants such as acenocoumarol, phenprocoumon , ximelagatran, dabigatran, rivaroxaban,heparin & aspirin are used in the various countries in the world.
3.Pharmacology
Warfarin is found under different brand names. They may have the same function but different in their formula. So patients must pay attention on that. so it will be an intelligent thing to keep taking the brand that the patient were started on unless directed otherwise the doctor should keep recording on the brands that he is treating the patient. Different strength of Warfarin are colour coded.[5]
1mg red
2mg blue
5mg yellow[5]
3.1.Mechanism of action
Inside the body blood clotting occur as a natural barrier for excessive bleeding from internal or external wounds. Clotting occur as a cascade pathway and there are two pathways which are
Known as intrinsic & extrinsic pathways. ( diagram in next page)

Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the calcium-dependent clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S, and protein Z. Other proteins not involved in blood clotting, such as osteocalcin, or matrix Gla protein, may also be affected. Some proteins must undergo conformational changes after the synthesis. That process is known as post transcriptional modification. Above mentioned clotting factors are some of those proteins which need post transcriptional modification to be activated. They contain glutamic acid in their amino acid sequence. Those glutamic acid must be further carboxylated to enable the protein to maintain an active tertiary structure.[2]this carboxylation activity is carried out by the carboxylase enzyme. That carboxylase enzyme require vitamin k as an co factor. vitamin k is converted to vitamin k epoxide during this reaction. So for the continual action of this process the vitamin k must be converted back to it’s active form. That action is catalyzed by the vitamin k epoxide reductase enzyme.warfarin inhibit the carboxylation cycle.[2] Therefore prevent reutilization of vitamin k inside the body.The process occurs at different rate for individual clotting factors,vII half life(t1/2 h) IX& X t1/2 24h.Moreover,the anticoagulant proteins C & S have a shorter half life than procoagulant protein and their more rapid decline in concentration creates a transient hypercoagulatable state.[1]

3.2.Pharmacokinetic
As for each other drugs the effectiveness of the warfarin depend on the absorption in the human body.Poor stirrin of the intestinal content yield a preepithelial barrier for diffusion which is responsible for rate limitting step of many drug activity.warfarin is readily absorbed from the gastrointestinal tract and is transported bound to plasma proteins.More than 90% bound to plasma proteins.[1] University of Tokyo has done an experiment on wrafarin uptake & metabolism by the liver by using rat liver. The results showed that the predicted concentration of the unbound warfarin is not high enough to explain the observed uptake rate; the liver cell surface appears to reduce the binding affinity of warfarin for bovine serum albumin (BSA) to 1/20 of that observed in vitro. A kinetic model which considers the interaction between albumin and the liver cell surface was fitted to the uptake rates of warfarin over a wide range of BSA concentration.[12]Metabolism of the warfarin terminate at the liver.warfarin which is an derivative of 4-hydroxy derivative shows isomerism.warffarin .Effective ness of these tow drugs are different from each others. Warfarin is four times more potent than R warfarin.[1]Warfarin which has a half life of 36 hours is racemic mixture of approximately equal amount of two isomers. Half life of S-warfarin and R-warfarin is 35 hours and 50 hours respectively.So interaction with food and other drugs should be different from one isomer to other. Measurements showed that the maximal preepithelial resistance in conscious rats was equivalent to an unstirred layer of only approximately 100 micron. Anesthesia roughly doubled this resistance, and anesthesia and laparoscopy caused a six fold increase (unstirred layer of approximately 600 micron[13]
3.3.Pharmacodynamics & Antagonism
The main action of the warfarin is to reduce the vitamin k concentration,which is need for clotting prosess.So simply the effects of warfarin can be reversed with vitamin K suppliment. when rapid reversal is needed (such as in case of severe bleeding), with prothrombin complex concentrate—which contains only the factors inhibited by warfarin—or fresh frozen plasma (depending upon the clinical indication) in addition to intravenous vitamin K.Several experment has done with the aim of investigating the effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin. There was a significant difference in both S-warfarin and R-warfarin following treatment with St John’s wort. By contrast, there were no significant changes in these parameters following treatment with ginseng[15]

3.4.Pharmacogenomics
Pharmacogenomic is the study of how variations in the human genome affect the response to medications. Power of action of the warfarin isdepend on the concentration of the reductase enzyme. in the individual. high concentration of enzyme can overcome the activity of inhibitors in competitive inhibition of an enzyme. As enzymes are proteins their synthesis is regulated by gene.So it is not surprise that the action of warfarin is depend on the genetic code of an individual. Two types of genetic variations have found that affect on the activity of the warfarin those are, VKORC1 gene on chromosome16,which is the gene for the warfarin epoxide reductase and the CYP2C9*1, CYP2C9*2 and CYP2C9*3 variants in the cytochrome p450 2C gene on chromosome 10.individuals with some variations are much more sensitive to warfarin than others. Variations in VKORC1 have a much greater impact on warfarin sensitivity than variations in CYP2C9, particularly during the initiation of therapy[11]Thus when prescribing dosage of warfarin to a patient paying enough attention on the genetic code may important in some cases. the patient with those variations in genotype are treated with some special methods. Thus warfarin treatments become expensive in those cases. The total number of events and the direct medical cost per 100 patient-years in the genotyped and non-geno-typed groups were 9.58 and USD155,700, and, 10.48 and USD 150,500, respectively. The marginal cost per additional major bleeding averted in the genotyped group was USD 5,778.In conclusion, the pharmacogenetics-oriented management of warfarin therapy is potentially more effective in preventing bleeding with a marginal cost[14]

3.5.Adjusting the maintenance dose
As over dosage of warfarin may cause hemorrhage & low dose may be insufficient patient must have strictly controlled dosage of warfarin. As mentioned above, there are variations among dosages required by different patients. It is usual to initiate therapy with 10 mg daily for 2 days, with the maintenance dose then adjusted according to the INR using an established protocol[1]
The levels should be adjusted match the perceived risk of the thrombosis, by the following guidelines.
1. INR 2.0-2.5 Prophylaxis of DVT including surgery on high-risk patients92.0-3.0 for hip surgery and fractured femur operations)[1]
2. INR 2.0-3.0 Treatment of DVT ,PE,systemic embolism in myocardial infraction,mitral stenosis with embolism; transient ischemic attacks; trial fibrillation.[1]
3. INR 3.0-4.5 Recurrent DVT and PE;atrial disease including myocardial infraction;mechanical prosthetic heart valves.[1]
3.7.Self testing &home monitoring
Patients are making increasing use of self-testing and home monitoring of oral anticoagulation The international guidelines study stated: “The consensus agrees that patient self-testing and patient self-management are effective methods of monitoring oral anticoagulation therapy, providing outcomes at least as good as, and possibly better than, those achieved with an anticoagulation clinic. All patients must be appropriately selected and trained”
4.Contraindications (Pregnancy)
Contradictions relate mostly conditions in where there is a tendency to bleed and are relative rather than absolute. Those include,
• Behavioural-unwilling,depedency on alcohol
• Neurological-Stroke within three weeks
• Alimentary-active peptic ulcer, active inflammatory bowel disease.ect
• Cardiovascular-uncontrolled severe hypertension
• Renal disease
• Pregnancy
• Hematological-pre-existing bleeding disorder.[1]
When prescribing any drug to a pregnant woman special attention should be paid on it’s ability to cross the placenta because some drugs can be teratogens to the fetus. Other than that as warfarin is an anticoagulant special consideration must be paid to the dosage, as it can lead to increase bleeding during child birth and therefore hemorrhagic shock. Warfarin can cross the placenta therefore warfarin is contradiction in pregnancy. As there is rapid growth in embryo during six to twelve weeks,warfarin treatment during this period may induce embryopathy.there is a relatively high incidence of spontaneous abortion & stillbirth & usage during 1st trimester has been associated with “Coumarone embryopathy” in 15% of infant so exposed.[3]This syndrome include hyperplasia of the nasal bone & epiphysis stippling(Chondrodysplasia punctuate),central nerves system(CNS) disease including otic atrophy & blindness, mental retardation, cerebral palsy & intracranial bleeding. So discontinuing the warfarin treatment from the very first moment that pregnancy is conformed is the best way to reduce the risk.So, patient should be told of these risks before conception and advised to have early pregnant test to detect pregnancy before six weeks of gestation.[5] But anticoagulant therapy cannot be suppressed as normally during pregnancy there is tendency in venous blood to be accumulated in the leg area. Therefore the therapy is continued with subcutaneous heparin which has high molecular weight and unable to cross the plasenta.But complication of long term subcutaneous therapy include haematoma abscess formation in the abdominal wall, thrombocytopenia & osteoporosis can occur.[3]But during labour warfarin become important again.Heparin should be withdrawn at the second stage of labour and warfarin therapy is restarted after third stage of labour.[5] If a lactating mother is having warfarin treatment the infant should be provide with vitamin K supplement. Maternal warfarin therapy does not pose a problem for breast fed infant as long as they are given vitamin K. [5]

5.Adverse effect
The only common side effect of warfarin is hemorrhage (bleeding) and long term anticoagulant prophylaxis can occur if treatment is not managed properly.
5.1.Hemorrhage
Hemorrhage due to warfarin treatment is due to an increased effect of wrfarin that is produced by many conditions including intake of drugs that is mentioned below under the topic ,warfarin interaction. Cardiac failure, liver or renal disease, hyperthyroidism & febrile illness which result in potentition of the effect of warfarin also increase the anticoagulant effect of warfarin.[4].Bleeding occurs in about 0.5%-1% of patient each ear.[2] So it is obvious that the anticoagulant benefit of warfarin must be greater than the risk of serious bleeding to be prescribed for a patient. Risk of bleeding is augmented if the INR is out of range (due to accidental or deliberate overdose or due to interactions), and may cause hemoptysis (coughing up blood), excessive bruising, bleeding from nose or gums, or blood in urine or stool. To prevent the risk regular INR tests are done[6].if the INR is above the desired therapeutic level,the dose should be reduced or withheld. If patent bleeding occurs the anticoagulant effect of warfarin is reversed by administration of vitamin K 1-5mg slowly. but this takes about six hours.[2]But if the bleeding is sever vitamin K administration is not enough.[2]Treatment for over dosage can be treated as follows,
• INR 6 to 8 discontinue the drug for 2-3 days keep under observation.
• INR 8-small oral dosage of vitamin K (tablets are 5mg but requre only 1mg)
• Minor bleeding(epistaxis) vitaminK 1-3 mg with local measures to stop bleeding
• Excessive bleeding fresh frozen plasma which contain ciltting factor,II,VII,IX,XI is given[5]

5.2.Warferin necrosis
A rare but serious complication resulting from treatment with warfarin is warfarin necrosis, which occurs more frequently shortly after commencing treatment in patients with a deficiency of protein C. Protein C is an innate anticoagulant that, like the procoagulant factors that warfarin inhibits, requires vitamin K-dependent carboxylation for its activity. Since warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the blood’s tendency to coagulate when treatment is first begun leading to massive thrombosis with skin necrosis and gangrene of limbs.[3]
5.3.Osteoporosis
After initial reports that warfarin could reduce bone mineral density, several studies have demonstrated a link between warfarin use and osteoporosis-related fracture.
5.4. Purple toe syndrome
Another rare complication that may occur early during warfarin treatment (usually within 3 to 8 weeks) is Purple toe syndrome[3]This condition is thought to result from small deposits of cholesterol breaking loose and flowing into the blood vessels in the skin of the feet, which causes a bluefish purple color and may be painful.
6.Interaction
Warfarin interacts with many commonly-used drugs. Some foods have also been reported to interact with warfarin as the metabolism of warfarin varies greatly between patients the foods and drugs tat interact with warfarin may be varies from each individual. Some of important drug groups that interact with warfarin are, Salicylates, Antimalarial,Antibiotic,Antiepileptic, Antidepressant,Antiviral,Antiinfammatory,Antiarrythmic.[5]Drugs and foods that interact with warfarin may either potentates or inhibit the action of warfarin.
Potentiation of effect Inhibition of effect
Antibiotic
Cotrimaxazole,erythromycin,Fluconazole,isoniazid,metronidasole,miconazole
Cardiac drugs
Amiodarone,clofibrate,propafenone,popranolol,sulfinpyrazone(Biphasic with later inhibition
Miscellaneous drugs
Anabolic steroids, Phenyl butazone,piraxicam,alcohol (if comitant liver dusease,cimetidine,omeprazole. Antibiotic
Griseofulvin,rifampin,nafacillin
CNS active drugs
Barbiturates,carbamazepnic,chloridazepoxide
Miscellaneous drugs
Cholestaramine,sucralfate
Food
Food that conatain large amount of vitamin K[3]

Some of the foods that interact with waefarin include,

Danshen (salvia miltiorrhiza), devil’s claw (harpagophytum procumbens), dong quai (also known as danggui). Chinese angelica (angelica sinensis) ,feverfew (tanacetum parthenium) ,fenugreek together with boldo (peumus boldus) ,fish oil supplements that contain eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ,ginkgo biloba ,ginseng (panax ginseng) – also known as Asian ginseng. Chinese ginseng. Japanese ginseng, Korean ginseng ,American ginseng (Panax quinquefolius) ,green tea (camellia sinensis) ,horse chestnut (aesculus hippocastanum) ,papaya extract (containing papain) ,certain brands of quilinggao – also known as ‘essence of tortoise shell’ St. John’s Wort (hyperacid perforatum) ,vitamin A ,vitamin K ,wintergreen (used on the skin) – also known as methyl salicylate. [16]Alcohol also interact with the effect of warfarin.But the type of interaction,(weather increase or decrease the activity)is depend on the amount and frequency. Alcohol itself is an anticoagulant and interacts with warfarin metabolism. Two to three drinks per day – glasses of wine. Beer etc -(typical cardiologist input) are unlikely to affect warfarin levels. Intermittent binge drinking leads to an increase in INR due to warfarin being metabolized more slowly. Chronic heavy alcohol intake results in a lower warfarin level because the alcohol increases the metabolism of warfarin. [16] above mentioned drugs affect warfare activity in different ways such as
• Cimetidine,sulphanomide and amiodarone cause reduction in warfarin metabolism
• Clofibrate & quinidine increase the sensitivity of hepatic receptors for warfarin.
• Sullphonamide displace warfarin from it’s binding site on serum albumin[4]

7.withdrawal of warfarin
When patient is in condition where can be a bleeding it is intelligent to stop warfarin treatment but the procedure to withdraw is debatable.Trombosis may occur again following a sudden withdrawal of warfarin.Long term treatment could be tailed off over several weeks and short-term treatment can be withdrawn quickly.[5]For elective surgery warfarin may be withdrawn about 5 days before surgery and resumed after about 3 days later if condition seem appropriate.[1]Warfarin is restarted when patient resume oral intake.
8. Patients experiences
Warfarin treatment should be strictly under controlled. Therefore patients who are receiving the therapy must visit regular clinics & INR testing and must follow the advices given by the doctor strictly and in that case doctor-patient relationship plays a major role. Patient are advised to keep remember on three main factors on INR testing. Those are.
• Having the INR test done every time it is ordered by the doctor
• Calling the doctor or laboratory as instructed within 24 hours in case ,warfarin dose needs adjusting
• Recording the test result on the record sheet that is provided.[6]Even though strictly control is needed missing a dose is not a condition to be hesitate. patient can restart dosage within two or three hours but in longer time missing patient must contact the doctor or laboratory. Some other advices that should be given to patient are
• Maintain a well balanced and consistent diet
• Avoid Crash dieting and binge eating
• Stabilize intake of vitamin K
• Consider on alcohol intake(As explained above)
• Take exact amount of medicine
• Inform other doctors and dentists
• Check with doctor before beginning any activity that may cause bleeding
• Check with the doctor before starting a trip
• Avoid pregnancy.[6]
Other than that patient are advised about the bleeding that can be occur including drugs that interact and signs of bleeding into alimentary and urinary tract. Before starting with warfarin.All patient should carry a card stating that they are receiving oral anticoagulant.[1]
• 9.Uses as pesticides
To this day, coumarins are used as rodenticides for controlling rats and mice in residential, industrial, and agricultural areas. Warfarin is both odorless and tasteless, and is effective when mixed with food bait, because the rodents will return to the bait and continue to feed over a period of days until a lethal dose is accumulated (considered to be 1 mg/kg/day over about six days).

DEFINITION
1. A condition that was formerly known by the popular name of ‘blood poisoning’is now called ‘septic shock’. This simply means bacterial infection widely disseminated to many areas of the body. With the infection being borne through the blood from one tissue to another and causing extensive damage.1
2. Septic shock is a common and serious condition in which infections , usually due to gram negative bacteria cause shock which has both distributive and hypovolemic features.2
3. Septic shock is a serious medical condition caused by decreased tissue perfusion and oxygen delivery as a result of infection and sepsis, through the microbe may be systemic or localized to a particular site.
4. An inadequate tissue perfusion as a result of a systemic response of the body to overwhelming infection or other severe insult.4
ORGANISMS
Mainly caused by gram negative bacteria .Endotoxin is a lipopolysaccharide can be seen in the cell wall of gram negative bacteria. It is responsible for many of the features of septic shock. Staphylococci, Streptococci and Pseudomonas bacteria species are important here.70% of septic shock cases are due to gram negative bacilli.5
But septic shock is also caused by gram positive bacilli and other microorganisms such as fungi which carry even greater risk of mortality.6
During septicemia Escherichia coli is the most common organism that can be isolated,with species Klebsiella,Proteus,Pseudomonas,and Bacteroids.4
Frequently the infection will be with multiple organisms,often crossing the boundary between gram negative and gram positive and often including both aerobic and anerobic organisms.4
PATHOPHYSIOLOGY
Most of the features that are present in septic shock is mediated by endotoxins. Endotoxins are phospholipopolysaccharide protein complexes that are found in gram negative bacteria cell wall as acomponent .Polysaccharide is the so called O antigen.True toxicity of Endotoxin is derived from lipid component.
Without bacteria introduction of Endotoxin into blood stream can cause septic shock. Quantity of Endotoxin and host defense factors largely determine the extent of the septic response .
A growing body of evidence suggests that the body ‘s response to endotoxemia causes septic shock. That is various inflammatory mediators become activated and result in the hemodynamic derangements that characterize septic shock.4
The lipid a portion of LPS can be bound by a protein normaly present in human serum known as lipopolysaccharide binding protein [LBS].LBS\LPS complex attaches to the cell surface5
DEVELOPMENT
Septic shock is the clinical manifestation of overwheiming inflammation .Failure of normal inhibitory mechanisms result in excessive production of pro inflammatory cytokines by macrophages .This results in hypotention, hypovolaemia,decreased perfusion and tissue edema.In addition ,uncontrolled neutrophil activation causes the release of proteases and oxygen free radicals within blood vessels.Causing damage to the vascular endothelium and of the coagulation pathway combines with endothelial cell distruption to form clots within the damaged vessels.
A major component of the tissue damage in septic shock is the inability to take up and use oxygen at mitochondrial level even if global oxygen delivery is supra normal.This effective by passing of the tissue result in a reduced arterio venous oxygen difference.
If both the precipitating cause and accompanying circulatory failure [hypotention,and frequently severe hypovolaemia due to venodilatation and fluid loss through the leaky vascular endothelium] are promptly controlled before significant organ failure occurs.[early shock] the prognosis is good. However if the global and peripheral circulatory failure is not corrected promptly and particularly if the underling cause is not effectively treated,progressive deferioration in organ function occurs and multiple organ failure [MOF] ensues. [Late shock].
The mortality of MOF is high and increases with the number of organs that have failed ,the duration of organ failure and the patient’s age .failure of four or more organs is associated with a mortality more than 80%
Prognosis in multisystem organ failure
NUMBER OF FAILING SYSTEMS
0

1 MORTALITY
3
30
2 50-60
3 85-100
4 72-100
5 100

MEDIATORS
Mediators are two types .
1.Inflammatory response mediators
2.Neuroendocrine mediators
Inflammatory response can have local effects as well as systemic effects.
Compliment cascade is initially activated system .Anaphylotoxins [C3a and C5a] are the components that have immediate hemodynamic effects.These effects include increase vascular permeability, vasodilatation and chemotaxis.
Metabolites of arachidonic acid is a main mediator.
TXA2 is a potent vasoconstrictor and broncho constrictor.It promote platelet aggregation and has membrane destabilizing properties.
Prostaglandin relative amounts determine the predominant hemodynamic effects.Cytokine and coagulant reactions that are initiated by endotoxins can lead eventually to multiple organ failure.

CLINICAL CHARACTERISTICS
In adults septic shock is defined as a systolic blood pressure <90mmHg or MAP<60mmHg without the requirement for inotrophic support ,or a reduction of 40mmHg in the systolic blood pressure from base line.
In children it is BP<2SD of the normal blood pressure.3.
Fever7
Tachycardia7

Hypotention7
Usually have warm peripheries7
Pyrexia and rigors or hypothermia[unusual]5

Bounding pulses with moist skin7

Often mental status changes7

Oliguria some times 7

Nausea5

Vomiting and diarrhea are non specific symptoms that frequently occur7

Occasionaly signs of cutaneous vasoconstriction5

Clinical jaundice5

Rarely coma5

Rash and meningism5

Bleeding due to coagulopathy[from vascular puncture sites, GI tract and surgical wounds]5

Hyperglycaemia and in more severe cases hypoglycaemia5

Rapid capillary refill5

Increase plasma creatinine5

Glucose intolerance5

Marked respiratory alkalosis[caused by hyperventilation, but this usually progress to compensated metabolic acidosis3

Pulmonary insufficiency ranges from mild transient hypoxemiato moderate atelectasis and onto pneumonia and then severe acute respiratory distress syndrome3

Distruption of pulmonary capillary endothelium and basement membrane result extravasation of fluid into the interstial space3

Alveolar disfunction3
Decreased functional residual capacity3

Positive blood cultures

Increased primary responses to bacteremia6

Unlike other forms of shock [cardiogenic ,hypovolaemic,obstructive] that are characterized by a compensatory increase in systemic vascular resistance. Septic shock often present with hypovolaemia because of arterial and venous dilatation and leakage of plasma in to the interstitial space6

Decreased cardiac out put6

Low systemic vascular resistence6

When condition progress cardiac function decreased6

Heart is dilated6

Ejection fraction decreased6

HEMODYNAMIC PATTERNS IN SEPTIC SHOCK

HYPODYNAMMIC

Altered venous capacitance

Hypotention

Decreased peripheral resistance

Decreased cardiac out put

Decreased PCWP

Widened[a-v]d O2

Decreased CVP

HYPERDYNAMIC

Failure of O2 utilization by cells of vital organs

Hypotention

Decreased peripheral resistance

Increased cardiac output

Normal or increased CVP

Normal or increased PCWP

Narrowed[a-v]d O2

In early stages of septic shock ,patient doesn’t have features of circulatory collapse but only

signs of bacterial infection .

as the infection become severe,the circulatory system usually involve either because of direct

extension of the infection or secondarily as a result of toxins from the bacteria ,with resultant

loss of plasma in to infected tissues through deteriorating blood capillary walls.The end stages of

septic shock is not greatly different from that of haemorrhogic shock.1

ost people have a fever,but some have a low body temperature.People may have shaking chills and feel week.Other symptoms may also be present depending on the type and location of the initial infection.
Breathing,heart rate or both may be rapid.

As sepsis worsen ,people become confused and less alert. The skin become warm and flushed.the pulse is rapid and pounding the people breath rapidly.
People urinate less often and in smaller amounts and blood pressure decreases. Later body temperature often falls below normal and breathing becomes very difficult.

The skin may becomes cool and mottled or blue beause blood flow is reduced.Reduced blood flow may cause tissue,including tissue in vital organs[such as the intestine,to die ,resulting in gangrene.
When septic shock develops ,blood pressure is low even despite treatment.
With the treatment the risk of death is about 15% for people with sepsis and 40% more for

people with septic shock.
DIAGNOSIS
Doctors usually suspect sepsis when a person who has an infection suddenly develops a very high or low temperature , a rapid heart rate or rapid breathing rate or low blood pressure .To confirm the diagnosis , doctors look for bacteria in the blood stream [bacteremia].Evidence of another infection that could be causing sepsis and an abnormal number of white blood cells in a blood sample .Sample of blood from the patients are taken to try to grow the bacteria in the laboratory [blood culture ] –a process that takes 1to 3 days. However if people have been taking antibiotics for their initial infection , bacteria may present in blood but they not grow in the culture .Some times catheters are removed from the body and the tips of them are cut off and sent for culture .Finding of bacteria in a catheter that had contact with the blood indicates that bacteria are probably in the tested blood stream.7
In addition to blood sputum ,intravascular lives ,urine and any other wound discharges ,coagulation profile ,plasma lactate ,arterial blood gases analysis ,urinalysis and chest x-rays are used in diagnosis.8
SEPTIC SHOCK PREVOLUME LOAD POST VOLUME LOAD
Right atrial pressure
Central venous pressure 3 9 mmHg

Left atrial pressure
Pulmonary artery wedge pressure 8 15 mmHg

Pulmonary artery pressure 16 23 mmHg

Mean arterial pressure 55 60 mmHg

Heart rate 130 120 /min

Cardiac out put 4.5 7.5 L/min

Systemic vascular resistance 12 7 Sec/cm5

Pulmonary vascular resistance 1.3 1.1 Sec/cm5

Arterial oxygen content 150 140 ml/L

Globel oxygen delivery 675 1050 ml/min

ECG is taken and is used to look for abnormalities in heart rhythm and thus can be determine whether the blood supply to the heart is adequate.3

Risk factors

The risk is increased in people who have some conditions that reduce their ability to fight serious infections.These conditions include following.
Being a new born
Being over 38 years
Being pregnant
Having certain chronic disorders such as diabetes or cirrhosis
Having a weakened immune system .Due to use of drugs that suppress the immune system [immuno suppressants,such as chemotherapy drugs] or corticosteroids.
Or
Other disorders such as cancers,AIDS and immune disorders.
Injecting recreational drugs The drugs and needles used are rarely sterile.each injection may cause bacteremia to varying degrees.People who use these drugs are also at risk of disorders that can weaken the immune system.[such as AIDS]
Having an artificial [prosthetic] joint or heart valve abnormalities. Bacteria tend to lodge and collect on these structures.
The bacteria may continuasly or periodically be released into the blood stream .
Being treated with antibiotics for other infections ,some bacteria that cause infections and sepsis are resistant to antibiotics .Antibiotics do not eradicate the resistant bacteria.Thus if an infection persists in people who are taking antibiotics.It is more likely to be caused bacteriatha are resistant to antibiotics and that can cause sepsis .7

Treatment

Treatment for septic shock primarily consist of following
1.Volume resuscitation.
2.Early antibiotic administration.
3.Rapid source identification and control.
4.Support of major organ dysfunction.3
Most important factor in treating is prompt recognition.
Many causes of septic shock are atrogenic and preventative measures can certainly influence its incidence.
This includes judicious use of antibiotics attention to nutrition ,meticulous care of indwelling lines and catheters ,strict adherence to sterile technique during invasive procedures and avoidance of indiscriminal use of steroids and other immuno suppressive drugs .4
Among the choices for pressors ,a randomized controlled trial concluded that there was no difference between norepineprine.[plus dobutamine as needed for cardiac out put]
Versus epinephrine –
However dopamine has more B-adrenergic activity and therefore is more likely to cause arrhythmia or myocardial infarction .
Antimediator agents may be of some limited use in severe clinical situations .
Low dose steroids [hydrocortisone] for 5-7 days lead to improved out comes .
Recombinant activated protein C [drotrecoginalpha] has been shown in large randomized clinical trials to be associated with reduced mortality [number needed to treat [NNT] of 16] in patients with multi-organ failure. If this is given ,heparin should probably be continued.
Treatment by the head down position
When the pressure falls too low in most types of shock placing the patient with the head at least 12 inches lower than the feet helps tremendously in promoting venous return ,thereby also increasing cardiac out put .this head down position is the first essential step in the treatment of many types of shock .
Oxygen therapy
Because the major delererious effect of most types of shock is too little delivery of oxygen to tissues ,giving the patient oxygen to breathe can be benefit in many instances.however this frequently is far less beneficial than one might expect, because the problem in most type of shock is not inadequate oxygenation of the blood by the lungs but inadequate transport of the blood after it is oxygenated
Treatment of glucocorticoids
Administer in severe shock due to
1.glucocorticoids frequently increase the strength of heart in late stages of shock
2.glucocorticoids stabilize lyzosomes.so prevent release of lysosomal enzymes in to the cytoplasm ,thus prevent deterioration
3.glucocorticoids might aid in metabolism of glucose by the severely damaged cells.10

COMPLICATIONS
In the case of septic shock there are several complications that can be arised either due to the shock itself or due to treatment – management process of the disease. One of the major complications is multiple organ dysfunction syndrome.

Multiple Organ Dysfunction Syndrome.
DEFINITION
The presence of altered organ function in a acutely ill patient who is unable to maintain his homeostasis without intervention of a professional physician or such a health professioner is normally known as multiple organ dysfunction failure.
Septic patients are also liable to die due to organ failure. The brain and kidneys are normally protected from swings in blood pressure by autoregulation: In early sepsis – autoregulation curve shifts rightwards (due to and increase in sympathetic tone). In late sepsis – vasoparesis occurs & autoregulation fails, “steal phenomena” may occur (areas of ischaemia may have their blood stolen by areas with good perfusion).
Figure 01 shows the occurrence of multiple organ dysfunction syndrome .It may be a bacteria or a virus or such thing. When an infection causes inflammatory mediators in the circulation get activated.
This lead to occlusion of microvascular blood flow that is the blood flow within capillaries.
They mediate it via
Vasodilatation
Endothelial dysfunction
Micro vascular plugging
Vasoconstriction
Oedema like processes
Final result is maldysfunction of microvascular blood flow.
So some organs are unable to receive blood inadequately where as some organs receive enough blood flow .So in organs which are receives less blood ischemia occurs.So cell death takes place. Cell death leads to organ dysfunction.

HYDROCORTISONE THERAPY FOR PATIENTS WITH SEPTIC SHOCK

BACK GROUND
Hydrocortisone is widely used in patients with shock eventhough a survival benefit has been reported only in patients who remained hypotensive after fluid and vassopressure resuscitation and whose plasma cortisol level did not rise appropriately after the administration of corticotrophin.
METHODS
In this multi center,randomized ,double-blind ,placebo-controlled trial,we assigned 251 patients to receive 50mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days ; the dose was then tapered during a 6-day period .At 28 days ,the primary out come was death among patients who did not have a response to a corticotrophin test.

RESULTS
Of the 499 patients in the study, 233[46.7%] did not have a response to corticotrophin [125 in the hydrocortisone group and 108 in the placebo group].At 28 days ,there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotrophin [39.2% in the hydrocortisone group and 36.1%in the placebo group p=0.69]or between those who had a response to corticotrophin[28.8% in the hydrocortisone group and 28.7% in the placebo group ,p=1.00] At 28 days ,86 of 251 patients in the hydrocortisone group [31.5%] had died [p=0.51]. In the hydrocortisone group ,shock was reserved more quickly than in the placebo group ,however ,there were more episodes of superinfection ,including new sepsis and septic shock.

CONCLUSIONS
Hydrocortisone did not improve survival or reversal of shock in patients with septic shock ,either overall or in patients who did not have a response to corticotropin ,although hydrocortisone hastened reversal of shock in patients in whom shock was reversed.

Background
Clinicians often use the terms sepsis and septic shock without a commonly understood definition. In 1992, a consensus conference of the American College of Chest Physicians and the Society of Critical Care Medicine published the following definitions of sepsis syndromes to clarify the terminology used to describe the spectrum of disease that results from severe infection.
The basis of sepsis is the presence of infection and a subsequent systemic inflammatory response to that infection that results in physiologic alterations that occur at the capillary endothelial level. Systemic inflammatory response syndrome (SIRS) is a term that was developed in an attempt to describe the clinical manifestations that result from this inflammatory cascade, or systemic response to infection. Meeting SIRS criteria is considered having at least 2 of the following 4 clinical parameters abnormal:
1) body temperature
2) heart rate
3) peripheral leukocyte count
Sepsis syndromes are clinically defined on a spectrum of increasing disease severity as sepsis, severe sepsis, and septic shock. Sepsis is the presence of SIRS in the setting of infection. Severe sepsis is infection with evidence of end-organ dysfunction as a result of hypoperfusion. Septic shock is severe sepsis with persistent hypotension despite fluid resuscitation and resulting tissue hypoperfusion.
Bacteremia is defined as the presence of viable bacteria within the liquid component of blood. Bacteremia may be primary (without an identifiable focus of infection) or, more often, secondary (with an intravascular or extravascular focus of infection). While sepsis is commonly associated with bacterial infection, bacteremia is not a necessary ingredient in the activation of the inflammatory response that results in severe sepsis. In fact, septic shock is associated with culture-positive bacteremia in only 30-50% of cases

lternative Names
Bacteremic shock; Endotoxic shock; Septicemic shock; Warm shock
Definition
Septic shock is a potentially lethal drop in blood pressure due to the presence of bacteria in the blood
Description
Septic shock is a possible consequence of bacteremia, or bacteria in the bloodstream. Bacterial toxins, and the immune system response to them, cause a dramatic drop in blood pressure, preventing the delivery of blood to the organs. Septic shock can lead to multiple organ failure including respiratory failure, and may cause rapid death. Toxic shock syndrome is one type of septic shock.
Types of septic shock
A subclass of distributive shock, shock refers specifically to decreased tissue perfusion resulting in end-organ dysfunction. Cytokines TNFα, IL-1β, IL-6 released in a large scale inflammatory response results in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension. Hypotension reduces tissue perfusion pressure and thus tissue hypoxia ensues. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction will occur.
Physical
The hallmark of severe sepsis and septic shock are changes that occur at the microvascular and cellular level with diffuse activation of inflammatory and coagulation cascades, vasodilation and maldistribution of perfusing blood, capillary endothelial leak, and dysfunctional utilization of oxygen and nutrients at the cellular level. The challenge for the clinician is recognize that this process is underway when it may not be clearly manifest in the vital signs or clinical examination.
The American College of Chest Physicians/Society of Critical Care Medicine in 1992 defined the systemic inflammatory response syndrome (SIRS) as a group of vital signs and a laboratory value that if abnormal may indicate that sepsis physiology is occurring at the microvascular and cellular level.1 Meeting SIRS criteria is defined by the having at least 2 of the following 4 abnormalities:
• Temperature higher than 38°C or lower than 36°C
• Heart rate greater than 90 beats per minute
• Respiratory rate greater than 20 breaths per minute
• WBC count higher than 12,000/mm3 or lower than 4,000/mm3 or with more than 10% immature forms (bands)
Of course, a patient can have either severe sepsis or septic shock without meeting SIRS criteria, and conversely, SIRS criteria may be present in the setting of many other illnesses. One large observational study demonstrated that, in the setting of suspected infection, just meeting SIRS criteria without evidence of organ dysfunction did not predict increased mortality, which emphasizes the importance of identifying organ dysfunction over the presence of SIRS criteria. However, there is evidence that suggests that meeting increasing number of SIRS criteria is associated with increased mortality.
Fever is a common feature of sepsis. An inquiry should be made about fever onset (abrupt or gradual), duration, and maximal temperature. These features have been associated with increased infectious burden and severity of illness. However, note that simply mounting a fever is an insensitive indicator of sepsis. In fact, hypothermia is more predictive of illness severity.
Tachycardia is a common feature of sepsis and indicative of a systemic response to a stressor. Tachycardia is the physiologic mechanism of increasing cardiac output and increasing oxygen delivery to tissues. It is an indicator of hypovolemia and the need for intravascular fluid repletion. It may also result from fever itself. Narrow pulse pressure and tachycardia are also considered the earliest signs of shock.
Increased respiratory rate is also a common and often unappreciated feature of sepsis. Stimulation of the medullary ventilatory center by endotoxins and other inflammatory mediators has been proposed as a cause. As tissue hypoperfusion ensues, the respiratory rate also increases in order to compensate for metabolic acidosis. The patient often feels short of breath or appears mildly anxious. Of note, tachypnea is the most predictive of the SIRS criteria of adverse outcome. This is likely because tachypnea is also an indicator of pulmonary organ dysfunction, and a feature commonly associated with pneumonia and ARDS, all of which are associated with increased mortality in sepsis.
Altered mental status is a common feature of sepsis syndromes. It is considered a sign of organ dysfunction and is associated with increased mortality. Mild disorientation or confusion is especially common in elderly individuals. Other manifestations include apprehension, anxiety, and agitation. Profound cases may involve obtundation or comatose states. The cause of these mental status abnormalities is not entirely understood, but, in addition to cerebral hypoperfusion, altered amino acid metabolism has been proposed as a cause.
The physical examination should first involve assessment of the patient’s general condition, including an assessment of airway, breathing, and circulation (ABCs) and mental status. Attention should be paid to skin color and temperature. Pallor, grayish, or mottled skin are signs of poor tissue perfusion seen in septic shock. Skin is often warm in early septic shock as peripheral dilation and increased cardiac output occur (warm shock). As septic shock progresses, depletion of intravascular volume and decreased cardiac output lead to cool, clammy extremities and delayed capillary refill. Petechiae or purpura can be associated with disseminated intravascular coagulation (DIC) and are an ominous sign.
It is important in septic shock to perform a thorough physical examination in order to elucidate any potential source of infection. This is particularly important in cases where a site of infection can be removed or drained as in certain intra-abdominal infections, soft tissue abscesses and fasciitis, or perirectal abscesses. The following physical findings suggest a focal (usually bacterial) infection:
• CNS infection – Profound depression in mental status, meningismus
• Head and neck infections – Inflamed or swollen tympanic membranes, sinus tenderness, nasal congestion or exudate, pharyngeal exudate, stridor, cervical lymphadenopathy
• Chest and pulmonary infections – Localized rales or evidence of consolidation
• Cardiac infections – Any new murmur, especially in patients with a history of intravenous drug use
• Abdominal and gastrointestinal infections – Focal tenderness, guarding or rebound, rectal tenderness or swelling
• Pelvic and genitourinary infections – Costovertebral angle tenderness, pelvic tenderness, cervical motion pain, adnexal tenderness or masses, cervical discharge
• Bone and soft-tissue infections – Focal skin erythema and associated pain or tenderness, fluctuance, pain with joint range of motion, joint effusions and associated warmth/erythema
• Skin infections – Petechiae, purpura, erythema, fluctuance

Causes and symptoms
During an infection, certain bacteria can release complex molecules, called endotoxins, that may provoke a dramatic response by the body’s immune system. Endotoxins are particularly dangerous; as they become widely dispersed, they cause arteries and the smaller arterioles to dilate. At the same time, the walls of the blood vessels become leaky, allowing fluid to seep into the tissues, lowering intravascular volume (the amount of fluid left in circulation). This combination, of arterial dilation and decreased intravascular volume, causes a dramatic decrease in blood pressure and impaired blood flow to multiple organs. Other changes seen in septic shock are disseminated intravascular coagulation (DIC), which can further impair organ perfusion (blood flow).
Septic shock is seen most often in patients with impaired host defenses (patients who are immunosuppressed), and is often due to nosocomial (hospitalacquired) infections. The immune system is suppressed by drugs used to treat cancer, autoimmune disorders, organ transplants, and diseases of immune deficiency such as AIDS. Malnutrition, chronic drug abuse, and long-term illness also increase the likelihood of succumbing to bacterial infection. Bacteremia is more likely with preexisting infections such as urinary or gastrointestinal tract infections, or skin ulcers. Bacteria may be introduced to the blood stream by surgical procedures, catheters, or intravenous equipment.
Toxic shock syndrome (TSS) is a potentially fatal disorder resulting from infection with Staphylococcus aureus, a toxin-producing strain of a bacteria. When it was first reported about 25 years ago, toxic shock syndrome was associated with menstruation and linked to super-absorbent tampon use. Today, it is recognized that use of super-absorbent tampons does increase the risk of TSS, as does use of a contraceptive sponge or diaphragm. Postpartum patients (women who have just given birth) and patients with wound infections, or recovering from nasal surgery also are at risk for TSS. The illness appears suddenly, with fever, rash, low blood pressure, and episodes of fainting. Survival has improved since the 1980s, approximately 2–5% of patients die from this dis-order. Patients recovering from TSS face increased risk of recurrence. To prevent TSS, menstruating women are advised to avoid use of super-absorbent tampons.
Symptoms
Septic shock is usually preceded by bacteremia, which causes fever, malaise, chills, and nausea. The first sign of shock is often confusion and decreased consciousness. In this beginning stage, the extremities are usually warm. Later, as the blood pressure drops, they may become cool, pale, and cyanotic (bluish). Fever may subside to normal temperatures later on in sepsis.
Other symptoms include:
• rapid heartbeat
• shallow, rapid breathing
• decreased urination
• reddish patches in the skin
Septic shock may progress to cause “adult respiratory distress syndrome,” (also called non-cardiogenic pulmonary edema) in which the pulmonary capillaries become leaky and the lungs fill with fluid. This can lead to respiratory failure. When this occurs the patient can no longer breathe without mechanical ventilation and supplemental oxygen.
Diagnosis
Diagnosis of septic shock is made when a patient with a severe infection has hypotension (low blood pressure) for which other causes such as major bleeding, dehydration, or massive myocardial infarction have been excluded. Pulmonary artery pressure may be monitored with a Swan-Ganz catheter, a catheter inserted into the pulmonary artery. Blood, urine, sputum, and cultures from other possible sites of infection determine the type of bacteria responsible for the infection. Arterial blood gases are also monitored to assess changes in respiratory function.
Treatment
Prehospital Care
The initial treatment of sepsis and septic shock involves the administration of supplemental oxygen and volume infusion with isotonic crystalloids. Prehospital personnel should initiate these therapies.
Emergency Department Care
Sepsis treatment has evolved considerably over the past 10 years as it has transitioned from a disease that is a primary concern of critical care physicians in an ICU setting to one that has a major impact in the emergency department as well. Early recognition and early aggressive therapy for patients with sepsis have a significant impact on mortality.
Rivers et al brought this issue to the forefront with a landmark study in 2001, where they instituted a treatment protocol for patients with septic shock, termed Early Goal Directed Therapy (EGDT).15 EGDT emphasizes early recognition of patients with potential sepsis in the ED, early broad-spectrum antibiotics, and a rapid crystalloid fluid challenge, followed by goal-directed therapy for those patients who remain hypotensive or severely ill after this initial therapy. In the study by Rivers et al, the patients who did not respond to an initial fluid challenge (20-30 mL/kg bolus) and antibiotics received a CV catheter in the internal jugular or subclavian vein to measure central venous pressure (CVP) and an arterial catheter to directly measure arterial blood pressure.
EGDT is basically a 3-step protocol aimed at optimizing tissue perfusion.
 The first step involves titrating crystalloid fluid administration to CVP by administering 500-mL boluses of fluid until the CVP measures between 8 and 12 mm Hg. CVP is a surrogate for intravascular volume, as excess circulating blood volume is contained within the venous system. Patients with septic shock will frequently require 4-6 L or more of crystalloid to achieve this goal. Clinical signs of volume overload should be monitored as well, including developing periorbital or extremity edema, crackles on pulmonary examination, increasing oxygen requirement, or increased difficulty breathing. In patients who are mechanically ventilated, the target CVP goal is 12-15 mm Hg due to increased intrathoracic pressure.
 The second step, if the patient has not improved with fluid alone, is to administer vasopressors to attain a mean arterial pressure (MAP) greater than 65 mm Hg. It is important to first administer an adequate crystalloid fluid challenge (at least 2 L normal saline) before administering vasopressors, unless the patient is in extremis and requires immediate vasopressor support.
 The third step is to evaluate the central venous oxygen saturation (ScvO2), which is measured from the CV line in the superior vena cava. ScvO2 is the oxygen saturation of blood returning from tissue capillary beds, and it reflects the difference between overall oxygen supply and demand. Similar to lactate, ScvO2 is an indicator of adequate tissue oxygenation. An SvO2 of less than 70% is considered abnormal and indicative of suboptimal oxygen delivery compared with oxygen demand.
• Adequate oxygen delivery is first achieved by administering supplemental oxygen by face mask, increasing intravascular circulating volume, and increasing mean arterial pressure, or namely the first two steps of EGDT.
• Additional means of increasing tissue oxygen delivery are to maximize oxygen delivery to the alveoli (mechanical ventilation with FiO2 1.0), maximize the hemoglobin concentration (transfuse pRBCs if anemic), and augment cardiac output (dobutamine to increase inotropy once preload has been optimized). The protocol by Rivers et al called for a blood transfusion for hematocrit <30%.
• As a last step in the protocol, dobutamine infusion was started (increasing cardiac output) if ScvO2 <70% despite all the above measures being optimized.
 ScvO2 >70 mm Hg is therefore the target goal of EGDT, indicating adequate oxygen delivery. Rivers et al measured ScvO2 by means of a fiberoptic sensor at the tip of the CV catheter and a stand-alone monitor that displayed ScvO2 continuously. This concept was based on earlier work that targeted treatment goals that were based on increasing tissue oxygen delivery.16,17 An alternative to continuous ScvO2 measurement is to send a venous blood gas from the CV line for oxygen saturation, measured by a standard blood gas analyzer.
Rivers et al enrolled 263 patients who met criteria for septic shock:
 Suspected infection
 2 of the 4 SIRS criteria
 Persistent systolic blood pressure <90 mm Hg after initial fluid bolus or lactate concentration >4 mmol/L
These patients were randomized to EGDT versus “standard” therapy, the latter which included placement of a CV line and arterial catheter (both relatively invasive measures and probably not standard in most EDs). Despite this, they found an absolute mortality benefit of 16% with EGDT (30% mortality with EGDT vs 46% mortality with standard therapy).
When the data were examined closely, it was found that patients in the EGDT group received, on average, more crystalloid fluid (5.0 L vs 3.5 L) and a much higher percentage of patients received blood transfusion (64% vs 18%). The resulting average SvO2 measured after therapy was 95% for the EGDT group versus 60% in the standard group.

Since the publication of the Rivers et al trial, data from several centers have shown the value of protocolized care and what are referred to as sepsis treatment bundles, which include early broad-spectrum antibiotic administration, EGDT focused on achieving ScvO2 >70%, and rapid lactate clearance. Sepsis bundles also include administration of corticosteroids for refractory shock, tight glycemic control, low tidal volume ventilatory strategies, and administration of recombinant activated protein C in an ICU setting.18,19,20,21

Prognosis
Septic shock is most likely to develop in the hospital, since it frequently results from hospital-acquired infection. Close monitoring and early, aggressive therapy can minimize the likelihood of progression. Nonetheless, death occurs in at least 25% of all cases.
The likelihood of recovery from septic shock depends on many factors, including the degree of immuno suppression of the patient, underlying disease, timeliness of treatment, and type of bacteria responsible. Mortality is highest in the very young and the elderly, those with persistent or recurrent infection, and those with compromised immune systems.
Health care team roles
Generally, care for the septic patient is delivered by hospital-based health care professionals in the hospital ICU (intensive care unit). Physicians, intensive care nurses, and other nursing personnel closely monitor patients’ vital signs and administer antibiotics and fluids. Laboratory technologists perform necessary blood tests, and respiratory therapists may provide oxygen to patients in respiratory distress.
Prevention
The risk of developing septic shock can be minimized through treatment of underlying bacterial infections and prompt attention to signs of bacteremia. In the hospital, scrupulous aseptic technique on the part of medical professionals reduces the risk of introducing bacteria into the bloodstream.

INTRODUCTION:

Medicine is the science of preventing and curing illness and disease. (1)
We, medical students learn medicine in medical colleges under various categories step by step. Because ‘medicine’ is a vast, not stable subject that one can even say it is as big as the ocean.
By learning medicine privately our final goal to achieve is becoming a professional doctor. With in the word ‘professional doctor’ I think there is a ‘big meaning’. That is there should be a kind, honest, courageous, human being with full of humane qualities inside a professional doctor. Anyway to become such a person we should learn hard not only the academic matters but also everything we can gather, actually with the sense of being a professional doctor in the mind.
It is true that it is not an easy task, and also personally I think it shouldn’t be an easy task for a person to achieve.
So, on the way of becoming a professional doctor there are various types of challenges that one should face and should win.
Actually, when I first look at my Short Analytical Essay (SAE) topic my first impression wasn’t such a pleasant one. But anyway I have to manage it along with my teachers, colleagues, parents and all. So, on my way through the Systemic Inflammatory Response Syndrome (SIRS), that is my SAE topic, on the internet and in the books I realized that it isn’t such a ‘syndrome’, that I should bother that much. Then only I used to greet ‘the syndrome’ whenever I remember it.

Anyway as the name it self suggests,
Systemic Inflammatory Response Syndrome

Systemic- relating to a system (2)

Inflammatory Response- any response to an inflammation

Syndrome- collection of signs and symptoms (2)
is the collection of signs and symptoms that occur in relation to a system in the body in response to an inflammation. Specially this occurs in patients with infections. (3)
Inflammation is a fundamental pathologic process consisting of a dynamic complex of cytologic and chemical reactions that occur in the affected blood vessels and adjacent tissues in response to an injury or abnormal stimulation caused by a physical, chemical or biologic agent including,
I. The local reactions and resulting morphologic changes,
II. The destruction or removal of the injurious material,
III. The responses that lead to repair and healing,
The so called ‘cardinal signs’ of inflammation are,

All of the signs may be observed in certain instances, but no one of them is necessarily always
present. (2)

As mentioned above if the medicine is an ocean my topic, Systemic Inflammatory Response Syndrome is a handful of water from that ocean.
But due to it’s somewhat complexity it is decided to go along as separate sub topics.
So I am going to enter my topic properly under the following sub topics.
1. definition
2. aetiology
3. risk factors
4. pathophysiology
5. clinical features
6. investigations
7. complications
8. prevention
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS).
Hospital the institution for the treatment, care and cure of the sick and wounded, for the study of disease and for the training of physicians, nurses and allied health personnel, (2) has various types of sections for the purpose of easiness of both patients and health care professionals.
In somewhat highly facilitated hospitals as our Teaching Hospital Karapitiya, have a special unit as Intensive Care Unit in which patients who need immediate high quality treatment for their survival are included.
It is said that major causes for a patient to enter the Intensive Care Unit nowadays are SIRS and sepsis that is SIRS resulting from a documented infection.(4)

DEFINITION:
Systemic Inflammatory Response Syndrome is defined as two of the four following features, (5)
1. tachycardia > 90 beats per minute
2. tachypnoea > 20 beats per minute
3. pyrexia > 38 0C OR hypothermia <36 0C
4. WBC count > 12  109 / L OR < 4  109 / L
OR
> 10% immature neutrophils
TACHYCARDIA
Tachycardia is usually defined in an adult person as Heart Rate is faster than 100 beats per minute. An electrocardiogram of such a person is shown comparatively to a normal report in the figure 01. (6)

TACHYPNOEA
Tachypnoea is rapid shallow breathing. (7)

PYREXIA
Pyrexia is fever or hypothermia.
Fever is a body temperature above the usual range of normal.
Usual range of normal = 36-38 0C (6)

AETIOLOGY:
It is very difficult to focus a cause of SIRS exactly although there are some likely factors which are able to cause SIRS. Some of them are as follows, (8)
1. acute pancreatitis
2. Splanchnic hypo perfusion
3. infected skin lesions
4. burns
5. severe trauma
6. as a complication of surgery
7. haemorrhage
8. myocardial infarction
9. cardiac tamponade
10. anaphylactic shock
11. complicated aortic aneurysm
12. pulmonary embolism
13. drug overdose
14. adrenal insufficiency
15. immunodeficiency

01. ACUTE PANCREATITIS.
ACUTE PANCREA TITIS

Acute – sudden

Pancrea – regarding the pancreas

Itis – inflammation
So, acute pancreatitis is referred to a sudden inflammation in the pancreas. Depending on the severity of the inflammation it can even has systemic complications although treatments are continuously done. One such major complication is Systemic Inflammatory Response Syndrome and then it even can cause Multiple Organ Dysfunction Syndrome (MODS). As a disease it can be cured with conservative measures such as IV fluid rehydration. But cases may need admission to the ICU or even surgery. (9)

02. SPLANCHNIC HYPOPERFUSION.
Causes gut ischaemia that is local anaemia due to mechanical obstruction of the blood supply to the gut. (2)
Associated with mucosal permeability and translocation of organisms from the GIT lumen in to the portal venous and lymphatic circulations.

Subsequent release of inflammatory mediators including cytokines (interleukin-1, TNF) from hepatic kupffer cells and other macrophages or circulating monocytes.

Initiates a sequence of events reaching acutely in the clinical signs of SIRS or sepsis. (8)

03. INFECTED SKIN LESIONS.
An infected skin lesion is a zone of tissue in the skin with impaired function as a result of damage by infections (10). Skin lesions are able to lead to severe complications as Systemic Inflammatory Response Syndrome. Thus, evidences also suggest that patients with severe infected skin lesions are prone to get SIRS although most studies are in experimental stages.

04. BURNS.
A burn is tissue damage caused by agents such as heat,
chemicals, electricity, sunlight, nuclear radiation or any
other thing.
A first degree burn is a burn that affect only the epidermis
of the skin.
A second degree burn affects both the epidermis & dermis.
(Figure 02)
A third degree burn not only damages the skin to it’s full
length but also damage to underlying tissues.(10)

Thus such burns cause dehydration, which is excessive loss of water from the body.
In dehydration fluid loss occur from the extra cellular compartment. Plasma is about ¼ of the extra cellular compartment. So in such a dehydration, plasma loss occurs owing to damage of blood vessels. Thus these burns can be leaded to severe complications as SIRS, MODS. So, although most patients affected by burns are able to recover with normal treatment, some patients need ICU protection & also even surgeries.

05. SEVERE TRAUMA.
Trauma is any body wound or shock produced by sudden physical injury as from accident, injury

or hit. (10)
Trauma patients are prone to have secondary complications such as shock, respiratory failure, SIRS & even death. (Figure 03)
Thus traumatic patients are able to exhibit SIRS
with out evidence of infection. And it was believed
that SIRS from infection has some connection
with hypoadrenalism. But, modern researches supply
evidences that hypoadrenalism can accompany SIRS
from trauma even without infection.
But further investigations are needed to prove this deeply
and to find which group of patients are most susceptible. (11)

06. AS A COMPLICATION OF SURGERY.
Similar physiological responses can be seen to trauma, burns, sepsis & also surgery as tissue injury, infection, hypovolaemia and hypoxia. It involves both local & systemic reactions. And extent of response is proportionate to the severity of surgery. Thus an appropriate response maintains homeostasis & allows wound healing. Further, an excessive response is able to
produce a systemic response. This leads to SIRS & even to MODS.

07. MYOCARDIDL INFARCTION.
Myocardial infarction is death of muscle cells of the myocardium of the heart due to irreversible changes that occur as a result of blood flow to the myocardium. (7)
In some patients the diagnosis of the acute myocardial infarction is complicated by cardiogenic shock. And almost about 1/5 of such patients show clinical signs of severe SIRS & patients who were having sepsis have twice the risk of death.

08. HAEMORRHAGE.
Haemorrhage is bleeding that is the escape of blood from a ruptured blood vessel. It can be either external or internal or both.
Rupture of a major blood vessel such as the femoral artery can lead to the loss of several liters of blood in a few minutes resulting shock, collapse and death if untreated. (10)
Thus it can be cured by giving normal medical treatment in most situations. But sometimes it leads to SIRS needing ICU care, surgeries and such high quality treatment to make the patient alive.

09. CARDIAC TAMPONADE.

Cardiac tamponade or pericardial tamponade is the abnormal accumulation of fluid with in the pericardial sac.
Fluid in the pericardial sac

Limit the filling of the ventricles

Decreased End Diastolic Ventricular Volume

Decreased Stroke Volume

Decreased Cardiac Output

Shock and even death.
Therefore such a condition can be the aetiology of several severe consequences as SIRS & MODS. So immediate diagnose & treatment are essential in these conditions. Thus prompt surgical intervention is required to prevent death. (7)

10. ANAPHYLACTIC SHOCK.
Anaphylactic shock – a distributive shock, is a multi systemic and very severe Type – I hypersensitivity allergic reaction that occurs when an individual who has been previously sensitized to an antigen is reexposed to it.
The resultant antibody – antigen reaction triggers a quick release of large quantities of histamine, prostaglandin and leukotrienes from mast cells leading to increased capillary permeability, wide spread dilation of arterioles & capillaries and bronchial mucosal oedema. So, a sudden drop of blood pressure & difficult in breathing due to bronchoconstriction result.
Thus anaphylactic shock is a matter of death if untreated on time. Further, before reaching to the death it can cause severe consequences as SIRS. So real treatment on time is very important in dealing with such patients.

11. COMPLICATED AORTIC ANEURYSM.
An aortic aneurysm is a balloon like swelling in the wall of the aorta. Most frequently it occurs in the abdominal aorta below the level of the renal arteries. Because in here area the aortic wall contains less elastin fibers than that of other areas.
When the swelling enlarges beyond a certain level it is prone to rupture resulting abdominal pain, back pain, haemorrhagic shock and quick death if untreated. (10)
the definitive treatment for aortic aneurysm is surgical repair of the aortic wall after opening the abdominal cavity. And it is an invasive method. Thus the latest method is the endovascular treatment which is a minimally invasive method.
Due to these invasive methods, a surgical trauma occurs in patients experienced the condition. It releases catabolic stress hormones which cause the breakdown of fats, proteins & carbohydrate stores and so interfere with immune function. So it delays wound healing increasing the risk of having SIRS.
Thus it should be noted that the risk of SIRS is less in the endovascular treatment than in the opened abdominal correction.

12. PULMONARY EMBOLISM.
An embolus is a material such as a blood clot, fat, air, amniotic fluid or a foreign body that is carried by the blood from one part in the circulation to lodge at another point. When such an embolus lodges a pulmonary artery or one of its branches, obstructing the blood flow – the condition is known as pulmonary embolism.(7), (10)
Patients show common symptoms as difficult in breathing, chest pain in inspiration & palpitations.

Thus clinical signs are hypoxia, tachypnoea & tachycardia. Further it can lead to collapse, circulatory instability, SIRS & even sudden death if untreated.

13. DRUG OVERDOSE.
A drug is a substance that affect the structure or functioning of a living organism. Drugs are widely used in the world for the prevention, diagnosis & treatment of disease & also for the relief of symptoms. (10)
Drug market is one of the world’s most profitable businesses. It supplies evidences that how much people in the world use drugs. But the usage should be done in according to the thorough advise of a professional doctor.
Taking overdoses of drugs causes various consequences that vary from drowsiness to SIRS, MODS & also even death unless any eligible step is taken to reduce the consequences.

14. ADRENAL INSUFFICIENCY.
Adrenal insufficiency is the inability of the adrenal glands to carry its normal function. So it doesn’t produce adequate amounts of steroid hormones which regulate organ function, cortisol & aldesterone which regulates sodium, potassium & water retention.
Addison’s disease is the worst degree of adrenal insufficiency. (12) If it is not treated severe abdominal pains, diarrhoea, vomiting, profound muscle weakness & fatigue, extremely low blood pressure, weight loss, heart failure, changes in mood & personality, shock & SIRS leading to MODS can be occurred. (7)

15. IMMUNODEFFICIENCY.
Shortly, immunodeficiency is the deficiency in the immune responses. So the ability of the immune system to fight against infections is compromised or completely absent. Most people having acquired (or secondary) Immune deficiency. And some people having primary immune deficiency due to birth with defects in the immune system.
So in a such immunodeficiency many specific directly or indirectly affect the immune system giving rise to cancers in bone marrow & blood, and several other chronic infections. Therefore it also a condition that leads to SIRS.

RISK FACTORS:
Risk factors are some ‘agents’ that are able to either increase the likelihood of developing an illness in an individual or increase the danger of already existing illness. These ‘agents’ are variable and some are coming from the environment without the interference of the man and some are unfortunately enters the body due to the man himself. Such most common ‘agents’ are habits as using cigarettes, liquor etc., exposure to some environmental factors as flood, dust, wind, etc., invasion of the body by some microorganisms as bacterias, viruses, fungi etc.
In the case of SIRS, so many risk factors can be recognized. Those risk factors enhance the condition in many ways. (8)
Up to now we realized that so many factors are responsible for the occurrence of SIRS. It is vary from a major surgery to a small injury on the skin. So it is obvious that risk factors that enhance these causes are more or less responsible for the enhancement of SIRS.
Therefore as a whole we can consider as,
1. chemicals.

2. environmental factors.
3. injuries.
i. external.
ii. internal.
4. inflammation.
5. clinical procedures.
6. congenital conditions.
7. others.
1. CHEMICALS:
i. some drugs as polymyxin, morphine& fluorescein used for the examination of eyes in ophthalmology
ii. some vaccinations
iii. caustic chemical compounds as,
a) sodium hydroxide
b) silver nitrate
c) sulphuric acid
d) nitric acid
e) hydrofluoric acid
iv. ethanol
v. oestrogen

2. ENVIRONMENTAL FACTORS:
i. insect bites
ii. food allergies such as pea nuts, tree nuts, etc.
iii. lightning
iv. UV light

3. i. EXTERNAL INJURIES:
i. head injury
ii. physical trauma
iii. surgery

3. ii. INTERNAL INJURIES:
i. kidney injuries
ii. surgery
iii. myocardial rupture

4. INFLAMMATION:
i. pericarditis
ii. mumps

5. CLINICAL PROCEDURES:
i. X- ray dyes

ii. radiation
iii. chest tubes that insert to drain blood in the first 24-48 hours after
heart surgeries.
iv. Endoscopic Retrograde Cholangio – Pancreatography

6. CONGENITAL CONDITIONS:
i. congenital hypopituitarism
ii. congenital hypoadrenalism

7. OTHERS:
i. autoimmune
ii. adrenoleukodystrophy
iii. severe adrenal suppression
iv. critical illnesses related to corticosteroid insufficiency
v. hypothyroidism
vi. haemophilia
vii. decreased platelet count – thrombocytopenia
viii. gallstones
ix. alterations in blood flow
x. pregnancy
xi. obesity

PATHOPHYSIOLOGY:
Pathophysiology is the study of the process of the disease to achieve the purpose of understanding the underlying cause and the nature of the disease.
Up to now it is obvious that SIRS is a result of so many causes. But SIRS from each and every cause has same pathological properties with minor changes.
The Pathophysiology or the development of the SIRS is best explained by Bone in 1996. according to Bone, it occurs in three stages.
Stage 01- In response to injury or infection cytokines are produced by the local
environment.

So, trigger inflammatory responses.
i. promote wound repairing.
ii. persuade the reticular endothelial system.
Stage 02- Small amounts of cytokines are released in to the circulation.

Improve the local response & establish homeostasis.
So, i. stimulation of growth factors.
ii. recruitment of macrophages.
iii. activation of platelets.

Well regulated by,
i. a decrease in the proinflammatory mediators
ii. release of endogenous antagonists

stage 03- If it is unable to establish homeostasis even in the stage 02, a significant systemic reaction occurs which leads to destruction rather than the protection.
Release of cytokines

Activation of numerous humoral cascades

Activation of reticular endothelial system

Loss of circulatory integrity

Organ dysfunction.
It also is able to cause stimulation of Nitric Oxide production & Maldistribution of microvascular blood flow. (3)

CLINICAL FEATURES:
Clinical features of any disease can be considered in two types. As,
i. Signs &
ii. Symptoms
Signs are the features that the physician is able to recognize in the patient by inspection or by analysis. (10) E.g.: pallor, high blood pressure, etc.
Thus, symptoms are the complains that the patient has got to tell the physician about his disease condition. (10) E.g.: pain, fever, etc.

But it should be noted that a patient with one or more clinical features of SIRS that appear in the table 01 can’t be considered as a patient with SIRS, with out further investigations. Thus, it shouldn’t be jumped in to conclusions at once when a person presents with these features. Because, these clinical features can be vary according to the aetiology.
Signs Symptoms
Lactic acidosis Hypotension Polyuria Fainting
Encephalitis Anxiety Unconsciousness Itching
Dehydration Hypoglycemia Vomiting Diarrhea
Utricaria Clammy skin Leg pain Back pain
Angioedema Flushed appearance Numbness Abdominal pain
Heart failure Pulsus paradoxus Weight loss Disorientation
Abnormal ECG Pallor Weakness Tiredness
Respiratory distress Oedema Dizziness No sensation
Leukocytosis Leckocytopenia Headache Fever
Tachycardia Tachypenia Cold Loss of appetite
Hyperuricaemia Cyanosis Steatorrhea Cough

Table 01: Clinical features of SIRS.

INVESTIGATIONS:
Investigations help in many ways for the survival of a patient. They help to the physician to make a diagnosis, to confirm the diagnosis, to assess the illness, even to assess the severity of the disease, to know the effectiveness of the treatment, etc.

In the case of SIRS a variety of investigations are done. SIRS is the result of a number of various conditions. So, there are also a number of investigations regarding SIRS as well. Such investigations include,
i. blood tests
ii. imaging
iii. recording
iv. screening tests
v. others
i. Blood Tests
# for tryptase
# for cortisol
# for ACTH
# for aldosterone
# for rennin
# for potassium
# for sodium
# full blood count
# clotting status – PT, APTT, TT
# serum amylase
# serum lipase
# arterial blood gas analysis
ii. Imaging
@ X-ray

@ Computed Tomography
@ Magnetic Resonance Imaging
@ Angiography
@ Echocardiography
iii. Recording
# Electrocardiography
# Electroencephalography
# Electroglottography
# Electrokymography
# Electromyography (12)
iv. Screening Tests
@ Erythrocyte Sedimentation Rate
@ Renal function
@ Liver enzymes
@ Electrolytes
v. Others
# Skin allergy testing (with or with out patch testing)
# ACTH stimulation test

COMPLICATIONS:
Complications are diseases or conditions arising during the course of or as a consequence of another disease. (10)

Such complications of SIRS are as follows, (13)
1. Sepsis
2. Severe sepsis
3. Septic shock
4. Multiple Organ Dysfunction Syndrome(MODS)
5. Acute lung injury
6. Acute kidney injury
1. Sepsis
Sepsis is also SIRS, but with a documented infection site. Clinical signs of sepsis include,
Fever
Leukocytosis
Tachypenia
Tachycardia
Reduced vascular tone
Organ dysfunction (10), (13)
2. Severe Sepsis
Severe sepsis is also sepsis, but associated with organ dysfunction, hypoperfusion or hypertension. Hypoperfusion and perfusion abnormalities can be involved with lactic acidosis, oligouria, or an acute alteration in mental state. But hypoperfusion and perfusion abnormalities are not limited to above conditions. (13)

3. Septic Shock
Septic shock is also but is more advanced than it. So it is sepsis induced with hypotension in the absence of other causes for hypotension and also occurs despite of adequate fluid resuscitation. It also presents with perfusion abnormalities which may include but not limited to lactic acidosis, oligouria or an acute alteration in mental status. (12), (13)
Clinical signs of septic shock include,
Haemodynamic alterations
Myocardial depression
Altered vasculature
Altered organ perfusion
Imbalance of CO2 delivery and consumption
It can also leads to multiple organ failure. (7)
4. Multiple Organ Dysfunction Syndrome (MODS)
MODS is present with altered organ functions & can be seen mostly in acutely ill patients whose homeostasis can’t be maintained without an external interference.

Figure 05

Figure 05 shows that mortality increases with increase in number of SIRS symptoms & in severity of the disease. (14)
5. Acute Lung Injury (ALI)
ALI is caused by any stimulus of local or systemic inflammation, principally sepsis. Clinical signs are severe dyspnea
tachypenia
resistant hypoxaemia
6. Acute Kidney Injury (AKI)
AKI is an abrupt change in serum creatinine & / or urine output, & a majority of patients admitted to the ICU have some evidence of the disorder. Clinical signs include,
Elevated serum creatinine levels.
Polyuria.

PREVENTION:
There is a famous here say as ‘prevention is better than cure’ which is also true in the case of SIRS. I’m prefer to consider the prevention as follows,

01. Prevention of SIRS prior to the condition occurs,
Most oftenly most causes responsible for SIRS are seem to be conditions that are ‘severe enough’ to take a patient to a hospital. So, to prevent such a patient entering to SIRS hospital

authority can play so many quick roles. So, professional hospital care with modern and accurate equipments is important.
Thus nutritional support to the patient is also effective. Further, early recognition of the condition by adequate investigations is also helpful.
Usage of drugs as antibiotics
antimicrobials
even pain killers is also effective as a measurer of prevention.

02. Prevention of SIRS after the condition developed (Treatment)
Treatment of SIRS can be regarded as pharmacological treatments and other methods.
As other methods, providing adequate mental and physical rest for the patient
doing some type of medication if possible are of some value. But it should be noted that these measurers can be done after the patient is out of the risk of loosing his life.
Pharmacological treatment
1. Indomethacin administration.
Patients with severe SIRS can benefit with Indomethacin administration. New experiments regarding the effectiveness are going on. (15)
2. Recombinant N-terminal bactericidal / Permeability increasing proteins (rBP123)
A well described Endotoxin neutralizing protein. Ex vivo experiments suggest that it is able to prevent SIRS triggered by circulating endotoxin. It also under further experimental studies. (16)

3. Methylprednisolone
Able to reduce the severity of SIRS in some patients. It is also under the laboratory tests & it is said that further study is needed about the role of Methylprednisolone in SIRS. (17)
4. Routinely Selenium, Glutamine, Eicosapentaenoic acid like drugs which are able to reduce the
severity of SIRS are used.
5. Antioxidants as vitamin E, C are also given. They are able to reduce the oxidative stress of
tissues & contribute to the prevention.

SIRS is a condition that is mostly undergoing various experimental studies in medicine. So, if one says that SIRS is the most unstable condition in the field, I agree with the statement at once without any hesitation!

SIRS is one of several conditions related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of cytokine storm, in which there is abnormal regulation of various cytokines. SIRS is also closely related to sepsis, in which patients satisfy criteria for SIRS and have a suspected or proven infection. R-01
Criteria for SIRS were established in 1992 as part of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference The conference concluded that the manifestations of SIRS include, but are not limited to.
Body temperature less than 36°C or greater than 38°C
Heart rate greater than 90 beats per minute
Tachypnea (high respiratory rate), with greater than 20 breaths per minute; or, an arterial partial pressure of carbon dioxide less than 4.3 kPa (32 mmHg)
White blood cell count less than 4000 cells/mm³ (4 x 109 cells/L) or greater than 12,000 cells/mm³ (12 x 109 cells/L); or the presence of greater than 10% immature neutrophils (band forms)
SIRS can be diagnosed when two or more of these criteria are present. The International Pediatric Sepsis Consensus has proposed some chages to adapt these criteria to the pediatric populationFever and leukocytosis are features of the acute-phase reaction, while tachycardia is often the initial sign of hemodynamic compromise. Tachypnea may be related to the increased metabolic stress due to infection and inflammation, but may also be an ominous sign of inadequate perfusion resulting in the onset of anaerobic cellular metabolism.R-01
In children, the SIRS criteria are modified in the following fashionHeart rate > 2 standard deviations above normal for age in the absence of stimuli such as pain and drug administration, OR unexplained persistent elevation for greater than 30 minutes to 4 hours. In infants, also includes Heart rate < 10th percentile for age in the absence of vagal stimuli, beta-blockers, or congenital heart disease OR unexplained persistent depression for greater than 30 minutes.
Body temperature obtained orally, rectally, from Foley catheter probe, or from central venous catheter probe > 38.5 °C or < 36 °C. Temperature must be abnormal to qualify as SIRS in pediatric patients.
Respiratory rate > 2 standard deviations above normal for age OR the requirement for mechanical ventilation not related to neuromuscular disease or the administration of anesthesia.
White blood cell count elevated or depressed for age not related to chemotherapy, or greater than 10% bands + other immature forms.R-01
Pathophysiology
Systemic inflammatory response syndrome (SIRS), independent of the etiology, has the same pathophysiologic properties, with minor differences in inciting cascades. Many consider the syndrome a self-defense mechanism. Inflammation is the body’s response to nonspecific insults that arise from chemical, traumatic, or infectious stimuli. The inflammatory cascade is a complex process that involves humoral and cellular responses, complement, and cytokine cascades. Bone best summarized the relationship between these complex interactions and SIRS as the following 3-stage process.R-01
Stage I: Following an insult, local cytokine is produced with the goal of inciting an inflammatory response, thereby promoting wound repair and recruitment of the reticular endothelial system.
Stage II: Small quantities of local cytokines are released into circulation to improve the local response. This leads to growth factor stimulation and the recruitment of macrophages and platelets. This acute phase response is typically well controlled by a decrease in the proinflammatory mediators and by the release of endogenous antagonists. The goal is homeostasis.
Stage III: If homeostasis is not restored, a significant systemic reaction occurs. The cytokine release leads to destruction rather than protection. A consequence of this is the activation of numerous humoral cascades and the activation of the reticular endothelial system and subsequent loss of circulatory integrity. This leads to end-organ dysfunction.
Bone also endorsed a multihit theory behind the progression of SIRS to organ dysfunction and possibly MODS. In this theory, the event that initiates the SIRS cascade primes the pump. With each additional event, an altered or exaggerated response occurs, leading to progressive illness. The key to preventing the multiple hits is adequate identification of the cause of SIRS and appropriate resuscitation and therapy.
Trauma, inflammation, or infection leads to the activation of the inflammatory cascade. When SIRS is mediated by an infectious insult, the inflammatory cascade is often initiated by endotoxin or exotoxin. Tissue macrophages, monocytes, mast cells, platelets, and endothelial cells are able to produce a multitude of cytokines. The cytokines tissue necrosis factor and interleukin (IL)–1 are released first and initiate several cascades. The release of IL-1 and TNF- (or the presence of endotoxin or exotoxin) leads to cleavage of the nuclear factor B inhibitor. Once the inhibitor is removed, NF- B is able to initiate the production of mRNA, which induces the production other proinflammatory cytokines.R-04,R-07
IL-6, IL-8, and interferon gamma are the primary proinflammatory mediators induced by NF- B. In vitro research suggests that glucocorticoids may function by inhibiting NF- B. TNF- and IL-1 have been shown to be released in large quantities within 1 hour of an insult and have both local and systemic effects. In vitro studies have shown that these 2 cytokines given individually produce no significant hemodynamic response but cause severe lung injury and hypotension when given together. TNF- and IL-1 are responsible for fever and the release of stress hormones (norepinephrine, vasopressin, activation of the renin-angiotensin-aldosterone system).
Other cytokines, especially IL-6, stimulate the release of acute-phase reactants such as C-reactive protein (CRP). Of note, infection has been shown to induce a greater release of TNF than trauma, which induces a greater release of IL-6 and IL-8. This is suggested to be the reason higher fever is associated with infection rather than trauma.
The proinflammatory interleukins either function directly on tissue or work via secondary mediators to activate the coagulation cascade, complement cascade, and the release of nitric oxide, platelet-activating factor, prostaglandins, and leukotrienes. Numerous proinflammatory polypeptides are found within the complement cascade. Protein complements C3a and C5a have been the most studied and are felt to contribute directly to the release of additional cytokines and to cause vasodilatation and increasing vascular permeability. Prostaglandins and leukotrienes incite endothelial damage, leading to multiorgan failure.
The correlation between inflammation and coagulation is critical to understanding the potential progression of SIRS. IL-1 and TNF directly affect endothelial surfaces, leading to the expression of tissue factor. Tissue factor initiates the production of thrombin, thereby promoting coagulation, and is a proinflammatory mediator itself. Fibrinolysis is impaired by IL-1 and TNF via production of plasminogen activator inhibitor-1. Proinflammatory cytokines also disrupt the naturally occurring anti-inflammatory mediator’s antithrombin and activated protein-C (APC). If unchecked, this coagulation cascade leads to complications of microvascular thrombosis, including organ dysfunction. The complement system also plays a role in the coagulation cascade. Infection-related procoagulant activity is generally more severe than that produced by trauma.
The cumulative effect of this inflammatory cascade is an unbalanced state with inflammation and coagulation dominating. To counteract the acute inflammatory response, the body is equipped to reverse this process via counter inflammatory response syndrome (CARS). IL-4 and IL-10 are cytokines responsible for decreasing the production of TNF, IL-1, IL-6, and IL-8. The acute phase response also produces antagonists to TNF and IL-1 receptors. These antagonists either bind the cytokine, and thereby inactivate it, or block the receptors. Comorbidities and other factors can influence a patient’s ability to respond appropriately. The balance of SIRS and CARS determines a patient’s prognosis after an insult. Some researchers believe that, because of CARS, many of the new medications meant to inhibit the proinflammatory mediators may lead to deleterious immunosuppression.
Causes
The differential diagnosis of SIRS is broad and includes infectious and noninfectious conditions, surgical procedures, trauma, and medications and therapies.
The following is partial list of the infectious causes of SIRS:
Bacterial sepsis,Burn wound infections,Candidiasis,Cellulitis,Cholecystitis,Community-acquired pneumonia,Diabetic foot infection,Erysipelas,Infective endocarditis,Influenza,Intraabdominal infections (eg, diverticulitis, appendicitis),Gas gangrene,Meningitis,Nosocomial pneumonia,Pseudomembranous colitis,Pyelonephritis,Septic arthritis,Toxic shock syndrome,Urinary tract infections (both male and female)
The following is a partial list of the noninfectious causes of SIRS:
Acute mesenteric ischemia,Autoimmune disorders,Burns,Chemical aspiration,Cirrhosis,Dehydration,Drug reaction,Electrical injuries,Erythema multiforme,Hemorrhagic shock,Intestinal perforation,Medication side effect (eg, theophylline),Myocardial infarction,Pancreatitis,Substance abuse (stimulants such as cocaine and amphetamines),Surgical procedures,Toxic epidermal necrolysis,Transfusion reactions,Upper gastrointestinal bleeding
Complications
SIRS is frequently complicated by failure of one or more organs or organ systems. The complications of SIRS include:
Acute lung injury
Acute kidney injury
Shock
Multiple organ dysfunction syndrome R-01
Acute lung injury (ALI) is a diffuse heterogeneous lung injury characterized by hypoxemia, non cardiogenic pulmonary edema, low lung compliance and widespread capillary leakage. ALI is caused by any stimulus of local or systemic inflammation, principally sepsis.R-10

cute renal failure (ARF), also known as acute kidney failure or acute kidney injury, is a rapid loss of renal function due to damage to the kidneys, resulting in retention of nitrogenous (urea and creatinine) and non-nitrogenous waste products that are normally excreted by the kidney. Depending on the severity and duration of the renal dysfunction, this accumulation is accompanied by metabolic disturbances, such as metabolic acidosis (acidification of the blood) and hyperkalaemia (elevated potassium levels), changes in body fluid balance, and effects on many other organ systems. It can be characterised by oliguria or anuria (decrease or cessation of urine production), although nonoliguric ARF may occur. It is a life-threatening medical emergency.R-11
Inadequate tissue perfusion due to absolute or relative cardiac output is known as shockR-08,R-09
Multiple organ dysfunction syndrome (MODS), previously known as multiple organ failure (MOF), is altered organ function in an acutely ill patient requiring medical intervention to achieve homeostasis. The use of “multiple organ failure” should be avoided since that term was based upon physiologic parameters to determine whether or not a particular organ was failing. The condition usually results from infection, injury (accident, surgery), hypoperfusion and hypermetabolism. The primary cause triggers an uncontrolled inflammatory response. In operative and non-operative patients sepsis is the most common cause. Sepsis may result in septic shock. In the absence of infection a sepsis-like disorder is termed systemic inflammatory response syndrome (SIRS). Both SIRS and sepsis could ultimately progress to multiple organ dysfunction syndrome. However, in one-third of the patients no primary focus can be found. Multiple organ dysfunction syndrome is well established as the final stage of a continuum Systemic inflammatory response syndrome -> sepsis ->severe sepsis ->Multiple organ dysfunction syndrome. Currently, investigators are looking into genetic targets for possible gene therapy to prevent the progression to Multiple organ dysfunction syndrome. Some authors have conjectured that the inactivation of the transcription factors NF-κB and AP-1 would be appropriate targets in preventing sepsis and Systemic inflammatory response syndrome. These two genes are pro-inflammatory. However, they are essential components of a normal healthy immune response, so there is risk of increasing vulnerability to infection, which can also cause clinical deterioration.R-02
Some have developed a mouse model sepsis via cecal ligation and puncture (CLP Male Balb/c mice subjected to CLP were given an IL-10-carrying vector or an empty control vector. Lung, Liver and kidney tissue destruction were measured by assessing myeloperoxidase and malonialdehyde activity. These last two are endogenous oxidizing compounds produced during tissue inflammation. The authors assessed the level neutrophil infiltration in lung and liver tissue. IL-10 protein expression was measured using immunohistochemistry. The expression of Tumor necrosis factor-alpha mRNA was measured at 3,8, and 24 hours after CLP using reverse transcription polymerase chain reaction. Their results show significantly reduced organ damage by IL-10 gene transfer, as quantified by reduced myeloperoxidase activity in the lung, liver, and kidney. The malonialdehyde level was not affected by the transfer into the liver. The livers of the mice infected with the adenoviral vector showed reduced neutrophil activity. The lung and kidney samples in mice carrying the gene showed lower expression of Tumor necrosis factor-alpha mRNA. The investigators concluded that increased IL-10 expression significantly reduced sepsis-induced Multiple organ injury.R-02
Sepsis
Sepsis is a serious medical condition characterized by a whole-body inflammatory state (called a systemic inflammatory response syndrome or SIRS) and the presence of a known or suspected infection. The body may develop this inflammatory response to microbes in the blood, urine, lungs, skin, or other tissues. An incorrect layman’s term for sepsis is blood poisoning, more aptly applied to Septicemia, below.R-03,R-06

Sepsis. Defined as SIRS in response to a confirmed infectious process. Infection can be suspected or proven (by culture, stain, or polymerase chain reaction (PCR)), or a clinical syndrome pathognomonic for infection. Specific evidence for infection includes WBCs in normally sterile fluid (such as urine or cerebrospinal fluid (CSF), evidence of a perforated viscus (free air on abdominal x-ray or CT scan, signs of acute peritonitis), abnormal chest x-ray (CXR) consistent with pneumonia (with focal opacification), or petechiae, purpura, or purpura fulminans.R-06
Severe sepsis
Defined as sepsis with organ dysfunction, hypoperfusion, or hypotension.
Septic shock. Defined as sepsis with refractory arterial hypotension or hypoperfusion abnormalities in spite of adequate fluid resuscitation. Signs of systemic hypoperfusion may be either end-organ dysfunction or serum lactate greater than 4 mmol/dL. Other signs include oliguria and altered mental status. Patients are defined as having septic shock if they have sepsis plus hypotension after aggressive fluid resuscitation (typically
upwards of 6 liters or 40 ml/kg of crystalloid).R-08,R-06

Septic shock is a serious condition that occurs when an overwhelming infection leads to life-threatening low blood pressure.R-08
See also
Acute respiratory distress syndrome
Disseminated intravascular coagulation
Meningococcemia
Waterhouse-Friderichsen syndrome
causes
Septic shock occurs most often in the very old and the very young. It also occurs in people who have other illnesses.
Any type of bacteria can cause septic shock. Fungi and (rarely) viruses may also cause the condition. Toxins released by the bacteria or fungi may cause tissue damage, and may lead to low blood pressure and poor organ function. Some researchers think that blood clots in small arteries cause the lack of blood flow and poor organ function.
The body also produces a strong inflammatory response to the toxins. This inflammation may contribute to organ damage.
Risk factors for septic shock include:
Diabetes
Diseases of the genitourinary system, biliary system, or intestinal system
Diseases that weaken the immune system such as AIDS
Indwelling catheters (those that remain in place for extended periods, especially intravenous lines and urinary catheters)
Leukemia
Long-term use of antibiotics
Lymphoma
Recent infection
Recent surgery or medical procedure
Recent use of steroid medicines
symptoms
Septic shock can affect any part of the body, including the heart, brain, kidneys, liver, and intestines. Symptoms may include:
Cool, pale extremities
High or very low temperature, chills
Lightheadedness
Low blood pressure, especially when standing
Low urine output
Palpitations
Rapid heart rate
Restlessness, agitation, lethargy, or confusion
Shortness of breathR-05
causes
Sepsis is caused by a bacte infection that can begin anywhere in the body. Common places where an infection might start include:
The bowel (usually seen with peritonitis)
The kidneys (upper urinary tract infection) The liver or the gall bladder
The lungs (bacterial pneumonia)
The skin (cellulitis)
Sepsis may also accompany meningitis. In children, sepsis may accompany infection of the bone (osteomyelitis). In hospitalized patients, common sites of infection include intravenous lines, surgical wounds, surgical drains, and sites of skin breakdown known as bedsores (decubitus ulcers).
The infection is often confirmed by a blood test. But, a blood test may not reveal infection in people who have been receiving antibiotics.
In sepsis, blood pressure drops, resulting in shock. Major organs and systems, including the kidneys, liver, lungs, and central nervous system, stop functioning normally.
A change in mental status and hyperventilation may be the earliest signs of sepsis coming on.
Sepsis is often life-threatening, especially in people with a weakened immune system or with other illness.R-06
Signs and symptoms
In addition to symptoms related to the provoking infection, sepsis is characterized by evidence of acute inflammation present throughout the entire body, and is, therefore, frequently associated with fever and elevated white blood cell count (leukocytosis) or low white blood cell count and lower-than-average temperature. The modern concept of sepsis is that the host’s immune response to the infection causes most of the symptoms of sepsis, resulting in hemodynamic consequences and damage to organs. This host response has been termed systemic inflammatory response syndrome (SIRS) and is characterized by hemodynamic compromise and resultant metabolic derangement. Outward physical symptoms of this response frequently include a high heart rate (above 90 beats per minute), high respiratory rate (above 20 breaths per minute), elevated WBC count (above 12,000) and elevated or lowered body temperature (under 36 °C or over 38 °C). Sepsis is differentiated from SIRS by the presence of a known pathogen. For example SIRS and a positive blood culture for a pathogen indicates the presence of sepsis. Without a known infection you can not classify the above symptoms as sepsis, only SIRS.
This immunological response causes widespread activation of acute-phase proteins, affecting the complement system and the coagulation pathways, which then cause damage to the vasculature as well as to the organs. Various neuroendocrine counter-regulatory systems are then activated as well, often compounding the problem. Even with immediate and aggressive treatment, this may progress to multiple organ dysfunction syndrome and eventually death.R-03
Exams and tests
The following may indicate sepsis:
Blood culture that reveals bacteria
Blood gases that reveal acidosis
Kidney function tests that are abnormal (early in the course of disease)
Platelet count that is lower than normal
White blood cell count that is lower or higher than normal
This disease may also change the normal results of the following tests:
Blood differential — showing immature white blood cells
Fibrin degradation products — often higher than normal, a condition that may be associated with a tendency to bleed
Peripheral smear — may show a low platelet count and destruction of red blood cells.R-03
Treatment
People with sepsis usually need to be in an intensive care unit (ICU). As soon as sepsis is suspected, “broad spectrum” (able to destroy a wide array of bacteria) intravenous (directly in the vein) antibiotic therapy is begun.
The number of antibiotics may be decreased when blood tests reveal which particular bacteria are causing the infection. The source of the infection should be discovered, if possible. This could mean more testing. Infected intravenous lines or surgical drains should be removed, and any abscesses should be surgically drained.
Oxygen, intravenous fluids, and medications that increase blood pressure may be needed. Dialysis may be necessary if there is kidney failure, and a breathing machine (mechanical ventilation) if there is respiratory failure. R-06

Introduction
The precise a etiology of SIRS is not yet defined, but one likely factor is splanchnic hypoperfusion, resulting in gut ischemia with mucosal permeability and translocation.The subsequent release of inflammatory mediators including cytokines [eg;interleuking-1 TNE] from hepatic kuffer cell and other machrophages or circulating Monocytes initiates a sequence of events culminating acutely in the clinical signs of sepsis or septic shock and thereafter in MOF factors implicated in the pathogenesis of MOF include inadequate tissue oxgen delivery. Sequestration of neutrophils damage to vascular endothelium and release of vasoactive Substance [eg; NO, endothelin, prostacyclin, thrombaxane] with resultant loss of microvascular regulation, cellular dysfunction also results with failure of oxygen Utilization.
Prevention is the key to success. Once failure is estabilished treatment is less and less value as the failure increases in severity. Early and successful intervention to eliminate the initiating cause followed by attention to every detail with obsessional avoidance of infection. Provides the best hope of recovery success is a team effort by the all the therapies.

Path physiology
The physiologic response to infection includes the activation of host defense mechanisms that result in the influx of activated neutrophils and monocytes, the release of inflammatory mediators, local vasodilation and increased endothelial permeability, and activation of coagulation pathways. Sepsis is characterized by a similar response to infection, although on a systemic level, resulting in diffuse endothelial dysfunction. In the case of bacterial infection, the inciting event is the interaction with the host immune cells of endotoxins contained within the bacterial cell wall of gram-negative organisms. In gram-positive organisms, this interaction occurs with either cell wall components or exotoxins released by the organism.
As a result of these interactions, cellular activation occurs with the release of cytokine and noncytokine mediators, the most notorious of which are tumor necrosis factor-alpha (TNF-alpha), interleukin 1 (IL-1), and interleukin 6 (IL-6). These factors are implicated in the diffuse activation of a systemic inflammatory response. As a result, mediators with vasodilatory and endotoxic properties are released systemically, including prostaglandins, thromboxane A2, and nitric oxide. This results in vasodilation and endothelial damage, which leads to hypoperfusion and capillary leak. In addition, cytokines activate the coagulation pathway, resulting in capillary microthrombi and end-organ ischemia.6,7

The following systems and mediators are stimulated in septic shock:
• Arachidonic acid metabolites (eg, leukotrienes, prostaglandins, thromboxanes)
• The complement system
• IL-1 and IL-6
• TNF-alpha
• The coagulation cascade
• The fibrinolytic system
• Catecholamines
• Glucocorticoids
• Prekallikrein
• Bradykinin
• Histamines
• Beta-endorphins
• Enkephalins
• Adrenocorticoid hormone
• Circulating myocardial depressant factor(s)
The complex interplay of inflammatory cells and mediators leads to dysfunction of capillary endothelium those results in vasodilation and capillary leak. This further initiates a cascade of endothelial injury, global tissue hypoxia, microthrombus formation, abnormal oxygen utilization due to mitochondrial dysfunction, all which leads to organ dysfunction and eventual failure.
The insidious nature of sepsis is that microcirculatory dysfunction can occur while global hemodynamic parameters such as blood pressure may remain normal.

Causes
The differential diagnosis of SIRS is broad and includes infectious and noninfectious conditions, surgical procedures, trauma, and medications and therapies.
• The following is partial list of the infectious causes of SIRS:
o Bacterial sepsis
o Burn wound infections
o Candidiasis
o Cellulitis
o Cholecystitis
o Community-acquired pneumonia
o Diabetic foot infection
o Erysipelas
o Infective endocarditis
o Influenza
o Intraabdominal infections (eg, diverticulitis, appendicitis)
o Gas gangrene
o Meningitis
o Nosocomial pneumonia
o Pseudomembranous colitis
o Pyelonephritis
o Septic arthritis
o Toxic shock syndrome
o Urinary tract infections (both male and female)
o The following is a partial list of the noninfectious causes of SIRS:
o Acute mesenteric ischemia
o Autoimmune disorders
o Burns
o Chemical aspiration
o Cirrhosis
o Dehydration
o Drug reaction
o Electrical injuries
o Erythema multiforme
o Hemorrhagic shock
o Intestinal perforation
o Medication side effect (eg, theophylline)
o Myocardial infarction
o Pancreatitis
o Substance abuse (stimulants such as cocaine and amphetamines)
o Surgical procedures
o Toxic epidermal necrolysis
o Transfusion reactions
o Upper gastrointestinal bleeding
o Vasculitis

SIRS
SIRS variety of severe clinical insulls. The response is manifested by
Or more of the following.
T>38oc or <36oc
HR>90bpm
Respiratory rate >20 breath/min or PaCO2<43Kpa
WBC count >12\/109 /h or 4\/109 /h or >10h
Immature forms.
The cause of SIRS in any postoperative patient should be sought.To ignore the signs or
their progression may lead to sepsis . Which is defined as SIRS with a proven infective
source sepsis inturn may lead to multiple organ dysfunction[MOD]or severe sepsis
[sepsis syndrome] characterized by failure of;

*Cerebrovascular system
-systemic vascular resistance [<800dyne/s/cm3]
-Lactate[>1.2mmol/1]
*Respiratory system
-PaO2/fiO2<30Kpa
-PaO2<9.3Kpa
-Acute respiratory distress syndromes [ARDS] with increasing positive end
expiratory pressure [PEEP] on ventilation.
*Renal function
-urine output<120ml/4h period
-rising urea and creatine
*Gstrointestinal system
-stress ulcers
-Ileus
*Hepatic function
-increase bilirubin and enzymes decrease albumin
*Haematological functions
-decrease platelets increase D-dimer& prothrombin time[PT]
-bleeding intravascular coagulation.
*Neurological function
-decrease Glasgow coma scale.

Classification
SIRS is one of several conditions related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of cytokine storm, in which there is abnormal regulation of various cytokines.[citation needed] SIRS is also closely related to sepsis, in which patients satisfy criteria for SIRS and have a suspected or proven infection
Sepsis
Sepsis is a life-threatening illness. Your body's response to a bacterial infection usually causes it. Your immune system goes into overdrive, overwhelming normal processes in your blood. The result is that small blood clots form, blocking blood flow to vital organs. This can lead to organ failure. Babies, old people and those with weakened immune systems are most likely to get sepsis. But even healthy people can become deathly ill from it. A quick diagnosis can be crucial, because one third of people who get sepsis die from it.
Sepsis is usually treated in a hospital intensive care unit (ICU). IV antibiotics and fluids may be given to try to knock out the infection and to keep blood pressure from dropping too low. Patients may also need respirators to help them breathe

Septic shock
In this condition bacterial toxins cause vasodilation ,In addition sepsis depresses the Myocardium and increase capillary permeability .so that plasma leaks into the tissues and blood volume falls, consequently septic shock is cardiogenic and hypovolemic as well as distributive. In febrile patients ,shock is likely top be more severe because the cutaneous blood Vessels are often dilated increasing the disparity between the capacity of the vascular System and the available circulating blood volume.
The gram-negative bacteria that often cause septic shock release endotoxin the cell Wall lipopolysaccharide of the organism.It causes macrophages to produce increased Amount of cachetin a polypeptide that inhibits lipoprotein lipase and his other effects .which make shock warse,which helps protect animals from endotoxin, shock, inhibits. The translation of cachectin mRNA in macrophages.Antibodies against endotoxin producing bacteria reduce the mortality rate in septic Shock.endotoxin causes release of IL-1 and other cytokines and an antibody against The IL-1 receptor has also been reported to beneficial in treating septic shock in experimental animals.
Refractory shock
Shock unresponsive to conventional therapy [intravenous fluid and inotropic/vasoactive agents ]within 1 hours.

The SIRS Criteria
Temperature < 36° C or > 38° C
Heart Rate > 90 bpm
Respiratory Rate > 20 breaths/min
or PaCO2 < 32 mmHg
White Blood Cell Count > 12,000 or < 4,000 cells/mm3
or > 10% bands

Initial assessment and management
Initial management of a critically ill patient includes:
• Immediate assessment of the airway, breathing and circulation
• A brief history
• A limited examination of the relevant systems of the body.
• A secondary assessment after stabilisation of the patient including a more thorough history, detailed examination by system and appropriate investigations.
Initial Management
Airway and breathing. Respiratory failure is common and may develop at any stage so repeated assessments are necessary. A depressed conscious level is the most common cause of airway obstruction. Patients with inadequate airway reflexes should be nursed in the recovery position and if possible intubated and mechanically ventilated.
A clear airway does not indicate effective breathing. Failure of gas exchange may be caused by lung parenchymal problems (pneumonia, lung collapse, pulmonary oedema), failure of the mechanics of ventilation (pneumothorax, haemothorax, airway rupture) or reduced respiratory drive (encephalopathy).
Respiratory failure is suggested by signs of respiratory distress including dyspnoea, increased respiratory rate, use of accessory muscles, cyanosis, confusion, tachycardia, sweating. The diagnosis is made clinically but may be confirmed by pulse oximetry and arterial blood gases. Patients with a depressed conscious level may not react normally to hypoxia and signs of respiratory failure may be difficult to detect. Patients with inadequate ventilation, gas exchange or both require ventilatory support. This usually necessitates intubation and mechanical ventilation although in some patient’s gas exchange and oxygenation can be improved by the application of continuous positive airway pressure (CPAP) by face mask or non-invasive ventilation

Treatment
Selenium, glutamine, and eicosapentaenoic acid have shown effectiveness in improving symptoms in clinical trials.[9] Other antioxidants such as vitamin E may be helpful as well.[10]

Introduction
The antidiuretic hormone of humans is arginine vasopressin, a nonapeptide, the gene for which located on chromosome 20.1 Arginine vasopressin is synthesized from a large precursor molecule (a single peptide which contain 145 amino acid) in the supraoptic and paraventricular nuclei of the hypothalamus, transported in neurosecretory granules to posterior pituitary, median eminence of hypothalamus and to a lesser extent to other areas of the brain and brainstem. It is secreted from the posterior pituitary into the systemic circulation to influence renal function, and into hypothalamopituitary portal circulation to enhance pituitary ACTH secretion. Molecular weight of vasopressin is about 1087Da. It is important mainly for its action on kidney, but it is also a powerful vasoconstrictor. Vasopressin causes generalized vasoconstriction ,including the coeliac,mesenteric and coronary vessels.9 The effects are initiated by two distinct types of receptors termed v1 and v2. A deficiency of this hormone is results in diabetes insipidus.2
Structure
Vasopressin is a nonapeptide with a six amino acids ring and a three amino acid side chain.2 The residue at position 8 is arginine in humans and in most other mammals except pigs and related species, whose vasopressin contains lysine at position 8.
Formation and release
There is no certainity as to the exact site of vasopressin synthesis.3 Resent evidence suggest that vasopressin is synthesized as part of a large protein chain, presumably in the cell bodies. The initial product contains vasopressin in an inactive form which is subsequently transformed in to active vasopressin. This second step may occur during transport of secretary product down the axons in to the neural lobe. Although it is not certain that vasopressin cannot be synthesized in the axons as well as cell bodies, the neural lobe isolated from hypothalamus cannot manufacture antidiuretic hormone. Whether the hypothalamic nuclei are the only sites of synthesis or not, their integrity is essential for production of the active peptides.
Vasopressin receptors
Three subtypes of vasopressin receptors have been identified.2 v1a receptors mediate the vasoconstrictor action of vasopressin.v1b receptors potentiate the release of ACTH by pituitary corticotropes, and v2 receptors mediate antidiuretic action.v1a effects are mediated by activation of phospholipase C,formation of inositol triphosphate and increased intracellular calcium concentration.v2 effects are mediated by activation of adenylyl cyclase.
Absorption, metabolism and excretion
Vasopressin is administrated by intravenous, intramuscular, or intranasal routes; oral absorption is slight.2 The half life of circulating ADH is approximately 20 minutes, with renal and hepatic catabolism via reduction of the disulfide bond and peptide cleavage. A small amount of vasopressin is excreted as such in the urine.
Osmoregulation of vasopressin secretion
Vasopressin plays a central role in osmoregulation because its release is directly affected by plasma osmolality8
At a plasma osmolality of less that 275 osm / kg which usually represents a plasma Na+ concentration less than 135-137 mmol / l there is essentially no circulating vasopressin vasopressin. As the plasma osmolality rises above this threshold however the secretion of ADH increase progressively .
Hemodynamic control of vasopressin secretion10
A decrease in blood volume or pressure also stimulates ADH secretion. The receptors activated by this response are located in both the low pressure ( left atrium and pulmonary vessels ) and the high pressure ( aortic arch and carotid sinus ) sides of the circulatory system .These receptors respond to stretch and are termed baroreceptors. The sensitivity of the barorecepter system is less than that of the osmoreceptors ; a 5% to 10% decrease in blood volume or pressure is required to stimulate ADH secretions.
Summary of stimuli affecting vasopressin secretion.7
Vasopressin Secretion Increased Vasopressin Secretion Decreased
Increased effective osmotic pressure of plasma Decreased effective osmotic pressure of plasma
Decreased extracellular fluid volume Increased extracellular fluid volume
Pain , emotion , “stress”, exercise Alcohol
Nausea and vomiting
Standing
Clofibrate carbamazepine
Angiotensin 11

ADH actions on the kidney
ADH has two primary action on kidneys. It stimulates NaCl reabsorption by the thick ascending limb of Henle’s loop, and it increases the permeability of collecting duct to water and urea.(the effects on urea is limited to the portion of the collecting duct located in the inner medulla).
The cellular events associated with ADH stimulated transport by the thick ascending limb have not been completely elucidated. However it is known that net reabsorption of NaCl is increased as a result of the enhanced activity of the 1Na+,2Cl-,1K+ symporter located in the apical membrane of cell.
ADH increases permeability of the collecting duct to water. ADH binds to a receptor on the basolateral membrane of the cell. Binding to this receptor, which is coupled to adenylyl cyclase, increases the intracellular levels of cyclic adenosine monophosphate (cAMP). The rise in intracellular cAMP activates one more protein kinases; activation in turn results in the insertion of vesicles containing water channels into the apical membrane. These water channels are performing and reside in vesicles located beneath the apical membrane of the cell. With the removal of ADH these water channels are reinternalized into the cell, and the apical membrane once again becomes impermeable to water. This shuttling of water channels into and out of apical membrane provides a rapid mechanism for controlling membrane permeability to water. The basolateral membrane is freely permeable to water. Thus any water that enters the cell through the apical membrane water channels exits across the basolateral membrane. These process results in the net reabsorption of water from the tubule fluid into the peritubular capillaries
Pharmacologic actions of the vasopressin
Antidiuretic action:
Very small amounts of vasopressin injected during water diuresis cause an abrupt fall in urine flow.3 Free water excretion is inhibited specifically. Glomerular filtration rate, renal plasma flow, and rate of solute excretion do not change. If antidiuresis is marked, urinary osmolar concentration rises well above that of plasma. In some animals vasopressin increases sodium excretion. This does not occur in man. Antidiuresis is usually brief, lasting ½ to 2 hr depending on dose and route of administration.
Antidiuresis can be prolonged by repeated injections or intramuscular administration of a slowly absorbed vasopressin preparation. Such chronic antidiuresis is relatively harmless unless water intake significantly exceeds water loss. Rapid overhydration can precipitate fetal water . intoxfication. Less severe hydration leads to fall in plasma sodium concentration greater than that possibly due to dilution alone. Sodium chloride excreted despite the presence of hyponatremia. Water ingestion in the presence of sustained antidiuresis expands body fluid volumes. This expantion appears to stimulate receptors that cause an increase in sodium excretion. This, in turn, intensifies the hyponatrimia. The vicious circle of hyperhydration and natriuresis can be broken by limiting water intake. If dietary sodium is adequate, the plasma sodium concentration then returns to normal.
Cardiovascular actions:
Anidiuretic doses of vasopressin have no discernible cardiovascular effects. Higher doses injected into men or animal may not raise systemic arteria pressure although the heart rate and cardiac output fall and the skin and mucous membrane become pale. Such doses can produce a systemic vasopressor response if compensatory reflexes are inhibited by deep anesthesia or by ganglionic or adrenergic blocking drugs. Even then, vasopressor responces require doses 10 to 100 times those that produce maximal antidiuresis. This indicate that direct vasopressor effects probably have little physiologic meaning under most circumstances. Conditions such as extreme hemorrhage, however, release amounts of vasopressin that are large enough to exert vasoconstrictor effects. Clear evidence, however, that vasopressin contributes to the ability of animals to survive hemorrhage is lacking. Small amounts of vasopressin that do not raise blood pressure can, however, increase the reactivity of blood vessels to the constrictor actions of catecholamines. Such an action may contribute to circulatory regulation under physiologic conditions. Subjects with diabetes insipidus regulate their blood pressure adequately. Therefore, if vasopressin participates in cardiovascular regulation, its contribution cannot be considered essential.
Vasopressin appears to act primarily on arterioles and capillaries. The splanchnic and skin circulations appear more responsive than that of limb muscles. The coronary circulation also decreased, and large doses of vasopressin can contributes to fatal myocardial ischemia.
Other actions:
Vasopressin have intrinsic oxytocic activity. The nonpregnant human uterus is more responsive to vasopressin than to oxytocin. Large doses of either hormone are needed to cause contraction. Uterine sensitivity to oxytocin increases tremendously during pregnancy while vasopressin remains relatively ineffective. Sufficient doses of vasopressin can, however, produce tonic uterine contractions that could be deleterious to the fetus.
Vasopressins have considerable milk ejection activity. This is probably of little physiologic importance during lactation since much more oxitocin than vasopressin is released by milk ejection reflex. Vasopressin in very large doses may also stimulate motility of large bowel.
Resent experiments on animals and trials in patients with impaired memory arising from various causes have shown that ADH plays an important role in learning and memory, producing improvement in concentration, retention and recall.4 In addition, ADH influences pain sensitivity and the quality of sleep; it may be involved in disorders of human behavior
Preparations used and pharmacokinetic aspects
Various analogues of vasopressin have been developed for clinical use, the aims being to increase the duration of action and to shift the potency between v1 and v2 receptors.5
The main analogues are ,
• Vasopressin (ADH) itself, the prototype
This has short duration of action, weak selectivity for v2 receptors and is usually given by subcutaneous or intramuscular injection, or by intravenous infusion. It has 0.8 times the diuretic action of ADH and 60% of its vasopressor potency.
• Desmopressin(1-deamino-DArg8-vasopressin)
This has increased duration of action, is v2 selective and is usually given as a nasal spray. It has 12 times the antidiuretic action of ADH and 0.4%of its vasopressor potency.
• Lypressin(Lys8-vasopressin)
This is similar in potency to vasopressin, but given as a nasal spray.
• Terlipressin(triglyceryl-Lys8-vasopressin)
This has increased duration of action, is v1 selective and is given intravenously. It has low but protracted vasopressor action and minimal antidiuretic properties.
• Felypressin(phe2-Lys8-vasopressin)
This has a short duration of action and is v1 selective. Its vasoconstriction effects is used with local anesthetics to prolong their action.

Vasopressin and lypressin are rapidly eliminated, both having plasma half life of 10 mins and a short duration of action. Metabolism is by tissue peptidases and 33% of vasopressin is removed by kidney.
Desmopressin is less subject to degradation by peptidases and its plasma half life is 75 mins.
Various synthetic peptide and non-peptide agonists and antagonists of vasopressin have been synthesized and are used as experimental tools.
Pharmacodynamics
Vasopressin interacts with two types of receptors. V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction.2 V2 receptors are found on the renal tubular cells and mediate antidiuresis through increase water permeability and water resorption in the collecting tubules. External V2 like receptors mediate release of coagulation factor VIII and von Willebrand factor. Desmopressin acetate (DDAVP, 1-desamino-8-D-arginine vasopressin) is a long-acting synthetic analog of vasopressin with minimal V1 activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin.
Standardization and preparations
Vasopressin preparations are assayed by intravenous injection into anesthetized rats pretreated with an adrenergic blocking drug.3 Vasopressor responses are matched repeatedly against responses to a reference powder.
Preparations:
 Posterior pituitary injection U.S.P, B.P. (Pituitrin)
A sterile solution of an extract of whole posterior pituitaries from domestic animals used for food by men. This may contain either arginie vasopressin or lysine vasopressin, as well as oxytocin. It is standardized by fowl vasodepressor assay which primarily measures oxytocin content. The amount of vasopressor and antidiuretic activities of such solutions may vary widely. The solution contains 10 U.S.P posterior pituitary (fowl vasodepressor) units per milliliter.
 Vasopressin injection U.S.P., B.P. (Pitressin)
This is partially purified natural or synthetic vasopressin in solution. It contains 20 U.S.P.vasopressor units per milliliter. This solution may contain either vasopressin or both, depending upon the source.
 Vasopressin tannate injection (Pitressin tanate in oil)
This water insoluble tannate of vasopressin is available as asuspension in oil containing 5 pressor units per milliliter.
Disorders of arginine vasopressin secretion
Diabetes insipidus:
Polyuria with dilute urine may result from vasopressin deficiency(cranial diabetes insipidus,DI), resistance to the actions of arginine vasopressin(nephrogenic DI), and excessive fluid drinking (primary polydipsia).
• Cranial diabetes insipidus:
Simple destruction or removal of the posterior pituitary gland, or damage to distal part of the pituitary stalk, usually results in temporary diabetes insipidus. Upper stalk, median eminence, or more extreme hypothalamic damage results in permanent diabetes insipidus. An individual deficient in arginine vasopressin will pass approximately 40ml/kg of urine in 24 h (between 3 and20 liters), leading to the clinical features of polyuria, polydipsia, nocturia, and in children nocturnal enuresis. In the complete absence of arginine vasopressin the maximally dilute urine has an osmolality of approximately 50 mOsmol/kg.
• Nephrogenic diabetes insipidus:
Nephrogenic diabetes insipidus has diverse causes. Congenital Nephrogenic DI typically presents with profound polyuria and hypernatraemia from birth. The X-linked condition is associated with mutations of the V2 receptor, whilst in autosomal recessive disease there’s a deficiency of aquaporin.
• Syndrome of inappropriate antidiuresis (SIADH)
Excessive and inappropriate secretion of vasopressin either from the posterior pituitary or from ectopic sources, such as small-cell lung cancer, results in inappropriately concentrated urine, dilute plasma, and hyponatraemia with continuing renal sodium excretion.

Excessive ADH secretion:
Excessive secretion of ADH occurs in some intracerebral disorders, notably tuberculosis meningitis, and in some cases of lung cancer (oat cell carcinoma of bronchus) in which the tumor itself produces large quantities of hormone.4 Limitation of fluid intake helps to control the resultant dilutional hyponatraemia, and treatment with a mineralocorticoid may be necessary to promote sodium retention.
The ADH analogue in which the C-terminal glycinamide is replaced by glycine is called vasopressionic acid: it inhibits the action of ADH on kidney tubules. Drugs of this type may be of use in the treatment of excessive secretion of ADH
Drug effects of antidiuretic hormone release
Release of antidiuretic hormone is influenced by variety of drugs.6 The existence of a cholinergic mechanism for this process has been suggested on the basis of experiments showing that injections of acetylcholine or diisopropyl fluorophosphates into the supraoptic nuclei caused release of antidiuretic hormone. Nicotine has been shown to inhibit water diuresis in humans, probably through the release of antidiuretic hormone. Alcohol inhibits release of antidiuretic hormone in response to dehydration and produces inappropriate water diuresis in a dehydrated individual. Alcohol does not block the action of nicotine on the release of hormone.
Antidiuresis that occurs during general anesthesia and following the injection of histamine, morphine, and barbiturates (but not thiopental) has also been attributed release of antidiuretic hormone. Since muscular exercise, pain, and emotional excitement also cause inhibition of water diuresis,it is likely that some central control mechanism of antidiuretic hormone release is very susceptible to neural or neurohumoral influences. Of the large variety of drugs that can influence antidiuretic hormone release, many are known to alter neural activity or to act as stressful stimuli.
Certain hyponatremic syndromes are associated with “inappropriate” secretion of the antidiuretic hormone. They are characterized by primary water retention unassociated with sodium retention and edema. Some of the underlying diseases are bronchogenic carcinoma, head injury, and tuberculosis meningitis.
Toxicity
Water intoxification can occur in individuals receiving vasopressin injections if water intake is excessive.3
Chronic overhydration can produce significant hyponatremia. If water intake is properly limited there is no danger involved in the use of antidiuretic doses of the vasopressin to control diabetes insipidus. Natural vasopressin preparations contain inactive contaminants that can provoke local or generalized allergic responces in some patients. These complications can be avoided by using synthetic lysine vasopressin.
Large doses of vasopressin cause pallor, hypertension, nausea, vomiting, abdominal cramps and diarrhea. There is a serious danger of coronary constriction. Those of vasopressin in large doses should be rigorously avoided, particularly in patients with coronary atherosclerosis or hypertension.
Therapeutic and diagnostic uses
1. As a drug for cranial diabetes insipidus.
Diabetes insipidus remains the only clear indication for the therapeutic use of antidiuretic hormones.3Very small doses can control polyuria and polydipsia in diabetes insipidus due to neurohypophysial insufficiency. This is treated with vasopressin/desmopressin/lypressin(short term)4 or related synthetic drug, Desmopressin.5 (long term)4 These replace naturally produced ADH and may be given by a injection or in the form of a nasal spray. The antidiuretic action of subcutaneous vasopressin is fleeting, and injections must be repeated at frequent intervals to control urine flow in diabetes insipidus. Vasopressin tannate suspended in oil is absorbed very slowly. Intramuscular injection of 2 to 5 units every 2 or 3 days may provide satisfactory control. Vasopressin solutions may also be administrated intranasally. Synthetic lysine vasopressin is a strong solution can be used as a nasal spray. This offers patients with diabetes insipidus a relatively easy method of self-medication that can be used repeatedly as needed to inhibit polyuria. Doses required are 4 to 10 times greater than those that are effective subcutaneously.
Dosages:
1. Demopressin, 10-20 micrograms bad. intranasally (100 microgram/ml solution);in short term treatment ,desmopressin can be given i.m.(1-2 microgrames o.d.)4
11. Lypressin,2.5-10 i.u. 3-7 times a day intranasally (rarely used)
111. Vasopressin,5-20i.u. s.c.or i.m. at twice daily. Rarely used.

2. To arrest bleeding from esophageal varices.
Vasopressin causes generalized vasoconstriction including the celiac, mesenteric and coronary vessels.5Because of this it is some times use to treat esophageal varices and portal hypertension before more definitive treatment.
Dosages:
Vasopressin is given either single doses (20 i.u.in 100ml of 5per cent dextrose infused over 20 min) or by continuous i.v. infusion (0.4 i.u./ min for 24 h)4
Terlipressin,2 mg initially i.v.followed by 1-2mg 4-to 6-hourly for up to 72 h.

3. With local anesthetics, to delay their absorption and thus potentiate their effects (felypressin).
Dosages:
Prilocaine 3 per cent is formulated with felypressin 0.03 i.u./ml;the maximum dose is 20ml

Synthetic 2-(phenylalanine)-8-lysine vasopressin (octapressin) has been introduced in Europe as a local vasoconstrictor used either alone for hemostasis or in combination with local anesthetics to retard absorption.3 It is about as effective as epinephrine for these purposes. One potential advantage is that it does not appear to precipitate cardiac arrhythmias as epinephrine may when used in large quantities, particularly in anesthetized patients. 2-(phenylalanine)-8-lysine vasopressin does constrict the coronaries of dogs. It’s effects on coronaries is quantitatively comparable to that of lysine vasopressin, unit for unit. The risk of myocardial ischemia following the use of this peptide ,particularly if inadvertently given intravenously, should be considered. Systemic side effects, including pallor, hypertension, intestinal cramps, nausea, and vomiting may occur following use of 2-phenylalanine lysine vasopressin as a local vasoconstrictor. This could be recommend it over lysine vasopressin for local infiltration, since better vasoconstriction should be possible at lower doses. The relative potency of these analogues in constricting the coronary circulation of man, however, is unknown. This advantage may thus be illusory. The fact that it much less anidiuretic to man has little relevance to its use in surgery.

Vasopressin may be used as diagnostic agents. The antidiuretic response is, of course, one of the key points in differentiating neurohypophysial diabetes insipidus from polyuria of renal origin. Large doses of vasopressin have also been used to test the concentrating ability of kidney. Such use does not justify the risk of precipitating coronary constriction.

Important adverse effects
Adverse effects are few with low dosages and are limited to nausea and occasionally abdominal cramps.
The nasal formulations can cause nasal congestion and ulceration.
In the i.v. doses in which vasopressin is used to stop bleeding from esophageal varices,adverse effects are common and consist of abdominal and uterine cramps and the urgent need to defecate.
Because it can cause coronary spasm, vasopressin should not be used in patients with a history of coronary artery disease.
Care should be taken in patients with a history of hypertension.
Hypersensitivity reactions can occur occasionally.