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.

Introduction.
In mammals the respiratory organ is the lung which is situated on either side of the thoracic cavity flanking the heart4. In air breathing vertebrates the lung is either of the two primary respiratory organs into which the atmospheric air is entered when the pressure inside the thoracic cavity becomes negative. Once the exchange of gases took place, the rest of the air is forced out to the atmosphere by generating a positive pressure in side the thoracic cavity there by squeezing the lung tissues.
The principal function of the lung is to transport oxygen from the atmosphere into the bloodstream and to excrete carbon dioxide from the bloodstream into the atmospheric air4. This nature of exchange of oxygen and carbon dioxide is very essential for the existence of life. The oxygen taken in from the atmosphere into the bloodstream powers the production of chemical energy in the form of ATP via what is called an aerobic respiration and the carbon dioxide a by-product of the energy producing mechanism (metabolism) is removed from the system as carbon dioxide is toxic to cells and tissues at high concentrations.
Even though the main functions of the lungs are respiratory functions, it also plays several important non-respiratory functions as well. Some of these non-respiratory functions include, serving as a physical layer of soft, shock-absorbent protecting function to the heart; removing fat from the bloodstream and storing it, storing and metabolizing of glycogen and also filtering out small blood clots formed in the venous system of the body etc.

Overall, the lung reflects not only the principles of give and receive (the movement of gases between the organism and the environment), but also the interconnectedness of the parts of the body4. The lung provides a function directed toward the preservation and development of the entire body; in turn, the body as a whole, and its parts, provides for the betterment of the lung, including supplying nutrients, removal of wastes from the cells, and so forth.
The evolution of lungs played a crucial role in the development of complex organisms. In single-celled organisms including bacteria etc, exchange of gases from the environment it lives take place entirely by the process of simple diffusion. However in larger organisms, only a small proportion of cells are close enough to the surface for oxygen from the atmospheric air to enter into the organism – through diffusion. Thus, two major adaptations are seen in such organisms to attain great multicellularity. One such adaptation is to have an efficient circulatory system that conveys gases to and from the deepest tissues in the body, The second type of adaptation is to have a large, internalized respiratory system that centralizes the task of obtaining oxygen from the atmosphere and bringing it into the body, where it could rapidly be distributed to any part of the circulatory system.

Overview.
Most lungs have a complex, honeycomb like structure in appearance designed to maximize the surface area for exchange of gases. In addition, lungs are spongy and also moist, which prevents them from drying out. This feature of the lung (sponginess and the moisture) also makes the environment hospitable to the bacteria associated with many respiratory illnesses4.
Though certain basic features are similar and shared, the respiratory mechanisms and the anatomy of the lungs are adapted to the particular needs of the organism. Air enters through the trachea, (a cartilaginous tube like structure commonly referred to as the windpipe,) and subdivides into smaller airways called bronchi. In most air-breathing vertebrates, the bronchi further subdivide into finer pathways of branching airways, until they culminate in specialized cells that form millions of tiny, exceptionally thin-walled air sacs called alveoli, where exchange of gas take place.

Picture -2. Lungs dissected to show the Bronchial tree

Air enters and leaves the lungs via a conduit of cartilaginous passageways called the bronchi and bronchioles. In the image above, lung tissue has been dissected away to reveal the bronchioles.
Although the details of respiration differ depending on organism some of the basic mechanisms seem shared:
• The atmospheric air is brought into the animal via the airways; this pathway often consists of the nose, pharynx, larynx, trachea, and bronchi.
• The drawing and expulsion of air (called ventilation) is driven by muscular action which involved muscular tissues of the thorax and some abdominal muscles.
• The volume of the thoracic cavity is increased by relaxing the chest muscle and the Diaphragm (there by creating a negative pressure in the thoracic cavity) and vice – versa by muscular contractions.
Anatomy
The lungs of mammals have a spongy texture and are honeycombed with epithelium (a thin layer of tightly packed cells), a structure that maximizes the surface area for gas exchange.

A schematic depicting the bronchi, bronchial tree, and lungs.
Mammalian lungs are located in two cavities on either side of the heart. Though similar in appearance, the two lungs are not identical to each other.. Both are separated into lobes, with three lobes on the right and two on the left. The lobes are further divided into lobules, hexagonal divisions that are the smallest subdivision visible to the naked eye.
Two main bronchi (produced by the bifurcation of the trachea) enter the roots of the lungs. The bronchi continue to divide within the lung, and after multiple divisions, give rise to bronchioles. The bronchial tree continues branching until it reaches the level of terminal bronchioles, which lead to alveolar sacs. The latter are made up of clusters of alveoli, which resemble individual grapes within a bunch. Each alveolus is tightly wrapped in blood vessels, and it is here that gas exchange occurs. Deoxygenated blood from the heart is pumped through the pulmonary artery to the lungs, where oxygen diffuses into blood and is exchanged for carbon dioxide in the hemoglobin of the erythrocytes. The oxygen-rich blood returns to the heart via the pulmonary veins to be pumped back into systemic circulation.
Mechanism of respiration

The human respiratory system9.
The muscular diaphragm situated at the bottom of the thorax largely drives breathing. The contraction of the diaphragm pulls down the bottom of the cavity in which the lung is enclosed. This increases the volume and creates a negative pressure causing the air enters through the oral and nasal cavities; it flows through the larynx and into the trachea, which branches out into bronchi. Relaxation of the diaphragm has the opposite effect, passively recoiling during normal breathing. During exercise, the diaphragm contracts, forcing the air out more quickly and forcefully. The rib cage also is able to expand and contract to some degree, through the action of other respiratory and accessory respiratory muscles. As a result, air is sucked into or expelled out of the lungs, always moving down its pressure gradient. This type of lung is known as a bellows lung as it resembles a blacksmith’s bellows. Because mammalian lungs culminate in dead ends (the alveolar sacs), the pathway of airflow is tidal (i.e., air comes in and flows out by the same route).
Non-respiratory functions.
In addition to respiratory functions such as gas exchange and regulation of hydrogen ion concentration, the lungs also play important non-respiratory roles, which help to ensure proper biological function.
Followings are some of the non-respiratory functions of the respiratory system;
1) Lung Defense mechanisms.
2) Vocalization
3) Coughing and sneezing
4) Alter the pH of blood by facilitating alterations in the partial pressure of carbon dioxide.
5) Filter out small blood clots formed in veins.
6) Filter out gas micro-bubbles occurring in the venous blood stream such as those created after scuba diving during decompression3, 6, and 7.
7) Influence the concentration of some biological substances and drugs used in medicine in blood
Metabolic function
9) Endocrine function
10) May serve as a layer of soft, shock-absorbent protection for the heart, which the lungs flank and nearly enclose.
11) Temperature control function.
12) Lung Defense Mechanisms:
The respiratory passages that lead from the exterior to the alveoli do more than serve as gas conduits. They prevent entrance of the harmful substances in to the body by several mechanisms.
1. Physical and physiological mechanisms.
2. Humoral and cellular mechanisms.
Physical and physiological mechanisms.
They humidify and cool or warm the inspired air and maintain the integrity of the mucosa7.
1. Humidification;
 This action prevents dehydration.
2. Prevention of Particles entering the Respiratory tract
3. This is an adaptation of the respiratory system to prevent particles from out side in to the Respiratory tract.
 The particles more than 10 micro meters in diameter are removed in the nostrils or nasopharynx.
 Particles more than 20micro meter in diameter are deposited in the nose or conjunctivae.
 5 to 10 micro meter size particles are impacted in the carina.
 1 to 2 micro meter size particles are deposited in the distal lungs.
4. Expulsion of Particles; this is another defense mechanism of the respiratory system.
 By coughing,
 Sneezing and gagging.

5. Respiratory tract secretions;
 Mucus
 Gelatinous substance consisting chiefly of acid and neutral polysaccharides.
 Consists of a 5 micro meter thick gel that is relatively impermeable to water.
 The gel layer is secreted by the Goblet cells and mucus glands. Under normal conditions the tips of the cilia are in contact with the under surface of the gel phase and coordinate their movements to push the mucus blanket upwards. One of the major complications of cigarette smoking is the reduction of the mucociliary action which leads to recurrent infections.
The epithelium of the Para nasal sinuses produce nitrous oxide which is bacteriostatic and prevent infections.
Humoral and cellular mechanisms.
It is observed that the bronchial secretions also contain secretary immunoglobulin (IgA) and other substances that help to resist infections6.
Non specific soluble factors.
 The lung secretions contain Alpha – 1 antitrypsin – This has an inhibitory action on chemical substances such as Chymotrypsin, Trypsin. It also neutralizes the proteases and elastases6.
 Lysozyme – formed in the granulocytes. They are having strong bactericidal properties6.
 Lactoferin – Synthesized from the epithelial cells and neutrophil granulocytes. They also fight against bacteria using their bactericidal properties6.
 Interferon – produced in response to a viral infection. It is a potent suppressor of the lymphocyte functions and lowers the threshold for mast cell histamine release. At the same time it renders the other cells resistant to infection by any other virus6, 7.
 Complements – Present in the secretions in association with antibodies. It plays an important cytotoxic role.

Pulmonary Alveolar Macrophages.
These are produced by the bone marrow and migrate to the lungs via the blood stream. They phagocytose particles including bacteria and are removed by the mucociliary escalator, lymphatic and blood stream. They are the dominant cells in the airway.

Lymphoid Tissue.
The Bronchus – Associated Tissue (BALT) consists of lymphocytes present either in aggregates (Tonsils and adenoids.) or scattered. This is an important immunological defense mechanism. The Lymphocytes once sensitized to antigen produce secretory IgA, IgG and IgE.

Vocalization.
The mechanism of speech in human beings is a result of the movement of gas through the larynx, pharynx and mouth. This produces sound that allows humans to speak, or phonate. In birds vocalization, or singing, occurs via the syrinx, an organ located at the base of the trachea. The vibration of air flowing across the larynx (vocal chords), in humans, and the syrinx, in birds, results in sound. Because of this, movement of gas is extremely important and vital for the purpose of communication.
Coughing and sneezing.
By the Irritation of nerves present within the nasal passages or airways, phenomenon of Coughing and sneezing can be induced. This is a protective mechanism. During the action of coughing or sneezing as a response to some irritation of nerves in the nasal passages the air is expelled forcefully out from the trachea or nose, respectively. In this manner, irritants caught in the mucus which lines the respiratory tract are expelled or moved to the mouth where they can be swallowed. This mechanism plays an important role to ensure a stable and safe response to the fluctuations in the outside environmental changes and weather conditions.
Acid-base homeostasis.
The body is capable of regulating its inner environment physiologically via the acid-base homeostasis as a part of the body’s ability to ensure its stability in response to fluctuations in the outside environment and the weather. Human homeostasis concerning the proper balance between acids and bases, in other words the pH. The body is very sensitive to its pH level. Outside the range of pH that is compatible with life, proteins are denatured and digested, enzymes lose their ability to function, and the body is unable to sustain itself.
The body compensates the acid-base imbalance which occurs in the body by regulating the rate of ventilation. By changing the ventilation rate, the body can alter the concentration of carbon dioxide in the blood, which alters the pH.
Respiratory Regulation of Acid-Base Balance.
How is the Respiratory System Linked to Acid-base Changes?
‘Respiratory regulation’ refers to changes in pH due to pCO2 changes from alterations in ventilation. This change in ventilation can occur rapidly with significant effects on pH. Carbon dioxide is lipid soluble and crosses cell membranes rapidly, so changes in pCO2 result in rapid changes in [H+] in all body fluid compartments1.
A quantitative appreciation of respiratory regulation requires knowledge of two relationships which provide the connection between alveolar ventilation and pH via pCO2. These 2 relationships are:
• First equation – relates alveolar ventilation (VA) and pCO2
• Second equation – relates pCO2 and pH.
The two key equations are outlined in the boxes below:
First Equation: Alveolar ventilation – Arterial pCO2 Relationship
Relationship: Changes in alveolar ventilation are inversely related to changes in arterial pCO2 (& directly proportional to total body CO2 production).
paCO2 is proportional to [VCO2 / VA]
where:
• paCO2 = Arterial partial pressure of CO2
• VCO2 = Carbon dioxide production by the body
• VA = Alveolar ventilation
Alternatively, this formula can be expressed as:
paCO2 = 0.863 x [ VCO2 / VA ]
(If VCO2 has units of mls/min at STP and VA has units of l/min at 37C and
atmospheric pressure.)
Second Equation: Henderson-Hasselbalch Equation
Relationship: These changes in arterial pCO2 cause changes in pH (as defined in the Henderson-Hasselbalch equation):
pH = pKa + log { [HCO3] / (0.03 x pCO2) }
or more simply: The Henderson equation:
[H+] = 24 x ( pCO2 / [HCO3] )
The key point is that these 2 equations can be used to calculate the effect on pH of a given change in ventilation provided of course the other variables in the equations (e.g. body’s CO2 production) are known.
The next question to consider is how all this is put together and controlled, that is, how does it works?
Control System for Respiratory Regulation
Using the model of a simple servo control system the control system for respiratory regulation of acid-base balance can be considered. The components of such a simple model are a controlled variable and a central integrator. That interprets the information from the sensor and an effector mechanism which can alter the controlled variable. The servo control means that the system works in such a way as to attempt to keep the controlled variable constant or at a particular set-point. This means that a negative feedback system is in operation and the elements of the system are connected in a loop.
Control systems in the body are generally much more complex than this simple model but it is still a very useful exercise to at first attempt such an analysis.

Control System for Respiratory Regulation of Acid-base Balance
Control Element Physiological or Anatomical Correlate Comment
Controlled variable Arterial pCO2 A change in arterial pCO2 alters arterial pH (as calculated by use of the Henderson-Hasselbalch Equation).
Sensors Central and peripheral chemoreceptors Both respond to changes in arterial pCO2 (as well as some other factors)
Central integrator The respiratory center in the medulla
Effectors The respiratory muscles An increase in minute ventilation increases alveolar ventilation and thus decreases arterial pCO2 (the controlled variable) as calculated from ‘Equation 1′(discussed previously). The net result is of negative feedback which tends to restore the pCO2 to the ‘set point’.
Filter out small blood clots formed in veins.
Lower extremity deep vein thrombosis (DVT) most often results from impaired venous return (e.g., in immobilized patients), endothelial injury or dysfunction (e.g., after leg fractures), or hypercoagulability7, 8, 10.
Upper extremity DVT most often results from endothelial injury due to central venous catheters, pacemakers, or injection drug use. Upper extremity DVT occasionally occurs as part of superior vena cava (SVC) syndrome or results from a hypercoagulable state or subclavian vein compression at the thoracic outlet. The compression may be due to a normal or an accessory first rib or fibrous band (thoracic outlet syndrome) or occur during strenuous arm activity (effort thrombosis, or Paget Schroetter syndrome, which accounts for 1 to 4% of upper extremity DVT cases).
DVT usually begins in venous valve cusps. Thrombi consist of thrombin, fibrin, and RBCs with relatively few platelets (red thrombi); without treatment, thrombi may propagate proximally or travel to the lungs and may cause pulmonary embolism which may be fatal. The Lungs contain a fibrinolytic system that lyses clots in the pulmonary vessels.
Decompression sickness.
Inert gases are dissolved in body tissues and liquids while the body is under pressure, say during a scuba dive at depth. On ascent from the dive, the excess inert gas comes out of solution in a process called “outgassing” or “offgassing”. Normally most offgassing occurs by gas exchange at the lungs during exhalation3, 6. If inert gas is forced to come out of solution too quickly to allow outgassing at the lungs then bubbles may form in the blood stream or within solid tissues inside the body. This causes the signs and symptoms of DCS which includes itching skin, rashes, joint pain and neurological disturbance. The formation of bubbles in the skin or joints results in the milder symptoms, while large numbers of bubbles in the venous blood can cause pulmonary (lung) damage. The most severe types of DCS interrupt—and ultimately damage—spinal cord nerve function, which may lead to paralysis, sensory system failure, and death.
In the presence of a right-to-left shunt, such as a patent foramen ovale (PFO), venous bubbles may migrate to the arterial system, resulting in an arterial gas embolism which may damage the brain.

Metabolic and Endocrine Functions.
The lungs have a number of metabolic functions.
They manufacture of surfactants for their use. They release a number of substances that enter the systemic arterial blood flow. They also remove a number of substances from the circulation that reaches via the pulmonary blood flow. Prostaglandins are removed from the circulation, but they are also synthesized in the lungs and release to the circulation when the lung tissues are stretched7.
The Lung also activate one hormone; the physiologically inactivate deca peptide angiotensin – 1 is converted to the pressor, aldosterone stimulating angiotensin – 11 in the pulmonary circulation. A Large amount of the angiotensin-converting enzyme responsible for this conversion is located on the endothelial cells of the pulmonary capillaries. The converting enzyme also inactivates bradykinin.
Removal of serotonin and norepinephrine reduces the amount of these vasoactive substances reaching the systemic circulation.

Biologically active substances metabolized by the Lungs.
Synthesized and used in the lungs.
• Surfactant.
Synthesized and stored and released into the blood.
• Prostaglandins.
• Histamine.
• Kallikrein.

Partially removed from the blood.
• Prostaglandins.
• Bradykinin.
• Adenine nucleotide.
• Serotonin.
• Norephrine.
• Acetylcholine.

Activated in the Lungs.
Angiotensin 1 → Angiotensin 113, 6, 7.

Temperature control.
Panting in dogs and some other animals provides a means of controlling body temperature. This physiological response is used as a cooling mechanism7.

Disseminated intravascular coagulation is a pathological activation of the coagulation mechanisms (1).the subcommittee on DIC of the international society on Thrombosis and haemostasis had suggested the following definition for DIC: An acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes .it can originate from and cause damage to the microvasculature, which if sufficiently sever, can produce organ dysfunction (2). It leads to formation of small blood clots inside the blood vessels throughout the body (1). As the small clots use up the clotting factors the normal clotting procedure is disrupted. This results in bleeding from skin, digestive tract and from surgical wounds. The small blood clots disturb blood flow to organs causing malfunction of that organs.
Clotting Mechanism
The clotting system like complement system is a proteolytic cascade. Each enzyme of the pathway is present as zymogens, which on activation undergoes proteolytic cleavage to release the activated factor from the precursor molecule. The ultimate goal of this pathway is to produce thrombin which converts the soluble fibrinogen to insoluble fibrin which forms a clot (3). The generation of thrombin can be divided to intrinsic, extrinsic and common pathways.
Intrinsic pathway.
The intrinsic pathway is activated when blood is activated when blood comes in contact with sub endothelial connective tissue(collagen) or negatively charged surfaces as a result of tissue damage. Quantitatively this is the most important of the two pathways but slower to cleave fibrin than extrinsic

pathway. The function of the pathway is to activate the inactive factor X to active factor X. Factors involved in intrinsic pathway are (3).
Factor XII – Hageman factor
Factor XI
Prekallikrein
High molecular weight kininogen–HMWK
The intrinsic pathway begins with the formation of the primary complex on sub endothelial collagen by HMWK, prekallikrein and Hegman factor. Prekallikrein is converted to kallikrein and inactive factor xII (XII) becomes active factor XII (XIIa).XIIa converts inactive factor XI (XI) to factor XI (XIa).This activation is also done with compliment of the factor VII of the extrinsic pathway. The activated IX with its cofactor VII form the Tenase complex which converts the X to Xa. (4)
INTRINSIC PATHWAY
HMW kininogen, Kallikrein

XII XIIa

VIIa

XI XIa
VIII VIIIa, PL, Ca+2
X Xa
Extrinsic pathway
Extrinsic pathway is an alternative pathway for activation of the clotting cascade. It provides a very rapid response to tissue injury, generating activated factor X almost instantaneously, compared to the seconds to even minutes required to the intrinsic pathway to activate the factor X. The main function of the extrinsic pathway is to augment the action of the intrinsic pathway (3). The factors unique to the extrinsic pathway are,
Factor III-Tissue factor
Factor VII
Following damage to a blood vessel endothelium tissue factorIII is released, forming a complex with factor VII and so doing it activating it to VIIa. This complex activates IX and X. The activation by VIIa is inhibited by the Tissue Factor pathway Inhibitor (TFI). (5)

EXTRINSIC PATHWAY
TPL TFI

VII VIIa IX XIa
V Va
PL,Ca+2
X Xa

Common pathway
The intrinsic pathway and extrinsic pathways converge at factor X to single common pathway. The activated factors X with its co-factor Va forms the prothrombinase complex which activates the prothrombin to thrombin. Thrombin then activates the other components of the clotting cascade. They include activation of fibrinogen to fibrin, the building block of haemostatic plug. In addition, it activates factors VII and V and their inhibitor protein C (in the presence of Thrombomodulin), and it activates factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers (5).
IX IXa
VIIa PL
Va,Ca2+
X Xa

Prothrombin (II) Thrombin (IIa)

Fibrinogen Fibrin Monomer

Cross linked fibrin network

Disseminated Intravascular Coagulation
DIC is a condition in which small blood clots develops through the bloodstream, blocking small blood vessels and depleting. The increased clotting depletes the platelets and and clotting factors needed to control the bleeding, causes extensive bleeding.
DIC begins with extensive clotting. This is usually stimulated by a substance that enters the blood as a part of a disease (such as an infection or certain cancer) or as a complication of a childbirth, retention of a dead fetus, or surgery. People with head injury or who have been bitten by a poisonous snake is also at risk. As clotting factors and platelets depleted, extensive bleeding occurs (6).

Causes
Causes of DIC can be classified as acute or chronic, systemic or localized. DIC may be the result of a single or multiple conditions.
• Acute DIC
o Infectious
 Bacterial (eg, gram-negative sepsis, gram-positive infections, rickettsial)
 Viral (eg, HIV, cytomegalovirus [CMV], varicella, hepatitis)
 Fungal (eg, Histoplasma)
 Parasitic (eg, malaria)
o Malignancy
 Hematologic (eg, acute myelocytic leukemias)
 Metastatic (eg, mucin-secreting adenocarcinomas)

o Obstetric
 Placental abruption
 Amniotic fluid embolism
 Acute fatty liver of pregnancy
 Eclampsia
o Trauma
o Burns
o Motor vehicle accidents (MVAs)
o Snake envenomation
o Transfusion
o Hemolytic reactions
o Massive transfusion
o Liver disease – Acute hepatic failure
o Prosthetic devices
o Shunts (Denver, LeVeen)
o Ventricular assist devices(8)

Infection
Infection is the common cause of disseminated intravascular coagulation. About 10%-20% of patients with Gram negative bacteraemia have evidence of disseminated intravascular coagulation, but Gram positive organisms may also be responsible, particularly patients with hyposplenism. Systemic viral infections, malaria, viral hemorrhagic fever, herpes, and influenza viruses are also recognized as causes.(8)

Obstetric complications
Placental separation and amniotic fluid embolism probably results in release of placental tissue factor and
a direct activator of the prothrombinase complex into the maternal circulation. Rapid resolution of disseminated intravascular coagulation after evacuation of the uterus suggests that the placenta is responsible for the persistent stimulus to disseminated intravascular coagulation.(8)
Trauma
A combination of mechanisms, including the release of fat and phospholipids from tissue into the circulation, hemolysis, and endothelial damage, may promote the systemic activation of coagulation. In addition, there is emerging evidence that cytokines have a pivotal role in the development of disseminated intravascular coagulation, since the systemic activation patterns of cytokines are virtually identical in patients with polytrauma and patients with sepsis(10).

Transfusion of incompatible ABO red cells
Transfusion of incompatible red cells can cause rapid disseminated intravascular coagulation. Naturally occurring IgM antibodies combine with A or B antigens on the surfaces of the transfused red cells to form complement activating immune complexes. Disseminated intravascular coagulatin is the result of the endothelial damage caused by assembly of the complement membrane attack complex rather than destruction of the red blood cells. Non-immune intravascular haemolysis is not associated with disseminated intravascular coagulation.

Liver disease
Liver disease associated with acute disseminated intravascular coagulation when there is acutehapatic necrosis, fatty liver of pregnancy, or insertion if a LeVeen shunt in a patient with chronic liver disease and acites.
Giant Hemangiomas
Giant hemangiomas (the Kasabach–Merritt syndrome) and even large aortic aneurysms may result in local activation of coagulation. In patients with these conditions, local activation of coagulation most commonly results in the systemic depletion of locally consumed coagulation factors and platelets, but activated coagulation factors can reach the systemic circulation and cause disseminated intravascular coagulation. The incidence of clinically overt disseminated intravascular coagulation is 25 percent among patients with giant hemangiomas, whereas the incidence is approximately 0.5 to 1 percent among patients with large aortic aneurysms (10).

• Chronic DIC
o Malignancies
 Solid tumors
 Leukemia
o Obstetric
 Retained dead fetus syndrome
 Retained products of conception
o Hematologic
 Myeloproliferative syndromes
 Paroxysmal nocturnal hemoglobinuria
o Vascular
 Rheumatoid arthritis
 Raynaud disease
o Cardiovascular – Myocardial infarction
o Inflammatory
 Ulcerative colitis
 Crohn disease
 Sarcoidosis
• Localized DIC
o Aortic aneurysms
o Giant hemangiomas (Kasabach-Merritt syndrome)
o Acute renal allograft rejection
o Hemolytic uremic syndrome(8)
Malignancy
Adenocarcinoma is a common cause. Recurrent venous thrombolism is a particular feature of this form of disseminated intravascular coagulation (Trousseau’s syndrome), and recurrence may be prevented by heparin but typically not wafferin. Carcinoma may cause disseminated intravascular coagulation by invasion of tissue and releasing tissue factor, or direct activation of the prothrombinase complex by mucin or a specific cancer procoagulent.(8)
Retained dead fetus
Retained dead fetus syndrome causes progressive disseminated intravascular coagulation over several weeks. At first mother can compensate for this, and the initial fall in fibrinogen concentration often falls that about 1 g/L.A t this stage production and consumption of fibrinogen seem to be in a equilibrium, andthis steady rate may persist for few days. However severe hypocoagulopathyeventuallyoccurs unless the uterus is removed.(8)
Liver disease
Liver disease may be a cause of disseminated intravascular coagulation, but it’s not very clear whether the intravascular coagulation is a major component of the coagulopathy of the major liver disease. The prolonged survival of the radiolabled fibrinogen in the circulation after the administration of heparin is the strongest evidence for coagulopathy in patients with liver failure, but it doesn’t seem to be a major contribution to the coagulopathy.(7)
Pathophysiology
DIC is caused by widespread and ongoing activation of coagulation, leading to vascular or microvascular fibrin deposition, thereby compromising an adequate blood supply to various organs. Four different mechanisms are primarily responsible for the hematologic derangements seen in DIC: increased thrombin generation, a suppression of anticoagulant pathways, impaired fibrinolysis, and inflammatory activation. Activation of intravascular coagulation is mediated almost entirely by the intrinsic clotting pathway.

Exposure to tissue factor in the circulation occurs via endothelial disruption, tissue damage, or inflammatory or tumor cell expression of procoagulant molecules, including tissue factor. Tissue factor

activates coagulation by the intrinsic pathway involving factor VIIa. Factor VIIa has been implicated as the central mediator of intravascular coagulation in sepsis. Blocking the factor VIIa pathway in sepsis has been shown to prevent the development of DIC, whereas interrupting alternative pathways did not demonstrate any effect on clotting. The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation. Evidence suggests that the intrinsic (or contact) pathway is also activated in DIC, while contributing more to hemodynamic instability and hypotension than to activation of clotting.

Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, once intravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated. Antithrombin is one such mechanism responsible for regulating thrombin levels. However, due to multiple factors, antithrombin activity is reduced in patients with sepsis. First, antithrombin is continuously consumed by ongoing activation of coagulation. Moreover, elastase produced by activated neutrophils degrades antithrombin as well as other proteins. Further antithrombin is lost to capillary leakage. Lastly, production of antithrombin is impaired secondary to liver damage resulting from under-perfusion and microvascular coagulation. Decreased levels of antithrombin correlate well with elevated mortality in patients with sepsis. (8)
Protein C, along with protein S, serves as an important anticoagulant compensatory mechanism. Under normal conditions, protein C is activated by thrombin and is complexed on the endothelial cell surface with thrombomodulin. Activated protein C combats coagulation via proteolytic cleavage of factors Va and VIIIa. However, the cytokines (tumor necrosis factor α [TNF-a], interleukin 1 [IL-1]) produced in sepsis and other generalized inflammatory states largely incapacitate the protein C pathway. Inflammatory cytokines down-regulate the expression of thrombomodulin on the endothelial cell surface. Protein C levels are further reduced via consumption, extravascular leakage, and reduced hepatic production and by a reduction in freely circulating protein S.(8) In addition to the decrease in antithrombin III, a significant
activates coagulation by the intrinsic pathway involving factor VIIa. Factor VIIa has been implicated as the central mediator of intravascular coagulation in sepsis. Blocking the factor VIIa pathway in sepsis has been shown to prevent the development of DIC, whereas interrupting alternative pathways did not demonstrate any effect on clotting. The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation. Evidence suggests that the intrinsic (or contact) pathway is also activated in DIC, while contributing more to hemodynamic instability and hypotension than to activation of clotting(8).

Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, once intravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated. Antithrombin is one such mechanism responsible for regulating thrombin levels. However, due to multiple factors, antithrombin activity is reduced in patients with sepsis(10). First, antithrombin is continuously consumed by ongoing activation of coagulation. Moreover, elastase produced by activated neutrophils degrades antithrombin as well as other proteins. Further antithrombin is lost to capillary leakage. Lastly, production of antithrombin is impaired secondary to liver damage resulting from under-perfusion and microvascular coagulation. Decreased levels of antithrombin correlate well with elevated mortality in patients with sepsis. (8)
Protein C, along with protein S, serves as an important anticoagulant compensatory mechanism. Under normal conditions, protein C is activated by thrombin and is complexed on the endothelial cell surface with thrombomodulin. Activated protein C combats coagulation via proteolytic cleavage of factors Va and VIIIa. However, the cytokines (tumor necrosis factor α [TNF-a], interleukin 1 [IL-1]) produced in sepsis and other generalized inflammatory states largely incapacitate the protein C pathway.(10) Inflammatory cytokines down-regulate the expression of thrombomodulin on the endothelial cell surface. Protein C levels are further reduced via consumption, extravascular leakage, and reduced hepatic production and by a reduction in freely circulating protein S.(8) In addition to the decrease in antithrombin III, a significant
depression of the protein C system may occur. This impaired function of the protein C pathway is mainly due to downregulation of thrombomodulin expression on endothelial cells by proinflammatory cytokines, like tumor necrosis factor-alpha (TNF-alpha) and interleukin 1b (IL-1b). The downregulation of thrombomodulin has been confirmed in studies in patients with meningococcal sepsis. This, in combination with low levels of zymogen protein C (due to similar mechanisms as described for antithrombin), results in diminished protein C activation, which will enhance the procoagulant state.
Animal experiments of severe inflammation-induced coagulation activation convincingly show that compromising the protein C system results in increased morbidity and mortality, whereas restoring an adequate function of activated protein C improves survival and organ failure.(2)
Tissue factor pathway inhibitor (TFPI) is another anticoagulant mechanism that is disabled in DIC. TFPI inhibits the tissue factor-VIIa complex. Although levels of TFPI are normal in patients with sepsis, a relative insufficiency in DIC is evident. TFPI depletion in animal models predisposes to DIC, and TFPI blocks the procoagulant effect of endotoxin in humans. The intravascular fibrin produced by thrombin is normally eliminated via a process termed fibrinolysis(8). The initial response to inflammation appears to be augmentation of fibrinolytic action; however, this response soon reverses as inhibitors (plasminogen activator inhibitor-1 [PAI-1], TAFI) of fibrinolysis are released. Indeed, high levels of PAI-1 precede DIC and predict poor outcomes(9). Fibrinolysis cannot keep pace with increased fibrin formation, eventually resulting in under-opposed fibrin deposition in the vasculature.

Inflammatory and coagulation pathways interact in substantial ways. Many of the activated coagulation factors produced in DIC contribute to the propagation of inflammation by stimulating endothelial cell release of proinflammatory cytokines. Factor Xa, thrombin, and the tissue factor-VIIa complex have each been demonstrated to elicit proinflammatory action. Furthermore, given the anti-inflammatory action of activated protein C and AT, their impairment in DIC contributes to further dysregulation of inflammation.
Components of DIC include the following
• Exposure of blood to procoagulant substances
• Fibrin deposition in the microvasculature
• Impaired fibrinolysis
• Depletion of coagulation factors and platelets (consumptive coagulopathy)
• Organ damage and failure(8)
Mortility and morbidity
Morbidity and mortality depend on both the underlying disease and the severity of coagulopathy. Assigning a numerical figure for DIC-specific morbidity and mortality is difficult. Below are examples of mortality rates in diseases complicated by DIC:
• Idiopathic purpura fulminans associated with DIC has a mortality rate of 18%.
• Septic abortion with clostridial infection and shock associated with severe DIC has a mortality rate of 50%.
• In the setting of major trauma, the presence of DIC approximately doubles the mortality rate(2)

Obviously, the clinical importance of a severe depletion of platelets and coagulation factors in patients with diffuse, widespread bleeding or in patients who need to undergo an invasive procedure is clear. In addition, the intravascular deposition of fibrin, as a result of the systemic activation of coagulation, contributes to organ failure and mortality.
Histological studies in patients with disseminated intravascular coagulation (DIC) show the presence of ischemia and necrosis due to fibrin deposition in small- and mid-size vessels of various organs. The presence of these intravascular thrombi appears to be clearly and specifically related to the clinical dysfunction of the organ. Specific thrombotic complications that are sometimes seen in the framework of disseminated intravascular coagulation (DIC) are acral cyanosis, hemorrhagic skin infarctions, and limb ischemia.
Secondly, experimental animal studies of disseminated intravascular coagulation (DIC) show fibrin deposition in various organs. Amelioration of disseminated intravascular coagulation (DIC) by various interventions appears to improve organ failure and, in some but not all cases, mortality.
Lastly, disseminated intravascular coagulation (DIC) has been shown to be an independent predictor of mortality in patients with sepsis and severe trauma. The presence of disseminated intravascular coagulation (DIC) may increase the risk of death by 1.5 to 2.0 in various studies. An increasing severity of disseminated intravascular coagulation (DIC) is directly related to an increased mortality.(8)
Diagnosis
There is no single laboratory test that can establish or rule out the diagnosis of disseminated intravascular coagulation. However, a combination of test results in a patient with a clinical condition known to be associated with disseminated intravascular coagulation can be used to diagnose the disorder with reasonable certainty in most cases. In clinical practice the disorder can be diagnosed on the basis of the following findings: an underlying disease known to be associated with disseminated intravascular coagulation; an initial platelet count of less than 100,000 per cubic millimeter or a rapid decline in the platelet count; prolongation of clotting times, such as the prothrombin time and the activated partial-thromboplastin time; the presence of fibrin-degradation products in plasma; and low plasma levels of coagulation inhibitors, such as antithrombin III(10).
Laboratory Studies
• No single routinely available laboratory test is sufficiently sensitive or specific to allow a diagnosis of disseminated intravascular coagulation (DIC).
• Specialized tests
o In a specialized setting, molecular markers for activation of coagulation or fibrin formation may be the most sensitive assays for disseminated intravascular coagulation (DIC). A number of clinical studies show that the presence of soluble fibrin in plasma has a 90-100% sensitivity for the diagnosis of disseminated intravascular coagulation (DIC), but unfortunately the specificity is low. Another problem is that a reliable test for quantifying soluble fibrin in plasma is not available, and one study showed a wide discordance among various assays.
o The dynamics of disseminated intravascular coagulation (DIC) can also be judged by measuring activation markers that are released upon the conversion of a coagulation factor zymogen to an active protease, such as prothrombin activation fragment F1+2 (F1+2). Indeed, these markers are markedly elevated in patients with disseminated intravascular coagulation (DIC), but, again, the specificity is a problem.
o In addition to these shortcomings, most of the sensitive and sophisticated tests described above are not available to general hematology laboratories. Although these tests may be very helpful in clinical trials or other research, they often cannot be used in a routine setting.
• Routine tests
o In clinical practice, a diagnosis of disseminated intravascular coagulation (DIC) can often be made by a combination of platelet count, measurement of global clotting times (aPTT and PT), measurement of 1 or 2 clotting factors and inhibitors (eg, antithrombin), and a test for fibrin degradation products (FDPs). It should be emphasized that serial coagulation tests are usually more helpful than single laboratory results in establishing the diagnosis of disseminated intravascular coagulation (DIC). A reduction in the platelet count or a clear downward trend at subsequent measurements is a sensitive (although not specific) sign of disseminated intravascular coagulation (DIC).
o The prolongation of global clotting times may reflect the consumption and depletion of various coagulation factors, which may be further substantiated by the measurement of selected coagulation factors, such as Factor V and facor VIII.
o Measurement of coagulation factors may also may be helpful to detect additional hemostatic abnormalities (eg, those caused by Vitamin k deficiency)
Management
The cornerstone of the management of disseminated intravascular coagulation is the treatment of the underlying disorder. Treatment of disseminated intravascular coagulation without treatment of the underlying cause is predestined to fail. Supportive measures may be necessary, although firm evidence on which to base management is scarce, and there is no consensus regarding the optimal treatment or supportive strategy. A patient with disseminated intravascular coagulation who has diffuse bleeding from various sites at presentation will need different supportive treatment from

what is appropriate for a patient with thrombotic obstruction of the vasculature and subsequent multiorgan failure(10).
Anticoagulants
Theoretically, interruption of coagulation should be of benefit in patients with disseminated intravascular coagulation.(11) Indeed, experimental studies have shown that heparin can partially inhibit the activation of coagulation in cases that are related to sepsis or other causes. Adequate prophylaxis is also needed to eliminate the risk of venous thromboembolism. Heparin has been shown to have a beneficial effect in small, uncontrolled studies of patients with disseminated intravascular coagulation, but not in controlled clinical trials(10).
Platelets and Plasma
Low levels of platelets and coagulation factors may cause serious bleeding or may increase the risk of bleeding in patients who require an invasive procedure. In such patients, the efficacy of treatment with platelet concentrate and plasma has clearly been shown. Treatment with coagulation-factor concentrates may overcome the need for large infusions of plasma, but their use in patients with disseminated intravascular coagulation is generally not advocated because the concentrates may be contaminated with traces of activated coagulation factors, which could exacerbate the coagulation disorder(10).
Trearment
The only effective treatment is the reversal of the underlying cause. Anticoagulants
are given exceedingly rarely when thrombus formation is likely to lead to imminent
death (such as in coronary artery thrombosis or cerebrovascular thrombosis). Platelets
may be transfused if counts are less than 5,000-10,000/mm3 and massive hemorrhage
is occurring, and fresh frozen plasma may be administered in an attempt to replenish
coagulation factors and anti-thrombotic factors, although these are only temporizing
measures and may result in the increased development of thrombosis.DIC results in
lower fibrinogen levels (as it has all been converted to fibrin), and this can be tested
for in the hospital lab. A more specific test is for “fibrin split products” (FSPs) or
“fibrin degradation products” (FDPs) which are produced when fibrin undergoes
degradation when blood clots are dissolved by fibrinolysis.In some situations,
infusion with antithrombin may be necessary. A new development is drotrecogin alfa
(Xigris), a recombinant activated protein C product. Activated Protein C (APC)
deactivates clotting factors V and VIII, and the presumed mechanism of action of
drotrecogin is the cessation of the intravascular coagulation. Due to its high cost and
its severe adverse effects, it is only used strictly on indication in intensive care
patients with severe sepsis. The large, multicenter ENHANCE trial provided more
evidence that there may be a favorable benefit/risk ratio to administering activated
protein C in adults, but was unable to make definitive conclusions about efficacy
due to the lack of a placebo control, and particularly in children, there is a high risk of
hemorrhage (27.4% in patients aged 0-18 years)(12)
Below passage contians results in a research of treatment of DIC sarried out by Marcel M Levi, MD:-
{Gabexate mesilate (FOY) was used to treat 215 patients with disseminated intravascular coagulation (DIC) and 146 patients with a predisposition to DIC (pre-DIC). Sixty percent of DIC patients and 48% of pre-DIC patients exhibited pretreatment organ failure, which resolved after FOY treatment in 16% of DIC patients and 17% of pre-DIC patients. Seventy percent of DIC patients and 49% of pre-DIC patients had a pretreatment bleeding tendency that was ameliorated by FOY treatment in 32% of DIC patients and 30% of pre-DIC patients. Comparison of pretreatment and posttreatment hemostatic studies of the DIC patients revealed that platelet count and levels of fibrinogen degradation products (FDP), thrombin-antithrombin-III complex, and FDP-D-dimer decreased significantly; fibrinogen level increased markedly; and prothrombin time was prolonged. DIC scores were significantly lowered in both leukemic and nonleukemic patients from the third day of treatment with FOY. Among leukemic DIC patients, 59% showed complete remission (CR), 21% partial remission (PR), and 7% exacerbation of their condition; 46% of the nonleukemic DIC patients demonstrated CR, 17% PR, and 17% exacerbation. Of the leukemic pre-DIC patients, 59% showed improvement and 7% exacerbation, whereas 55% of the nonleukemic pre-DIC patients showed improvement and 27% exacerbation}(9)

DEFINITION:
Systemic Inflammatory Response Syndrome (SIRS) is characterized by one or more of the following clinical features.1
• 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).2,3,4,5.
In children, the SIRS criteria are modified in the following fashion:7
• Heart rate > 2 standard deviations above normal for age in the absence of stimuli such as pain and drug administration. Body temperature obtained orally, rectally, from Foley catheter probe, or from central venous catheter probe > 38.5 °C or < 36 °C.
• 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.

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. SIRS is also closely related to sepsis, in which patients satisfy criteria for SIRS and have a suspected or proven infection.1,2,3
• 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)
• 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, Note that SIRS criteria are very non-specific,8 and must be interpreted carefully within the clinical context.
Bacteremia is the presence of bacteria within the blood stream, but this condition does not always lead to SIRS. Although not universally accepted terminology, severe SIRS and SIRS shock are terms that some authors have proposed. These terms suggest organ dysfunction or refractory hypotension related to an ischemic or inflammatory process rather than to an infectious etiology.
PATHOPHYSIOLOGY:
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:
• 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 pro inflammatory 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.
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 (TNF) 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 (NF-B) inhibitor. Once the inhibitor is removed, NF- B is able to initiate the production of mRNA, which induces the production other pro inflammatory cytokines.
IL-6, IL-8, and interferon gamma are the primary pro inflammatory 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, like 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 pro inflammatory 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 pro inflammatory 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 pro inflammatory mediator itself. Fibrinolysis is impaired by IL-1 and TNF via production of plasminogen activator inhibitor-1. Pro inflammatory 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 pro inflammatory mediators may lead to deleterious immunosuppression.
CAUSES:
• The causes of SIRS are broadly classified as infectious or noninfectious. As above, when SIRS is due to an infection, it is considered sepsis.
• 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)

• Noninfectious causes of SIRS include trauma, burns, pancreatitis, ischemia, and hemorrhage.1
• 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

Other causes are:
• Complications of surgery
• Adrenal insufficiency
• Pulmonary embolism
• Complicated aortic aneurysm
• Cardiac tamponade
EXAMINATION:
A focused physical examination based on a patient’s symptoms is adequate in most situations. Under certain circumstances, if no obvious etiology is obtained during the history or laboratory evaluation, a complete physical examination may be indicated. Patients who cannot provide any history should also undergo a complete physical examination, including a rectal examination, to rule out an abscess or gastrointestinal bleeding.
Clinical History
Despite having a relatively common physiologic pathway, systemic inflammatory response syndrome (SIRS) has numerous triggers, and patients may present in various manners. The clinician’s history should be focused around the chief symptom, with a pertinent review of systems being performed. Patients should be questioned regarding constitutional symptoms of fever, chills, and night sweats. This may help to differentiate infectious from noninfectious etiologies. The timing of symptom onset may also guide a differential diagnosis toward an infectious, traumatic, ischemic, or inflammatory etiology.
• Pain, especially when it can be localized, may guide a physician in both differential diagnosis and necessary evaluation. Although providing a differential for pain in the various body parts is beyond the scope of this article, a physician should carefully obtain the duration, location, radiation, quality, and exacerbating factors associated with the pain to help establish a thorough differential diagnosis.
• In patients for whom a diagnosis cannot be made based on initial history, a complete review of systems is indicated to try an undercover potential diagnosis.
• Patients’ medications should be reviewed. Medication side effects or pharmacologic properties may either induce or mask SIRS (ie, beta-blockers prevent tachycardia). Recent changes in medications should be addressed to rule out drug-drug interactions or a new side effect. Allergy information should be gathered and the specifics of the reaction should be obtained.
• Careful review of initial vital signs is an integral component to making the diagnosis. Repeating the review of vital signs periodically during the initial evaluation period is necessary, as multiple other factors (eg, stress, anxiety, exertion of walking to the examination room) may lead to a false diagnosis of SIRS.

• Extreme of ages (both young and old) may not manifest as typical criteria for SIRS; therefore, clinical suspicion may be required to diagnosis a serious illness (either infectious or noninfectious).
• Patients receiving a beta-blocker or a calcium channel blocker are likely unable to elevate their heart rate and, therefore, tachycardia may not be present.
• Although blood pressure is not one of the four criterias, it is still an important marker. If the blood pressure is low, the establishment of intravenous access and fluid resuscitation is of utmost importance. Frank hypotension associated with SIRS is uncommon unless the patient is septic or severely dehydrated. Hypotension may lead to the patient being admitted or transferred to a higher acuity unit.
COMPLICATIONS:
• Complications vary based on underlying etiology. Routine prophylaxis including deep vein thrombosis (DVT) and stress ulcer prophylaxis should be initiated when clinically indicated. Long-term antibiotics, when clinically indicated, should be as narrow spectrum as possible to limit potential for superinfection (suggested by a new fever, change in white blood cell count, or clinical deterioration). Unnecessary vascular catheters and Foley catheters should be removed as soon as possible.
• Other potential complications include the following:
o Respiratory failure, acute respiratory distress syndrome (ARDS) and pneumonia
o Renal failure
o GI bleeding and stress gastritis
o Anemia
o DVT
o Intravenous catheter–related bacteremia
o Electrolyte abnormalities
o Hyperglycemia
o Disseminated intravesicular coagulation (DIC)

TREATMENT:
The initial medical care should include prompt initiation of pertinent laboratory testing and imaging studies after obtaining a history and performing a physical examination. Treatment should then be focused based on possible inciting causes of systemic inflammatory response syndrome (SIRS; eg, appropriate treatment of acute myocardial infarction differs from the treatment of community-acquired pneumonia or pancreatitis).
• Empiric antibiotics are not indicated for all patients with SIRS. Indications for antibiotic therapy include
(1) suspected or diagnosed infectious etiology (eg, urinary tract infection [UTI], pneumonia, cellulitis)
(2) hemodynamic instability
(3) neutropenia (or other immunocompromised states)
(4) asplenia (due to the potential for overwhelming postsplenectomy infection [OPSI]).
When feasible, culture data should always be obtained prior to initiating antibiotic therapy. Empiric antibiotic therapy should be guided by available practice guidelines and knowledge of the local antibiogram, as well as the patient’s risk factors for resistant pathogens and allergies. Once bacteriologic diagnosis is obtained, narrowing the antibiotic spectrum to the most appropriate therapy is critical.
• Because of increasing bacterial resistance, broad-spectrum antibiotics should be initiated when an infectious cause for SIRS is a concern but no specific infection is diagnosed.
o With the increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the community, vancomycin or another anti-MRSA therapy should be considered.
o Gram-negative coverage with either cefepime or a quinolone is reasonable.
o Recent exposure to antibiotics must be considered when choosing empiric regimens because recent antibiotic therapy increases the risk for resistant pathogens.
o Care must be made not to use an antibiotic to which the patient is allergic. This may be a second hit and lead to worsening SIRS.
o Because of the high prevalence of patients with penicillin allergy, a quinolone or aztreonam is reasonable alternatives for gram-negative coverage.
o Antiviral therapy has no role in SIRS.
o Empiric antifungal therapy (fluconazole or an echinocandin) can be considered in patients who have already been treated with antibiotics, patients who are neutropenic, patients who are receiving total parenteral nutrition (TPN), or patients who have central venous access in place.
o Although empiric antibiotics may be reasonable in many situations, the key is to stop antibiotics when infection is ruled out or narrow the antibiotic spectrum once a pathogen is found.
o Proper culture data must be obtained prior to any antibiotic therapy. Antibiotics prior to culturing a patient may be a cause of sterile sepsis.
• TNF and IL-1 receptor antagonists, antibradykinin, platelet-activating factor receptor antagonists, and anticoagulants (antithrombin III) have been studied without showing statistically significant benefits in SIRS (with variable results for sepsis and septic shock). These medications have no role in treating patients who meet criteria for SIRS only.
• Drotrecogin alfa, a recombinant form of APC, warrants further comment. APC reduces microvascular dysfunction by reducing inflammation and coagulation and increasing fibrinolysis.
o The Patients in the Recombinant Human Activated Protein-C Worldwide Evaluation in Severe Sepsis (PROWESS) study demonstrated its ability to reduce 28-day all-cause mortality following severe sepsis. Further studies have demonstrated that it is best used in patients with gram-negative septic shock. In the PROWESS study, no clinical benefit was found in patients with acute physiology and chronic health evaluation (APACHE) scores of less than 25, and further studies have demonstrated worse outcomes in patients with lower APACHE scores.8
o Therefore, APC has no role in most SIRS cases unless the clinical presentation is consistent with septic shock. APC has strict inclusion and exclusion criteria that must be considered in all patients prior to initiating therapy. The greatest benefit of APC has been demonstrated when this medication is initiated early in the inflammatory cascade.
• Steroids for sepsis and septic shock have been extensively studied, but no SIRS-specific studies have been performed to date.
o The initial research in sepsis and septic shock showed a trend toward worse outcomes when treating with high doses of steroids (methylprednisolone sodium succinate 30 mg/kg every 6 h for 4 doses) compared with placebo. However, research into low-dose steroids (200-300 mg of hydrocortisone for 5-7 d) improved survival and the reversal of shock in vasopressor-dependent patients.
o As mentioned above, the inflammatory mediators and receptors associated with infectious insults (ie, septic shock) are the same as those of noninfectious insults (ie, trauma, inflammatory conditions, ischemia). Therefore, in patients with severe or progressive SIRS, even without an obvious infectious insult, low steroids could be considered.
o Current data do not support using ACTH stimulation testing to determine patients who should receive steroid therapy. Patients receiving steroids require careful monitoring for hyperglycemia.

• Patients who are hypotensive should receive intravenous fluids, and, if still hypotensive after adequate resuscitation, vasopressor agents should be administered while carefully monitoring hemodynamic status. All patients should have adequate intravenous access and commonly require 2 large-bore intravenous lines or a central venous catheter. For further details on the management of hypotension, please refer to the eMedicine article Septic Shock.

• Hyperglycemia, a common laboratory finding in SIRS, even in individuals without diabetes, has numerous deleterious systemic effects.
o An increase of counterregulatory hormones, namely cortisol and epinephrine, and relative hypoinsulinemia lead to increased hepatic glucose production, increased peripheral insulin resistance, and increased circulating free fatty acids. This has direct inhibitory action on the immune system. Oxidative stress and endothelial cell dysfunction, along with proinflammatory cytokines (IL-6, IL-8, and TNF) and other secondary mediators (NF B) have all been implicated as causes of cellular injury, tissue damage, and organ dysfunction in patients with hyperglycemia.
o Intensive control of blood glucose levels has been shown to diminish in-hospital morbidity and mortality in both the surgical and medical intensive care setting. Various trials have shown that glycemic control with insulin improves patient outcomes (including renal function and acute renal failure), reduces the need for red blood cell transfusions, reduces the number of days in the ICU, lowers the incidence of critical-illness polyneuropathy, and decreases the need for prolonged mechanical ventilation. Van den Berghe et al (2006) reported a reduction of in-hospital mortality rates with intensive insulin therapy (maintenance of blood glucose at 80-110 mg/dL) by 34%.9 The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus.

• Supplemental oxygen should be provided to any patient that demonstrates an increased oxygen requirement or decreased oxygen availability. Oxygen can be provided via nasal canula or mask, or, in certain situations, ventilator support may be required to maximize oxygen delivery. Supplying supraphysiologic oxygen has shown mixed results in a multitude of studies. Providing too much oxygen in a patient with severe chronic obstructive pulmonary disease (COPD) should be avoided because it can depress their respiratory drive. Patients who do not respond to increased oxygen supply have a poor prognosis. Patients with associated respiratory failure who require mechanical ventilation should be treated with low tidal volume mechanical ventilation (6 mL/kg).
Surgical Care
The details of surgical management are site-specific and are beyond the scope of this article. In general, however, abscesses or drainable foci of infection should be drained expeditiously to increase the efficacy of antibiotic therapy and to allow for adequate culture data. Patients with acute surgical issues (eg, ruptured appendix, cholecystitis) that cause SIRS should be treated with appropriate surgical measures. Prosthetic devices should be removed in a timely manner, when clinically feasible.
Consultations
Consultations vary depending on the admitting physician’s training and the cause of SIRS (ie, cardiology consultation for acute myocardial infarction or gastroenterology for acute GI bleeding). Patients with potential surgical issues should undergo a surgical evaluation, often in the emergency room, early in the course of illness.10
• Consider consultation with an intensivist, if one is available. If organ dysfunction develops, the intensivist or a consultant specialist in that organ system should be involved.
• Early consultation with an expert in infectious diseases is particularly helpful for patients who are immunocompromised, regardless of the cause (eg, HIV, AIDS, malignancy, solid organ transplantation). They can also provide guidance in situations in which patients are not responding to standard antibiotic therapy, have multiple drug allergies, or are infected with multidrug-resistant organisms or when a diagnosis is still uncertain.11
Diet
Enteral feedings with arginine and omega-3 fatty acids have been shown to be beneficial (decreased infectious complications, hospital days, and duration of mechanical ventilation) in critically ill patients. The ability to feed a patient and the route of nutrition vary based on the etiology of SIRS.
Activity
Because of the causative illness, many patients are bed-bound.11,12 Therefore, deep venous thrombosis (DVT) and GI stress ulcer prophylaxis should be considered to help prevent complications. Patients who are otherwise clinically stable and without contraindications to mobility should be permitted to do activity as tolerated.
Medication
No drugs of choice exist for this entity. Medication prescriptions target specific diagnoses, preexisting comorbidities, and prophylaxis regimens for complications. No pharmacologic agents have been demonstrated to improve the systemic inflammatory response syndrome (SIRS) outcome. Broad-spectrum antibiotics, insulin therapy (in patients with hyperglycemia), and steroids should be considered in patients who meet criteria for SIRS.
Patient Education
Education should ideally target the patient’s family. Family members need to understand the fluid nature of immune responsiveness and that SIRS is a potential harbinger of other more dire syndromes.
Special Concerns
• Pregnant patients require intensive evaluation because of the presence of 2 patients, as well as the propensity of uncontrolled inflammation to lead to preterm labor.
• Patients at the extremes of age, patients with immunosuppression, and patients with diabetes may present with sepsis or other complications of infection without meeting SIRS criteria.
Antibiotics
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Conclusions
In SAH patients, SIRS on admission reflected the extent of tissue damage at onset and predicted further tissue disruption, producing clinical worsening and, ultimately, a poor outcome.

Introduction
The term hydrocephalus is derived from the Greek words “hydro” meaning water and “cephalus” meaning head. It is a condition in which the primary characteristic is excessive accumulation of fluid in the brain (figure1). Hydrocephalus was once known as “water on the brain,” the “water” is actually cerebrospinal fluid (CSF)
CSF is a clear fluid that surrounds the brain and spinal cord. The excessive accumulation of CSF 1 due to impaired flow of CSF, 2, 6 impaired absorption of CSF 3, 6 excessive secretion, 6 or from complications of head injuries or infections,7 results in an abnormal widening of spaces in the brain called ventricles. It typically appears as very large ventricles on imaging studies. In a person without hydrocephalus, CSF continuously circulates through the brain, its ventricles and the spinal cord and is continuously drained away into the circulatory system.

Causes of hydrocephalus
• The most common cause of hydrocephalus is CSF flow obstruction, hindering the free passage of cerebrospinal fluid through the ventricular system and subarachnoid space (e.g., stenosis of the cerebral aqueduct or obstruction of the interventricular foramina – foramina of Monro secondary to tumors, hemorrhages, infections or congenital malformations).
• Hydrocephalus can also be caused by overproduction of cerebrospinal fluid (e.g., papilloma of choroid plexus).

Classifications of hydrocephalus
Hydrocephalus is a neurological disorder that spans all ages. It could be divided into congenital or acquired. Congenital hydrocephalus is present at birth, may be caused by genetic abnormalities, and may be associated with other developmental disorders such as neural tube defects like spina bifida 1, 2 or Dandy-Walker malformation. Often the cause is unknown. Acquired hydrocephalus develops at the time of birth or at some point afterward, and may be secondary to damage to the brain caused by hemorrhage, stroke, infection, tumor, or traumatic injury.1
Compression of the brain by the accumulating fluid eventually may cause convulsions and mental retardation.5 These signs occur sooner in adults, whose skulls no longer are able to expand to accommodate the increasing fluid volume within.
Fetuses, infants, and young children with hydrocephalus typically have an abnormally large head, 1, 3, and 5 excluding the face due to the pressure of the fluid on the individual skull bones, which haven’t fused yet. So it bulges outward at their juncture points. The medical sign, in infants, is a characteristic fixed downward gaze with whites of the eyes showing above the iris, as though the infant were trying to examine its own lower eyelids.8 Dilated veins are prominent over the scalp.1 Children who have had hydrocephalus may have very small ventricles, and presented as the “normal case”.
Hydrocephalus affects one in every 1000 live births, making it one of the most common developmental disabilities, more common than Down syndrome or deafness.9 There are over 180 different causes of the condition, one of the most common being brain hemorrhage associated with premature birth.
1. Internal hydrocephalus and External hydrocephalus
When there is a blockage of forth ventricle or the cerebral aqueduct, CSF accumulates and internal production of CSF continues so the fluid compresses the nervous tissue and forth ventricle dilates, resulting in internal hydrocephalus (figure 2). Irreversible brain damage can occur. The cerebral aqueduct may be blocked at birth or become blocked later in life due to tumor growing in brainstem.
Internal hydrocephalus can be successfully treated by placing a drainage tube (shunt) between the brain ventricles and abdominal cavity to eliminate the high internal pressures. There is some risk of infection being introduced into the brain through these shunts. These shunts must be replaced as the person grows.
If CSF accumulates in the space between the proper and arachnoid, containing CSF, the condition is called external hydrocephalus. In this condition, pressure is applied to the brain externally. This compress neural tissues and causes brain damage. Thus resulting in further damage of the brain tissue and leading to necrotization.

2. Communicating and Non communicating hydrocephalus
Hydrocephalus may also be classified into communicating or non-communicating. Communicating hydrocephalus occurs when the flow of CSF is blocked after it exits the ventricles. This form is called communicating because the CSF can still flow between the ventricles, which remain open. Non-communicating hydrocephalus is also called “obstructive” hydrocephalus – occurs when the flow of CSF is blocked along one or more of the narrow passages connecting the ventricles. One of the most common causes of hydrocephalus is “aqueductal stenosis.” In this case, hydrocephalus results from a narrowing of the aqueduct of Sylvius, a small passage between the third and fourth ventricles in the middle of the brain. Both forms can be either congenital or acquired.

2.1 Communicating hydrocephalus
Communicating hydrocephalus, also known as non-obstructive hydrocephalus, is caused by impaired cerebrospinal fluid resorption in the absence of any CSF-flow obstruction.This is due to functional impairment of the arachnoid granulations, which are located along the superior sagittal sinus and is the site of cerebrospinal fluid resorption back into the venous system. Various neurologic conditions may result in communicating hydrocephalus, including subarachnoid/intraventricular hemorrhage, meningitis, Chiari malformation, and congenital absence of arachnoid granulations (Pacchioni’s granulations).

2.2 Non-communicating hydrocephlus.
Non-communicating hydrocephalus, or obstructive hydrocephalus, is caused by a CSF-flow obstruction (either due to external compression or intraventricular mass lesions).4
2.2.1. Foramen of Monro obstruction may lead to dilation of one or, if large enough (e.g., in colloid cyst), both lateral ventricles.
2.2.2. The aqueduct of Sylvius, may be obstructed by a number of genetically or acquired lesions6 (e.g., atresia, ependymitis, hemorrhage, tumor) and lead to dilation of both lateral ventricles as well as the third ventricle.
2.2.3. Fourth ventricle5 obstruction will lead to dilatation of the aqueduct as well as the lateral and third ventricles.
2.2.4 The foramina of Luschka and foramen of Magendie may be obstructed due to congenital failure of opening (e.g., Dandy-Walker malformation6).
2.2.5. The subarachnoid space surrounding the brainstem may also be obstructed due to inflammatory or hemorrhagic fibrosing meningitis, leading to widespread dilatation, including the fourth ventricle

3. Congenital and Acquired Hydrocephalus.
3.1 Congenital Hydrocephalus
For head enlargement to occur, hydrocephalus must occur before the 3rd year. Because by the end of 3rd year the cranial bones fuse. The causes are usually genetic but can also be acquired and usually occur within the first few months of life, which include
1) intraventricular matrix hemorrhages in premature infants
2) infections
3) type II Arnold-Chiari malformation
4) aqueduct atresia and stenosis
5) Dandy-Walker malformation.
In newborns and toddlers with hydrocephalus, the head circumference is enlarged rapidly and soon surpasses the 97th percentile. Since the skull bones have not yet firmly joined together, bulging, firm anterior and posterior fontanelles may be present even when the patient is in an upright position.
The infant exhibits fretfulness, poor feeding, and frequent vomiting. As the hydrocephalus progresses, torpor sets in, and the infant shows lack of interest in his surroundings. Later on, the upper eyelids become retracted and the eyes are turned downwards (also called “sunsetting”), and seizures.10 Movements become weak and the arms may become tremulous. Papilledema is absent but there may be reduction of vision. The head becomes so enlarged that the child may eventually be confined to bed.
Hydrocephalus is a heterogeneous group of disorders and not a single disease unit.11About 80-90% of fetuses or newborn infants with spina bifida, often associated with meningocele or myelomeningocele, develop hydrocephalus.12
Older children and adults may experience different symptoms because their skulls cannot expand to accommodate the buildup of CSF. Symptoms may include headache followed by vomiting, nausea, papilledema (swelling of the optic disk which is part of the optic nerve),3 blurred or double vision, sunsetting of the eyes, problems with balance, poor coordination, gait disturbance, urinary incontinence, slowing or loss of developmental progress, lethargy, drowsiness, irritability, or other changes in personality or cognition including memory loss.10

3.2 Acquired hydrocephaus
This condition is acquired as a consequence of CNS infections, meningitis, brain tumors, head trauma, intracranial hemorrhage (subarachnoid or intraparenchymal) and is usually extremely painful. Post traumatic hydrocephalus (PTH) is a relatively rare condition.13,15,16,17,18 In PTH due to subarachnoid and intraventricular blockage, the dilated ventricles cause raised intracranial pressure, which has to be relieved at the earliest to prevent further brain damage.13
Even though PTH relatively rare, is a treatable condition.PTH may present with various clinical syndromes like obtundation, failure to improve and a tetrad of symptoms including psychomotor retardation, memory loss, gait ataxia and incontinence.14, 19 Sometimes, the patient may be too injured to demonstrate clinical signs and symptoms of PTH, or may present with atypical symptoms.14 PTH is rare among children. PTH commonly occurs in the 1st year post- trauma, it has been occasionally described as early as within seven hours post-trauma.13,20

4. Other forms of hydrocephalus.
There are two other forms of hydrocephalus which do not fit exactly into the categories mentioned above and primarily affect adults: hydrocephalus ex-vacuo and normal pressure hydrocephalus.
• Hydrocephalus ex vacuo also refers to an enlargement of cerebral ventricles and subarachnoid spaces, and is usually due to brain atrophy (as it occurs in dementias), post-traumatic brain injuries and even in some psychiatric disorders, such as schizophrenia. As opposed to hydrocephalus, this is a compensatory enlargement of the CSF-spaces in response to brain parenchyma loss – it is not the result of increased CSF pressure.

• Normal pressure hydrocephalus (NPH) is an abnormal increase of cerebrospinal fluid (CSF) in the brain’s ventricles, or cavities. It occurs if the normal flow of CSF through the cord is blocked in some way. This causes the ventricles to enlarge without cortical atrophy,2 putting pressure on the brain. Normal pressure hydrocephalus can occur in people of any age, but it is most common in the elderly population. It may result from a subarachnoid hemorrhage, head trauma, infection, tumor or complications of surgery. However, many people develop NPH even when none of these factors are present. In these cases the cause of the disorder is unknown.21
Symptoms of NPH include progressive mental impairment and dementia, problems with walking, and impaired bladder control leading to urinary frequency and/or incontinence. The person also may have a general slowing of movements or may complain that his or her feet feel “stuck.”
Doctors may use a variety of tests, including brain scans (CT and/or MRI), a spinal tap or lumbar catheter, intracranial pressure monitoring, and neuropsychological tests, to help them diagnose NPH and rule out other conditions.10
Treatment for NPH involves surgical placement of a shunt in the brain to drain excess CSF into the abdomen where it can be absorbed. This allows the brain ventricles to return to their normal size. Regular follow-up care by a physician is important in order to identify subtle changes that might indicate problems with the shunt.21

Diagnosis
Hydrocephalus is diagnosed through clinical neurological evaluation and by using cranial imaging techniques such as ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), or pressure-monitoring techniques.23 A physician selects the appropriate diagnostic tool based on an individual’s age, clinical presentation, and the presence of known or suspected abnormalities of the brain or spinal cord.23

Treatments
Hydrocephalus treatment is surgical. It involves inserting a shunt system.21 This system diverts the flow of CSF from the CNS to another area of the body where it can be absorbed as part of the normal circulatory process. A shunt is a flexible but sturdy plastic tube. A shunt system consists of the shunt, a catheter, and a valve. One end of the catheter is placed within a ventricle inside the brain or in the CSF outside the spinal cord. The other end of the catheter is commonly placed within the abdominal cavity, but may also be placed at other sites in the body. A valve located along the catheter maintains one-way flow4 and regulates the rate of CSF flow.
Most shunts drain the fluid into the peritoneal cavity, so known as ventriculo-peritoneal shunt. But alternative sites include the:
1. right atrium -ventriculo-atrial shunt
2. pleural cavity -ventriculo-pleural shunt
3. gallbladder.
4. peritoneal cavity -ventriculo-pleural shunt A shunt system can also be placed in the lumbar space of the spine and have the CSF redirected to the peritoneal cavity.
An alternative treatment for obstructive hydrocephalus in selected patients is the endoscopic third ventriculostomy (ETV), whereby a surgically created opening in the floor of the third ventricle allows the CSF to flow directly to the basal cisterns, thereby shortcutting any obstruction, as in aqueductal stenosis. This may or may not be appropriate based on individual anatomy.
In this procedure, a neuroendoscope is used. Neuroendoscope is a small camera that uses fiber optic technology to visualize small and difficult to reach surgical areas. This allows a doctor to view the ventricular surface. Once the scope is guided into position, a small tool makes a tiny hole in the floor of the third ventricle, which allows the CSF to bypass the obstruction and flow toward the site of resorption around the surface of the brain.

Complications of a shunt system
Shunt systems are not perfect devices. Complications may occur. They include mechanical failure, infections, obstructions, and the need to lengthen or replace the catheter. Generally, shunt systems require monitoring and regular medical follow up. When complications occur, the shunt system usually requires some type of correction.
Some complications can lead to other problems such as over draining or under draining. Over draining occurs when the shunt allows CSF to drain from the ventricles more quickly than it is produced by choroid plexus. Over draining can cause the ventricles to collapse, tearing blood vessels and causing headache, hemorrhage (subdural hematoma), or slit-like ventricles (slit ventricle syndrome).10 Other symptoms are listlessness, irritability, light sensitivity, auditory hyperesthesia (sound sensitivity), nausea, vomiting, dizziness, vertigo, migraines, seizures, a change in personality, weakness in the arms or legs, strabismus, and double vision – to appear when the patient is vertical. If the patient lies down, the symptoms usually vanish in a short period of time.
Under draining occurs when CSF is not removed quickly enough and the symptoms of hydrocephalus recur. In addition to the common symptoms of hydrocephalus, infections from a shunt may also produce symptoms such as a low-grade fever, soreness of the neck or shoulder muscles, and redness or tenderness along the shunt tract. When there is reason to suspect that a shunt system is not functioning properly (for example, if the symptoms of hydrocephalus return), medical attention should be sought immediately.10
Other complications include shunt malfunction. Although a shunt generally works well, it may stop working if it disconnects, becomes blocked (clogged), infected, or it is outgrown. If this happens the cerebrospinal fluid will begin to accumulate again and a number of physical symptoms will develop. Examples are headaches, nausea, vomiting and photophobia/light sensitivity. Some extremely serious, like seizures. The shunt failure rate is also relatively high (of the 40,000 surgeries performed annually to treat hydrocephalus, only 30% are a patient’s first surgery22 and it is not uncommon for patients to have multiple shunt revisions within their lifetime

Other Mechanisms which may lead to insult in hydrocephalus
This includes a number of factors. Grossly, these include compression, stretch, edema, ischemia, breakdown of the blood-brain barrier (BBB), and toxicity due to poorly circulation of CSF. On the cellular level, pathways of cell death (neurons and glia), axonal degeneration and demyelination, neurotransmitter alterations, gliosis, changes in metabolism, and aberrant regeneration are probably important.
Studies in animal models suggest that calcium mediated damage may contribute to the insult in hydrocephalus.11 There are connections between CSF and the lymphatic system. This has been demonstrated in several mammalian systems. Preliminary data suggest that these CSF-lymph connections form around the time that the CSF secretary capacity of the choroids plexus is developed in utero. There may be some relationship between CSF disorders and impaired CSF lymphatic transport.11

Research Resources for Hydrocephalus
A number of animal models are used to research on adult hydrocephalus. Animal hydrocephalus models have been made in hamster, guinea pig, dog, rat, lamb, cat, and monkey. Many of these have histopathological similarities to what has been seen in human hydrocephalus.11 These are needed in order to allow comparisons across models and with human clinical findings. So that features can be interpreted in therapeutically meaningful ways. In order to improve the process of moving from animal models into clinical trials, several suggestions were made which are consistent with recommendations for studies in other fields (such as stroke), including: assuring that animal trials are appropriately randomized and the evaluations are blinded, having both short and long term outcome measures in animals. Then the validating results in separate laboratories prior to human trials, testing any therapy in more than a single non-human species. Animal models of hydrocephalus would be useful for evaluation of prenatal treatments as well as surgeons to develop knowledge in fetal techniques.

Findings of hydrocephalus
The present observations demonstrate uneven distribution of intracranial pulsatility in patients with hydrocephalus, higher pulse pressure amplitudes within the ventricular CSF than within the brain parenchyma. This may be one mechanism behind ventricular enlargement in hydrocephalus.24
Community-acquired Pseudomonas meningitis causes acute obstructive hydrocephalus. Pseudomonas aeruginosa (PS) infection is serious in children and can cause malignant external otitis, endophthalmitis, endocarditis, meningitis, pneumonia, and septicemia. The early stage of obstructive hydrocephalus caused by community-acquired Pseudomonas is rare and should be immediately detected.25
External ventricular drains (EVD) were placed for traumatic brain injury (TBI), ventriculoperitoneal shunt failure and new-onset hydrocephalus. The overall complication rate was 26%. Complication rates were similar in TBI and hydrocephalus patients, and with EVDs inserted in either the pediatric critical care unit or. Prophylactic antibiotics or antimicrobial-impregnated catheters directed against coagulase-negative Staphylococcus may reduce EVD infections.26

Decompressive craniectomy and postoperative complication management in infants and toddlers with severe traumatic brain injuries: Infants with severe traumatic brain injury can safely undergo decompressive craniectomy with reasonable neurological recovery. Due to the high rate of CSF fistulas encountered in most of the infants, it’s better to recommend both the suturing in of a dural augmentation graft and the placement of either a subdural drain or a ventriculostomy catheter to relieve pressure on the healing surgical incision. And also can use a T-shaped incision as opposed to the traditional reverse question mark-shaped incision. Because wound healing may be compromised due to the potential interruption of the circulation to the posterior and inferior limb with this latter incision.27
Although intracranial pressure (ICP) elevation can induce significant structural and functional changes within the central nervous system (CNS), almost complete neuronal recovery is possible. But ICP and associated pathogenic factors should be restored in the acute phase of the disease process. Endothelial cell nitric oxide synthase (ecNOS), an enzyme that plays a protective role in the CNS, is up-regulated in a time-dependent manner after pressure elevation. ecNOS levels increase after axonal and astrocyte injury, suggesting that it might be a compensatory response that is initiated in an effort to preserve CNS function. Changes in ecNOS levels are therefore be important in the development of neuronal tolerance in the early stages of CNS diseases such as hydrocephalus. 28
Visual disturbance in hydrocephalus occurs due to raised intracranial pressure. Patient who presented with marked loss of peripheral visual fields, but without features suggestive of raised intracranial pressure, MR scan showed an enlarged third ventricle and a downward displacement of the optic chiasm, Chiari II malformation. These radiological changes and the visual field deficits reversed after endoscopic third ventriculostomy and foramen magnum decompression. So the treatment of the hydrocephalus in such patients can help to reverse the change in the position of the optic chiasm and the visual field deficits.29
Neonatal ruptured intracranial aneurysms: Neonatal intracranial aneurysms are rare. Clinical presentation of subarachnoid haemorrhage in this age group is often non-specific. First-line investigation should start with transfontanelle cranial ultrasound, followed by MR angiography then CTA if necessary. Posterior circulation aneurysms and large or giant aneurysms are more frequent in neonates and children than in adults. Early diagnosis and treatment are important for improved outcome. Surgery is better tolerated than in adults.30
Exceptional case
One case involved a person with past hydrocephalus. He was a 44-year old French man, whose brain had been reduced to little more than a thin sheet of actual brain tissue. This was due to the buildup of fluid in his skull. The man had a shunt inserted into his head to drain away fluid (which was removed when he was 14), went to a hospital after he had been experiencing mild weakness in his left leg.
In July 2007, Fox News quoted Dr. Lionel Feuillet of Hôpital de la Timone in Marseille as saying: “The images were most unusual… the brain was virtually absent.31
When doctors learned of the man’s medical history, they performed a CT scan (figure 3) and MRI scan, and were astonished to see “massive enlargement” of the lateral ventricles in the skull. Intelligence tests showed the man had an IQ of 75, below the average score of 100 but not considered mentally retarded or disabled, either.
Remarkably, the man was a married father of two children, and worked as a civil servant, leading a normal life, despite having little brain tissue. “What I find amazing to this day is how the brain can deal with something which you think should not be compatible with life,” commented Dr. Max Muenke, a pediatric brain defect specialist at the National Human Genome Research Institute. “If something happens very slowly over quite some time, maybe over decades, the different parts of the brain take up functions that would normally be done by the part that is pushed to the side.”32, 33

Hydrocephalus is a disorder that occurs in the head due to various causes. The term hydrocephalus is actually derived from a Greek word which means accumulation of fluid within the head. One could add to the definition, ‘with a secondary increase in the CSF spaces’1, so that in practical clinical terms, one can observe an increase in the ventricular or subarachnoid space in a CT scan. However, the definition makes no reference to the level of intracranial pressure (ICP). But generally, hydrocephalus has to be associated the increased intracranial pressure1. This has to be very much correct because when there is an increased CSF volume, it should definitely lead to an increased pressure in the cranium.

CSF
Cerebrospinal fluid is a fluid that circulates in the cavities of the brain. It is produced by the choroid plexus in the lateral ventricles, from where it flows through the foramen of Munro into the third ventricle and then into the fourth ventricle via the aqueduct of Sylvius. It leaves the ventricular system via small openings in the roof of the fourth ventricle, called the foramina of Magendie and Luschka. From here the fluid flows in the subarachnoid space before being reabsorbed into the blood supply via arachnoid villae.
In normal subjects, CSF is produced at a rate of 0.3-0.5 ml/min. But even when the production rate is normal, the accumulation of CSF can occur due to some obstruction, leading to the hydrocephalus condition.
The CSF formation rate can be influenced by: increased secretion that occurs with a choroid plexus papilloma, Frusemide and Acetazolamide and hypothermia2.
The cerebrospinal fluid production occurs by two main mechanisms:
→ That dependent on choroidal capillary blood flow from which itself is a two step process with, first, an ultra filtrate of plasma produced hydrostatically through the lax choroidal capillary endothelium and second, an active process involving secretion of sodium into and out of the apical choroidal villi. The raised osmotic pressure causes water to follow passively.
→ The second mechanism is a direct neurogenic stimulation of choroidal villi, which is independent of choroidal blood flow. Stimulation of adrenergic fibres may reduce CSF flow by approximately one-third.

CLASSIFICATION OF HYDROCEPHALUS
Hydrocephalus can be generally classified into a communicating and a non-communicating type.
In communicating hydrocephalus, the ventricular pathways are clear and a failure of reabsorption (following, for example, in the case of bleeding into the subarachnoid space) results in increased cerebrospinal fluid volume.
In non-communicating type or obstructive hydrocephalus, the blockage occurs at one of the ventricular levels, with expansion of the ventricular system above the block.
Hydrocephalus can also be classified further into:
→ Panventricular hydrocephalus :- dilation of the lateral third and fourth ventricles (in aqueduct stenosis the fourth ventricle is smaller than the normal size). An isolated fourth ventricle (‘double compartment hydrocephalus’ or ‘trapped fourth ventricle’) occurs when there is outlet obstruction from that ventricle and stricture of the aqueduct.

→ Unilateral hydrocephalus:- abnormal dilation of the body, frontal and/or posterior horn of the lateral ventricle on one side. This may be due to compression of the ventricular system on the opposite side, obstruction to one foramen of Munro, slit ventricle syndrome or a hemi parenchymal atrophy.

→ Slit ventricle:- a reduction in the size of the ventricular system seen on a CT scan, usually in response to excessive CSF drainage. The slit ventricle syndrome is distinguished from radiological slit ventricles by the presence of symptoms and clinical signs caused due to this overdrainage.

AETIOLOGY
Hydrocephalus may be due to congenital causes such as the Arnold-Chiari malformation in Spina bifida cystica, stenosis or forking of the aqueduct of Sylvius, atresia of the Foramina of Magendie and Luschka, failure of development of the basal subarachnoid cisterns, and congenital toxoplasmosis. Rarely, the disease is inherited as a recessive sex-linked condition when due to atresia of the aqueduct. There is also an autosomal recessive form due to atresia of the foramina of Luschka and Magendie, when the fourth ventricle distends into a huge cyst (Dandy-Walker syndrome). Acquired causes of hydrocephalus include the reaction of the meninges to pyogenic or tuberculous meningitis, intracranial tumours, intracranial haemmorhage at birth, metastatic tumours and brain abscess.
The general aetiology of hydrocephalus is summarized in the Table 1 below.

Table 1 Aetiology of hydrocephalus
Causes of prenatally determined hydrocephalus

Congenital (chromosomal) malformations
Maternal diabetes resulting in holoprosencephaly
Neural tube defects
Occipital meningocele and encephalocele
The Cleland-Chiari II malformation
Dandy-Walker syndrome
Hydraencephaly
Multicystic encephalomalacia
Schizencephaly
Achondroplasia
Arachnoid cysts
Quadrigeminal plate cysts, retrocerebellar cysts, cysts of the cerebellopontaine angle and supracellar cysts
Congenital craniosynostosis (e.g. Apert’s Syndrome)
Agenesis of the corpus callosum and cysts of the cavum septum pellucidum and cavum vergae
Encephalocraniocutaneous lipomatosis
Isolated stenosis of the Aqueduct of Sylvius
Sex-linked stenosis of the Aqueduct of Sylvius
Hydrocephalus associated with giant hairy nervus (melanosis of the leptomeninges)
Aneurysm of the great vein of Galen
Hurler’s disease
Basilar impression
Osteogenesis imperfecta (rarely)
Paget’s disease
Colpocephaly
Lissencephaly
Say-Gerald syndrome

Causes of acquired hydrocephalus

Posthemorrhagic causes
Neonatal intraventricular hemorrhage
Subarachnoid hemorrhage
Subdural hemorrhage
Postmeningetic causes
Toxoplasmosis
Mumps (aqueductitis, ependymitis)
Pyogenic organisms (pneumococcus, haemophilus, etc.)
Cytomegalovirus
Other viral meningitides
Rubella
Tuberculous meningitis and tuberculoma
Space occupying causes
Tumor
Clot
Cyst
Abscess
Postasphyxial
Injury

Other causes
Stenosis of the aqueduct of Sylvius
1. Due to raised intracranial pressure with secondary kinking of the aqueduct
2. Due to aqueductitis and ependymitis associated with mumps, toxoplasma, tuberculomas, pyogenic meningitis, rarely CMV, rubella and tumors.

Dystrophia myotonia
Otitic hydrocephalus
Choroid plexus papilloma
Intrathecal contrast agents
Fungal infection (Cryptococcus and blastomyces)
Cysticercosis
Sarcoidosis
Spinal tumor
Dural venous thrombosis
Isolated Chiari type I deformity

Alcohol can also have a serious damaging effect on the developing nervous system. It is one of the commonest causes of learning difficulty and neuro behavioural disturbance in young children across the world. The reduced brain mass and neuro behavioural disturbances associated with fetal alcohol syndrome may be reflected in the recent observation in rats that ethanol can trigger widespread apoptotic neurodegeneration.
Alcohol has harmful effects throughout the developing pregnancy, unlike some known teratogens. There is a significant risk of fetal alcohol syndrome associated with higher dose exposure (estimated blood alcohol concentration of 150 mg per deciliter or more, at least weekly for several weeks in the first trimester).
Congenital infections can occur due to teratogens like cytomegalovirus, herpes simplex, parovirus, rubella, syphilis, toxoplasmosis and varicella. The risk of congenital infections and the outcome of such infection is crucially dependent on the stage of pregnancy.
The differential diagnosis of microcephaly is important for the recognisation of congenital infections. Intracranial calcification identified on a cranial ultrasound or CT scan during the investigation of developmental delay or seizures should arouse suspicion of congenital infection, especially cytomegalovirus or toxoplasmosis (calcification is not picked up well by MRI). Detailed ophthalmological assessments may reveal clues such as chorioretinis or cataract that may help in the retrospective diagnosis of congenital infection.

SIGNS AND SYMPTOMS
The clinical features depend on whether the disease process is acute or chronic and whether the process produces complete or partial obstruction. The acute presentation is usually accompanied by severe headache, nausea and vomiting. There are usually no localizing symptoms or signs, but there is papilloedema and there may be a sixth nerve lesion.
The symptoms and signs of progressive hydrocephalus in infants are listed in Table 2 below.

Table 2 Most common clinical features of progressive infantile hydrocephalus (50% of cases are asymptomatic)

Symptoms
Headache or irritability
Vomiting
Anorexia
Drowsiness or lethargy

Signs
Inappropriately increasing OFC (approx. 75%)
Tense anterior fontanel
Splayed sutures
Scalp vein distension
Sunsetting (loss of upward gaze)
Neck retraction or rigidity
Pupillary changes
Neurogenic stridor
Decerebration

Usually the symptoms of progressive hydrocephalus in infants are vague. They may show irritability and vomiting. But about half the cases, no symptoms can be felt.
But some common clinical signs are inappropriately increasing head circumference, followed by a tense nonpulsatile fontanel, then clinical and radiological separation of the sutures, scalp vein distension with taut skin over the scalp. A very common sign of hydrocephalus is due to compensation for raised ventricular pressure called ‘sunsetting’. This is the inability to look upwards. It may initially be intermittent but becomes continuous later. This is caused due to the pressure on the superior quadrigeminal plate against the free edge of the tentorium causing paralysis of the fourth nerve.
Neurogenic stridor is a result of deranged lower brainstem function caused by bilateral corticobulbar disruption and is a feature of pseudobulbar paresis. Abnormalities of sucking and feeding may also occur in hydrocephalic infants with seriously raised intracranial pressure.
The symptoms of chronic hydrocephalus can be see in poor performance at school, intermittent headaches over many months, behavioral and personality changes, failure to thrive and dizziness.
Arrested long standing hydrocephalus show distinct signs and symptoms, such as ataxic and spastic cerebral palsy, precious puberty, mental retardation and specific learning problems. Older infants who present with enlarged head circumference but is otherwise asymptomatic is likely to have hydrocephalus if there is additional development retardation.
Since unusual features of raised ventricular pressure include neurogenic pulmonary edema, profuse sweating, ptosis, neurogenic stridor, pseudobulbar paresis and skin rashes.

DIAGNOSIS AND ASSESSMENTS
Prenatal diagnosis and termination of affected pregnancies is only one of a range of reproductive options open to parents at increased risk of having children with neuro developmental abnormalities such as hydrocephalus (congenital). For the majority of developmental disorders of the nervous systems preimplantation genetic diagnosis is not yet feasible. For a condition with a strong environmental component, it is imperative that measures are taken to minimize the risk of exposure in future pregnancies. For neural tube defects, preconceptual supplementation with high-dose folic acid has been shown to reduce the risk of recurrence in future pregnancies. When a specific diagnosis has been made and a chromosomal anomaly, genetic mutation, or biochemical defect has been identified, it is normally possible to offer prenatal diagnosis by chorionic villus sampling at 11 weeks of gestation in a future pregnancy. If this is not the case, detailed ultrasound scanning may be helpful in some instances; for example, neural tube defects where anencephaly can be easily visualized by 13 or 14 weeks of gestation, and spina bifida by 18 to 20 weeks.

HOW TO APPROACH HYDROCEPHALUS?
Hydrocephalus is a condition which can be easily be observed in a patient. Except during early stages or during infancy (when there is a genetic defect), the abnormalities occurring due to hydrocephalus is very prominent. An abnormally large head, a frontal bulking, crushing pain in the head, a heavy feeling in the head are all probable symptoms of hydrocephalus.
When a patient is quite suspicious of his condition, to confirm his situation, he should visit a doctor. The meeting should be arranged as early as possible. The patient can also obtain lot information about hydrocephalus from the internet3. A lot people suffering from this problem discuss their condition in various forums dedicated to hydrocephalus. There are also contributions from expert doctors giving their advice. Even patients, who have been treated successfully from hydrocephalus, give advice and hope to others in the forum.
Not all forms of hydrocephalus are completely treatable. They can be relieved a little, but not always completely. In such cases, the person may turn out to be hopeless and depressed. But when one goes through the forum thoroughly, he may come across a person who might have had a similar problem or one who is sharing the same problem. They may share advice, tips and most importantly some hope between each other.
Counseling is always very helpful in such situations. The patient may feel depressed and embarrassed of his abnormality in his head. Thus they may be morally deteriorated. Hence, they should regularly undergo counseling till things turn out to be fine for them.

CLINICAL ASSESSMENT
X-ray examination of the skull may show a ‘copper-beaten’ appearance, shallow orbits and splayed sutures. Computed axial tomography, ultrasound or magnetic resonance image scans will all define ventricular size. Although repeated ultrasound examinations may show progressive hydrocephalus, it is advisable to have a definite CT or MRI investigation prior to any surgical intervention. The CT scan requires sedation or anesthesia in case of infants and young children. CT scans provide information about the size and symmetry of the ventricles and whether there is any underlying pathology. A single CT scan, like a single ultrasound or MRI scan, may not reveal whether there is a progressive or an arrested hydrocephalus. When there is significantly elevated intraventricular pressure from progressive hydrocephalus, periventricular lucenics, rounding of ventricles, absence of a cortical subarachnoid space and a spherical appearance of the third ventricle are seen on CT scan.
A study4 was done in Department of Radiology and Center for Imaging Science, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, to characterize the computed tomography (CT) and magnetic resonance (MR) imaging findings and clinical features of intraventricular (IV) meningiomas. 12 patients (Five men and seven women, whose mean age was 36 years and the age range was 14-68 years) with pathologically proven IV meningiomas were considered for this study. 8 of them had CT scans. Whereas all 12 of them had MRI scans taken. Particular attention was put on the size and shape of the mass; internal architecture such as necrosis or calcification within the tumor; peritumoral edema; associated hydrocephalus and clinical features such as symptoms, treatment, and prognosis. The result obtained was as such: There were five of benign, three of atypical, and four of malignant subtype. All lesions were located in the lateral ventricle ranging in maximum diameters from 4.0 to 7.3 cm (mean, 5.4 cm). All tumors had lobulated shape. Five (71%, 5/7) of the atypical and malignant IV meningiomas, but just two (40%, 2/5) benign IV meningiomas, had irregular lobulation. The tumors were isointense (n=7) or hypointense (n=5) to gray matter on T1-weighted images, whereas isointense (n=9) or hyperintense (n=3) on T2-weighted images. On gadolinium-enhanced T1-weighted images, homogeneous enhancement was seen in five lesions, and heterogeneous enhancement was seen in seven lesions, Most patients (n=10) had associated localized hydrocephalus due to ventricular entrapment. Intratumoral necrosis was seen in two cases (17%, 2/12), all of these were malignant subtype. In two cases of atypical and malignant subtypes, recurrences were found during the follow-up period after surgical resection. CONCLUSION: More than half (n=7, 58%) of the IV meningiomas were of atypical (n=3) or malignant (n=4) subtype. IV meningiomas tend to have a lobulated shape, especially irregular lobulation, and intratumoral necrosis was frequently seen in the atypical or malignant subtypes.
The most commonly used index of ventricular dilation is the V/P ratio, that is, the ventricular diameter at the mid-portion of the lateral ventricles divided by the biparietal diameter from inner table to outer table. Hydrocephalus is defined as a ration higher than 0.26.
The ultrasound for assessment of fetal hydrocephalus is indexed slightly differently. The commonly used parameters are biparietal diameter and the ratio of the lateral ventricular width divided by the width of the head. The latter is approximately 0.61 at 14 weeks, 0.29 at 27 weeks and 0.29 at term. Absolute measurements of ventricular width are done using the atrium as reference point. Ultrasound estimate of ventricomegaly in utero may be exaggerated by a factor of about 10% due to the distortion of sound signals passing through two thirds (amniotic and CSF). If hydrocephalus is suspected, ultrasound is done weekly with elective cesarean section at 36 weeks. Intracranial Doppler blood flow velocities should be measured in addition to the BPD.

TREATMENT
The primary priority of treating hydrocephalus would be to reduce the intracranial pressure. This can be done by creating valves and shunt systems in order to divert the CSF from the ventricular system to another site. There are various routes through which this can be done5. For example, Spitz-Holter valve (a device with a tiny one-way valve that released controlled amounts of the cerebrospinal fluid from the brain into the atrium of the heart), Dudenz-Hakin, the Indian valve, Raimondi, etc. with latest development in technology, more sophisticated types of pressure opening devices such as the Sophy programmable and multi programmable and the Cosman ICP telesensor, have been invented to make the treatment less and complicated and more safer.
One of the earliest routes of drainage was the ventricular atrial route in which the distal tube was passed by the common facial vein into the right atrium. On occasions a ventriculo azygous route was employed. But there were obvious complications evolving from this procedure leading to serious condition. Acute infection with these shunts may is automatically accompanied by septicemia and chronic infection may result in shunt nephritis or unexplained rashes of a vasculitc nature due to complement activation from chronic septic emboli. The other chronic effects from this procedure are right heart failure from pulmonary hypertension and bacterial endocarditis, thrombosis of the superior vena cava with superior vena caval syndrome arrhythmias and possible perforation of the myocardium. The probabilities of such infections occurring are 10-30%.
There are many variations in the basic shunt system. Some shunt systems have a twin valve, one arranged proximally and another distally and some include a pump or flushing device. In the newborn a device which opens at the low pressure is advisable to drain the CSF, but as the child grows it may be necessary to avoid the development of overdrainage and cranio cerebral disproportion. A valve may be incorporated in the pump (Spitz-Holter system) or it may be a distal ‘slit valve’ at the peritoneal end. It may be a single continuous stiff tube with radiopaque gradation to avoid kinking, such as the Raimondi System.
Table 3 Complications of CSF shunting

Blockage by choroid plexus, fibrin, neuroglia, blood clot and brain segments causing raised intracranial pressure
Fractured tubing: fracture off the distal tubing may occur in the neck as a result of direct trauma or kinking of the tubing with repeated movements (fracture can also occur over the surface of the chest and exaggerated flexion/extension movements may result in a crack in the distal tube)
Infection (colonization and ventriculitis) with raised intracranial pressure
Shunt dependence
Slit Ventricle syndrome
Other decompressive effects (e.g. subdural hematoma)
the tubing Migration of proximally or distally: cases have been reported of migration of the distal tubing through the gut wall or penetration of other organs. (Cases are known where the tubing has dramatically retracted from the abdominal cavity to the intracranial space. Migration of the distal tubing may cause a volvulus. Commonly if insufficient length is implanted initially, the tubing may retract subcutaneously over the chest wall with growth. Migration of the proximal catheter extending into a different ventricle or into subcortical structures)
Intestinal obstruction (volvulus)
Peritonitis and peritoneal fibrosis
Endocarditis (VA shunts)
Chronic pulmonary hypertension (VA shunts)
Superior vena caval syndrome (VA shunts)
Arrhythmias (VA shunts)
Shunt nephritis (VA shunts): a case has been reported of shunt nephritis following a VP shunt
Hyperlordosis (TP shunts)
Acute noncomminucation (with TP shunts)
Product failure due to mechanical deficiency and faulty valve
Surgical technique (malplacement or displacement)
Ventricular collapse from excessive drainage causing the tip of the catheter to impinge through the ependyma or brain substance
Pseudocyst formation with defective drainage

Introduction
The term hydrocephalus is of Greek origin which means “the abnormal accumulation of fluid within the head“.1 Hydrocephalus results from the expansion of ventricles secondary to a block in the normal pathway of cerebrospinal fluid (CSF).2 The normal intracranial pressure in humans represents a balance between the intracranial contents that is blood brain n CSF. Any increase in the production, obstruction of flow or absorption will result in ventricular dilation.2 In hydrocephalus there is an increased pressure in the ventricular system.It is usually secondary to obstruction of CSF flow in the ventricular system(non-communicating) or failure of CSF reabsorption (communicating).6 In normal subjects CSF is formed at a rate of 0.3-0.5ml/min.In hydrocephalus patients on external drainage the CSF production rate is similar .
The production rate is similar in newborn and older children. A number of factors influence the CSF formation rate .Increased secretion may occur with a choroid plexus papilloma. Frusemide and acetazolamide reduce CSF production .Hypothermia will also reduce the rate of production and although pressure, when high intraventricular pressures exist the production rate falls,due to decreased choroidal perfusion. Ventricular outflow rates appear to be pulsatile so that peaks and troughs of CSF evaluation occur from ventricles when measured objectively in children undergoing closed ventricular drainage.2
It is usual to measure CSF pressure by lumbar puncture,but this may accurately reflect pressure in the brain,for example if there is obstruction by spinal tumours or herniation of brain through the foramen magnum .The main causes include tumours, abscesses, hydrocephalus ,haemotomas and benign intracranial hypertension.

Effects of raised intracranial pressure
A rise in the intracranial pressure is usually associated with headache ,especially in the morning, nausea, vomiting and loss of vision and balance. There may be false localizing signs, for example sixth nerve palsies. The most reliable sign is the appearance of papilloedema but this is not always seen even when the pressure is high. Urgent action to reduce pressure is needed in patients with impending herniation of brain through foramen magnum.4
Raised intracranial pressure results in either ischemic or brain shift. The ischemia results from a reduced cerebral perfusion pressure(CPP) (mean arterial pressure minus intracranial pressure). At levels of CPP below 60mmHg in the older child there is a progressive reduction in brain perfusion .At 40-50mmHg profound ischemic results. In the newborn , cerebral perfusion pressures 30mmHg may be associated with a normal neurodevelopment outcome.1 The subarachnoid space and the aqueduct are obliterated after shunting ,presumably because they are used less, and the patient become totally shunt dependant.
Fourth ventricular entrapment , with ataxia ,vomiting , cranial nerve disturbances and headache, is a result of outlet obstruction. Treatment is shunting of ventricle itself. Fistulous communications and diverticulae of the ventricles are usually an accompaniment of severe ventricular dilation.This produces a complex CT scan appearance and intraventricular contrast studies are needed to distinguish these from primary arachnoid cysts.1

CSF production
CSF production occurs by two mechanisms:- One mechanism which depends on the choroidal capillary blood flow where an ultra filtrate of plasma produced hydrostatically through the lax choroidal capillary endothelium (blood-barrier).Also an active process involving secretion of sodium into and out of the apical choroidal villi. The raised osmotic pressure causes water to follow passively. The second mechanism is a direct neurogenic stimulation of choroidal villi which is independent of choroidal blood flow.1 CSF is produced by choroid plexus in the lateral ventricles,from where it flows through the foramen of Munro into the third ventricle and then the fourth venricle via aqueduct of Sylvius. It leaves the ventricular system through the small openings in the roof of the fourth ventricle, the foramen of Magdie and Luksha. From here the fluid flows in the subarachnoid space before being reabsorbed into the blood via arachnoid villae.2 Therefore hydrocephalus is an increase in the ventricular or subarachnoid space 1 which is clearly visible in a CT scan 1,2,3
A rise of pressure in CSF above 250mm is usually due to a serious neurological disease which is caused by space occupying lesion that is obstruction to the outflow of venous return.4
Causes of Hydrocephalus
Hydrocephalus may result from a variety of causes including :
Communicating hydrocephalus: Due to excess production of CSF in (choroid plexus papilloma) or impaired CSF absorption(in meningitis) or Cerebral dysgenesis or atrophy.4 In congenital malformation,tuberculous meningitis,Arnold-Chiari malformation,subaracnoid haemorrhage and post-hemorrhagic in preterm infant.6
Non-Communicating hydrocephalus: Due to obstruction of flow of CSF (intracerebral tumours, aqueduct or foramen stenosis,by blood in subarachnoid haemorrhage).4,5 In atresia of outflow foramina of fourth ventricle(Dandy-Walker Malformation and post-intracranial infection.6

Acquired causes of hydrocephalus include the reactions of the meninges to pyogenic or tuberculous meningitis , intracranial haemorrhages at birth, metastatic tumours and brain abscess. In non-communicating hydrocephalus a dye such as phenolsulphonphthalein, when injected into one of the greatly dilated ventricles, fails to reach the subarachnoid space.When communication exists between the fourth ventricle and the subarachnoid space the hydrocephalus is of communicating type .The distinction in relation to surgical treatment.5 Internal hydrocephalus, external hydrocephalus, and the syndrome of intracerebral cerebrospinal fluid entrapment : a challenge to current theories on the pathophysiology of communicating hydrocephalus is still debatable.11 Obstruction of the CSF circulation distal to the fourth ventricle is a rare cause of noncommunicating hydrocephalus.12

Obstruction of CSF

A choroid plexus tumour may not only induce excessive CSF production but may also block the outlet of the ventricles intracranial haemorrhage or meningitis may cause leptomeningeal adhesions and obsruction to the CSF flow as well as impairing absorption by blocking arachnoid granulations.A common site for the obstruction is the aqeduct of sylvius. Congenital atresia may result inadequate lumen or a total blind-ending channel with forking of the upper and lower components of aqueduct. Occasionally there is a filamentous or membranous obstruction which may be broken down either by an increase in the intraventricular pressure or by surgical bouginage from the fourth ventricle. This rarely results in an effective reduction of the hydrocephalus because inadequate development of the peripheral subarachnoid pathways, which has resulted from the noncommunicating hydrocephalus, means the dynamics are only changed from a no communicating to a communicating hydrocephalus. The aqueduct of Sylvius may also be occluded by organized blood clot after intracranial hemorrhage, inflammatory exudate following ventriculitis or from an aqueductitis resulting from mumps.
Obstruction to CSF flow at the outlet foramina of the fourth ventricle may be secondary to intracranial hemorrhage or infection or may be due to congenital failure of the foramania of Magendie and Luschka to open during development. Occlusion of the fourth ventricle results in a fourth ventricular cystic dilation with atrophy of the cerebellum (the Dandy-Walker cyst). Tumors or clots, cysts or acscesses within or adjacent to the ventricular system may result in hydrocephalus. Thalamic tumors may obstruct the foramen of Monro and third ventricle and pontine or brainstem gliomas may distort the aqueduct of Sylvius although frequently such pontine gliomas are invasive throughout the brainstem and do not usually cause a gross hydrocephalus.Cerebellar tumors will affect the CSF flow from the fourth ventricle.A choroid cyst of the third ventricle may give rise to intermittent high pressure and hydrocephalus by obstructing the foramen of Munro in a ‘ballcock’ fashion.During distention of the cyst or venous distention about it there is obstruction of CSF flow through the foramen of Munro.With a possible change of posture the obstruction may be rapidly released and the pressure declines.These children with cysts of the third ventricle frequently present with a ‘bobble-headed doll’ syndrome and progressive loss of interlect with a particular frontal horn dilation.1
Hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage. Numerous studies have dealt so far with the triggering cause of the chronic cerebrospinal fluid (CSF) absorptional and circulatory disorders.The rate of the incidence of chronic hydrocephalus suggests that disturbance of CSF circulation and/or absorption may be drainage, which avoided in the majority of cases by continuous external ventricular or lumbar CSF.9

Decreased absorption of CSF
Decreased absorption may result from obstruction of the arachnoid villi or either peripheral subarachnoid pathways.Absorption (unlike formation) of CSF is apressure dependant phenomenon and measures linearly with CSF pressure.There are three types of absorptive defect.Normally CSF absorption begins at a mean pressure of 5mmHg.In some patients the opening pressure for absorption is elevated but the subsequent slope is normal . In others the slope alone is decreased and in the third group the resistance to absorption is increased at the pressure is raised.1

Factors causing progression of hydrocephalus
Observations in experimenta hydrocephalus suggest that after CSF obstruction the ICP rises acutely. This is followed by a stage of per ventricular edema which expanded ventricles and subsequently by an increase in CSF absorption. Ventricular dilation and its eventual size depend on the external support of the brain. In infants up to 16 months of age the support of the brain is weak from the poorly myelinated soft parenchyma and there are unfused sutures.Clearly the level of pressure is important at first in the pathogenesis of ventricular dilation,together with the known increase in the outflow resistance and a higher ‘pressure volume index’(PVI) tan could be predicted from the volume of cranial and spinal axis.
In term n preterm infants we frequently see levels of intraventriclar pressure of 5mmHg (above normal for age) which are sufficient to interfere with the cerebral blood flow velocity and have the potential to cause ischemia.
A number of physiological buffers come into play in response to the hydrocephalus. There is collapse of cerebral veins , a shunting of CSF from the ventricular to the spinal CSF compartment, expansion of the skull and a increase in the CSF absorption from the raised pressure. There may also be increased CSF absorption about the spinal nerve roots and paranasal sinuses etc .Once these compensatory mechanisms have been exhausted then further progression of the hydrocephalus will occur.
The sequence of events is that at first the pressure will increase. The dilation of the ventricles in response to this high pressure is termed ’active or progressive hydrocephalus’. Finally the pressure returns to the normal levels with severely dilated ventricles ,a state of arrest (compensated or arrested hydrocephalus).Sometimes the active process may be followed by an intermittent pressure pattern with ventricular dilation until arrested is reached .This intermittent pattern may be reversible .However significant elevation of the pressure with increasing ventricular dimensions to the point where brain perfusion is compromised necessitates CSF diversion procedures before shunt-dependant or compensated arrest occurs.1

Infantile Hydrocephalus
Hydrocephalus maybe due to congenital causes such as Arnold-Chiari malformation in spina bifida cystica .3,5 There is an elongation of the medulla. Abnormal cerebella tonsils descend into the cervical canal associated spina bifida is common and Syringomyelia may develop.3 Stenosis or forking of aqueduct of Sylvius.3,5 This is either congenital or acquired following neonatal meningitis or haemorrhage.3 Atresia of the foramina of Magendie and Luschka ,failure of development of the basal subarachnoid cisterns ,and congenital toxoplasmosis.5 Rarely the disease is inherited as a recessive form due to atresia of the aqueduct .There is a also an autosomal recessive form due atresia of the foramina of Luschka and Magendie when the fourth ventricle distends into a huge cyst(Dandy-Walker syndrome).3,5 Head enlargement in infancy occurs in 1 in 2000 live births.3 New born baby’s head circumference is measured with a paper tape measure and it’s centile noted. This is a surrogate measure of brain size.6 A variety of congenital abnormalities may lead to hydrocephalus which may be present before birth (and hence produce difficulties at birth) or develop during childhood or adult life.
Progressive enlargement of the head is usually obvious with failure of closure of the frontanelles. Milestones of development are delayed and the end result may be mental retardation complicated by epilepsy and motor impairment. CT scan or MRI may show the abnormality and sometimes the cause, the early implantation of a shunt may arrest the physical and mental retardation that would otherwise occur.4
Most common clinical features of progressive infantile hydrocephalus;
Symptoms- headache or irritability, vomiting, anorexia, drowsiness or lethargic.
Signs- tense anterior fontanel, splayed sutures, scalp vein distension, sunsetting, neck retraction or rigidity, papillary changes, Neutrogena stridor, decerebration. 1
L1 disease is the most common genetic cause of congenital hydrocephalus.7 Mutations in the L1CAM gene are associated with an overlapping clinical spectrum of four X-linked neurological conditions, characterized by hydrocephalus, mental retardation, lower limb spasticity and adducted thumbs. Brain anomalies are frequently present in L1 disease. We describe these anomalies by reporting a case of a male newborn presenting with congenital hydrocephalus along with corpus callosum agenesis and enlargement of the massa intermedia. These findings, in association with the presence of clasped thumbs, raised the suspicion of L1 disease, which was confirmed by the detection of a mutation in the L1CAM gene. In cases of congenital hydrocephalus, recognition of the brain anomalies associated with L1 disease may contribute to pursuing the genetic analysis needed for the diagnosis and genetic counseling.7

Hydrocephalus in Adult life 3
Hydrocephalus can be an unsuspected symptomless finding or imaging ,or infantile hydrocephalus can become apparent in adult life .Combinations of headache , conginitve impairment, vomiting , papilloedema ,ataxia and bilateral pyramidal signs occur. Hydrocephalus may develop in cicumstances:
Posterior fossa brainstem tumours obstruct the aqueduct or fourth ventricle outflow.
Following subarachnoid haemorrhage, head injury or meningitis(particularly tuberclous)
A third ventricle colloid cyst causes lateral ventricle enlargement, headache and papillaoedema . These rare intraventricular tumours also sometimes produce intermittent hydrocephalus,recurrent prostrating headaches with episodes of lower limb weakness.
Choroid plexus papilloma (extremely rare) secretes CSF.3
Head circumference – occipital circumference is a measure of head and brain growth .The mean of 3 measurement is used. It is of particular importance in developmental delay or suspected hydrocephalus.6

Clinical features
In infants with hydrocephalus the head circumference is disproportionately large or its rate of growth is excessive, the sutures become separated and the veins get congested.The anterior frontanelle pressure ,with the infant relaxed , will feel increased on palpation and will subsequently bulge. If left untreated ,the eyes deviate downwards ( setting-sun sign).The infant subsequently develops signs and symptoms of raised intracranial pressure .hydrocephalus may be diagnosed on antenatal ultrasound scanning , when the infant is asymptomatic . In older children , clinical features are due to raised intracranial pressure. 6
The appearance and size of the head are related more to the age of onset of the hydrocephalus than to its cause. Thus, hydrocephalus can obstruct the course of labour. In most cases the hydrocephalus only appears after birth. In infancy it causes a progressive enlargement of the head which assumes a globular shape with overhanging forehead and disproportionately small face. The increasing enlargement should be assessd by regular measurements of the skull circumference. The fontanel’s are greatly enlarged and somewhat tense, and the sutures may gape widely. Dilated veins are often prominent over the scalp. The eyeballs tend to be pushed downwards so that a rim of sclera is visible between the iris and upper eyelid. Neurological manifestations include squints, optic atrophy, and spastic paraplegia or tetraplegia. The degree of mental retardation is variable and not closely related to the thickness of the cerebral cortex. In severe cases failure to thrive and marasmus are common.
When the obstruction to the cerebrospinal fluid pathway occurs later in childhood there may be little or no enlargement of the head, but there will be then be such signs of increased intracranial pressure as headache, cerebral vomiting, a cracked- pot sound on percussion of the skull, papilloedema and radiographic changes in the bones of the vault.5
The symptoms of infantile progressive hydrocephalus are vague and consist of irritability and vomiting but about half without symptoms. The most common clinical sign is an inappropriately increasing head circumference, followed by a tense nonpulsatile fontaniel, then clinical and radiological separation of the sutures, scalp vein distension with taut skin over the scalp. It is important to realize that the classic adult presentation of raised intracranial pressure is rare in children (headache, vomiting, papilledema).
Vomiting is a nonspecific symptom in childhood, as are behavioral changes (irritability).
The most common sign of hydrocephalus is really a sign of compensation for the raised ventricular pressure. “Sunsetting’- the inability to look upwards -may initially be intermittent and later continuous. It is due to pressure on the superior quadrigeminal plate against the free edge of the tentorium causing paralysis of the forth nerve.
Neurogenic stridor is a result of deranged lower brainstem function caused by bilateral corticobulbar disruption and is a feature of pseudo bulbar paresis. Abnormalities of sucking and feeding may also occur in hydrocephalic infants with seriously raised intracranial pressure. 1
Papilledema is rare but distended retinal veins are common.
The symptoms of chronic hydrocephalus are an isiduos deterioration in school performance,intermittent headaches over many months,behavioral and personality changes ,failure to thrive dizziness. These are distinct from the signs and the symptoms of arrested hydrocephalus of long standing which include features of ataxic and spastic cerebral palsy, precocious puberty , mental retardation and specific learning problems. The clinical features of hydrocephalus with raised intracranial pressure may be extremely variable and any infant with a rapidly increasing head circumference but is otherwise asymptomatic is likely to have hydrocephalus if there is additional development retardation.1
Clinical features of decompensate hydrocephalus
The possibility of a blockage of a shunted hydrocephalus is suggested by additional signs of raised pressure median survival time for a verticuloperitoneal shunt is 4.31years.
Unusual features of raised ventricular pressure include Neutrogena pulmonary edema, profuse swelling, ptosis, Neurogenic stridor, pseudobulbar paresis and skin rashes.1
Symptoms- vomiting, drowsiness or lethargy, headache, anorexia, valve malfunction, sleep disturbans, seizures.1
Signs- No clinical signs (approx 25 %),decreased conscious level,acute squint .neck retardation.distended retinal veins, sluggish palpable valve mechanisms.1
Differential Diagnosis
This is rarely difficult. The most important differentiation in infancy is from chronic subdural hecatomb , because the latter condition is eminently curable. Subdural taps should always be performed in doubtful cases. In the rare genetic disorder called macrocephaly there is generalized enlargement of the brain although the child is mentally diffective and may have optic atrophy. It can be differentiated from hydrocephalus by pneumoencephalography, but ultra sound and CT scanning are now the preferred techniques as they are non-invasive, free from risk and less disturbing for the patient.5
Management
Assesment of ventricular dilation is with cranial ultra sound/CT/MRI scan treatment required to release the raise in intra cranial pressure and minimize risk of neurological damage. The main stay is insertion of ventricular shunt, but endorscopic treatment is being developed. Shunt revision may be required if there is symptomatic malfunction from obstruction, infection (usually with coagulase negative staphylococcus) which is unresponsive to antibiotics or over drainage of fluid.6
Treatment

Ventricul-atrial or ventriculo-peritoneal shunting becomes necessary when progressive hydrocephalus causes symptoms. neurosurgical removal of tumours should be carried out where appropriate ,sometimes urgently.3 It is essential to realize that 40 percent of all cases of hydrocephalus in infancy undergo spontaneous arrest. Surgical treatment should be confined to cases in which serials measurements of head circumference show progressive and rapid enlargement. Hydrocephalus develops in about 80% of cases of meningomyelocele, especially when the site is dorsolumbar . Cervical myelomeningocele (CMMC) is a rare entity in neurosurgical practice, which presents different clinical characteristics compared with other more common lumbosacral variant.10 It can be diagnosed by ultrsonography or CT scanning in the early weeks of life and before head enlarges .It is probably not influenced by repair of the meningomyelocele. Operating is indicated in all but the mildest cases of this nature. Operation must always be preceded by detailed investigations to confirm the diagnosis beyond doubt and to demonstrate the type of hydrocephalus. Many surgical maneuvres have been deviced for this disease. The most popular or perhaps ventriculo-peritoneal drainage , or the use of Spitz-Holter or Pudence-Heyer valves to drain CSF from the lateral ventricle into the superior vena cava or atrium.Torkildsen’s operation drains CSF from the ventricle to the Cisternamagna.but it is suitable only for the small group of patient’s of pure aqueduct obstruction. In all operations involving plastic tubes or silicon valves there is a likelihood of later obstruction to the flow of fluid. There is also a risk of chronic bacterium from colonization of the valve or tube. It is notoriously difficult to assess the longterm results of operations for hydrocephalus. Undoubtedly they should be undertaken only by experienced surgeons working in large centres.5
Normal pressure hydrocephalus is a rare syndrome that describes enlarged cerebral ventricles without cortical atrophy, with dementia , urinary incontinence and gait aapraxia, as usually in elderly .CSF constituents and pressure are characteristically normal. Ventriculo-peritoneal shunting occasionally helps.3
Selected normal pressure hydrocephalus (NPH) patients cannot be treated by shunt operation because of the procedure’s high complication rate.8

Hydrocephalus is a term of Greek origin2 which describes an abnormal accumulation of cerebrospinal fluid ( CSF ) in the ventricles of the brain leading to an increase in the intracranial pressure.

Classification
Hydrocephalus is classified under 2 main subdivision : Communicating hydrocephalus and Non-communicating Hydrocephalus.

External or Communicating hydrocephalus occurs when communication exists between the fourth ventricle and the subarachnoid space 1 and an increase in the ventricular volume and the subarachnoid spaces of the cranium and spine is present. 2 Here the ventricular pathways are clear and a failure of reabsorption results in increased CSF . 3

Internal or Non-communicating Hydrocephalus occurs when there is a blockage at one of the ventricular levels and causes an excess of cerebrospinal fluid ( CSF ) 3 to be present within the ventricular system up to the level of the outlet foramina of the fourth ventricle.2 The common sites of obstruction are at the outlet foramina of the fourth ventricle, the aqueduct of Sylvius or at the foramina of Monro . 2

Aetiology
There are numerous causes for hydrocephalus. Prenatally determined hydrocephalus occurs due to congenital ( chromosomal ) malformations, maternal diabetes resulting in holoprosencephaly, neural tube defects, occipital meningocele and encephalocele. Dandy-Walker syndrome1 which occurs when the fourth ventricle distends into a huge cyst, 4 arachnoid cysts causes hydrocephalus.

Communicating Hydrocephalus occurs when there is an excess production of CSF in Choroid plexues papilloma, or in impaired CSF absorption which occurs in meningitis , Cerebral atrophy. 5

Noncommunicating Hydrocephalus occurs due to an obstruction to the flow of CSF in intracerebral tumors, Aqueduct or foramen stenosis , by blood in subarachnoid heamorrhage. 5

Congenital Hydrocephalus occurs due to Arnold-Chiari malformation in spina bifida cystica , also due to forking or stenosis of the aqueduct of Sylvius1. Atresia of foramina of Magendie and Luschka when the fourth ventricle distends into a large cyst ( Dandy-Walker syndrome) occurs as an autosomal recessive form and will result in hydrocephalus1. Developmental failure of subarachnoid cisterns and congenital toxoplasmosis is also another cause1.

Acquired Hydrocephalus Pyogenic or Tuberculous meningitis , intracranial tumors, intracranial tumors at birth, metastatic tumor and brain abscess 1.

Incidence
The incidence of hydrocephalus per 10 000 births around the world is particularly high in alexandria ( 20.8 ) , Belfast ( 12.5 ) and Dublin ( 35.0 ). A collaborative perinatal survey (Chung & Myrianthopolous 1975) found an incidence of 15 per 10 000 births , only half of which were evident at birth. 2 Infantile hydrocephalus where the common presenting sign is head enlargement during infancy occurs in 1 in 2000 live births. 4

In a study conducted by the World Health organization in Philippines it has been reported that Hydrocephalus ( Congenital type ) is one among the 12 most common birth defects occurring in that region. 6 In India hydrocephalus accounted for 9.5 out of 10, 000 infants with common craniofacial malformations. 6 A research done in the Royal Victoria Hospital in Gambia from January 1996 to May 1998 claims that children of ages in the range of 0.1 to 10 years accounted for 0.9% of the admissions to the hospital where Hydrocephalus was the top ranked in neurosurgical diagnosis . 7

Clinical Features
Infantile hydrocephalus occurs during infancy. The appearance and the size of the head are related more to the age of the onset of the hydrocephalus then to its cause. 1 The symptoms of infantile progressive hydrocephalus are vague and consists mainly of vomiting and irritability , but as vomiting is a non specific symptom and irritability is accounted for as a behavioral change, about 50% of the cases are considered asymptomatic . 2 The most common clinical sign is an inappropriately increasing head circumference ( until a child is eighteen months of age, the circumference of the head is approximately equal to that of the thorax an this ratio is disturbed in hydrocephalus 8, which assumes a globular shape with an overhanging forehead and a disproportionately small face. 1 The anterior fontanel which is normally measures 3 cm approximately and 2 cm transversely at birth and continues to decrease progressively in size with age, becomes enlarged, tense 8 and non-pulsative 1 , then clinical and radiological separation of the sutures ( which may gape widely1) and the scalp veins become distended ( which is an valuable sign in early cases of hydrocephalus 8with taut skin over the scalp . 2

When the obstruction to the cerebrospinal fluid pathway occurs later when the disease progresses, there maybe little or no enlargement of the head. 1 The classic presentation is of the signs of raised intracranial pressure as headaches, cerebral vomiting, a cracked-pot sound on percussion of the skull, papilloedema, radiographic changes in the bones of the skull. 1

The ‘sunsetting’ is another common sign in hydrocephalus. It occurs due to the compensation for the raised ventricular pressure.2 Here the eyeballs tend to be pushed downwards so that a rim of the sclera is visible between the iris and the upper eyelid1 and thus the patient is unable to look upwards 2 and appears to be always looking at the floor. 8 It is due to pressure on the superior quadrigeminal plate against the free edge of the tentorium causing paralysis of the fourth nerve. 2

Fig . Sunset eyes

Neurogenic stridor also occurs due to deranged lower brainstem function caused by bilateral corticobulbar disruption. There will be abnormalities in sucking and feeding in hydrocephalic infants with seriously raised intracranial pressure. 2 Other neurological manifestations are found such as squints, optic atrophy and specific paraplegia or tetraplegia. 1

Diagnosis
Various imaging techniques such as X-ray examinations, Computer Axial Tomography (CAT), Ultrasound and magnetic resonance imaging ( MRI ) are useful in the diagnosis purpose. X-ray examinations of the skull may show a ‘ Copper-beaten’ appearance, shallow orbits and splayed sutures . 2 CAT scans, MRI scans and ultrasounds are useful in detecting the abnormalities of the ventricles . 5 The scans will all define the ventricular size 2 and maybe useful in suggesting the site of block . 5

CAT scans provide information about the size and symmetry of the ventricles and also if there is any underlying cause for the disease. 2 However, a single scan has a limited use as it cannot be used if the hydrocephalus is progressive or arrested. 2 Periventricular lucencies, rounding of ventricles, absence of a cortical subarchnoid space and a spherical appearance of the third appearance instead of the usual barrel shape are seen on the CAT scans when there is increased intraventricular pressure from progressive hydrocephalus. 2

Repeated ultrasound investigations and MRI scans can be used to detect the progress of the condition. Also definitive CAT and MRI investigations are done prior to any surgical intervention.

Fig : A hydrocephalic MRI and a normal MRI scan respectively.

During neuroimaging, certain anatomical changes are seen in normal pressure hydrocephalus, such as flattening of cortical sulci, widening of temporal horns, a dilated third ventricle, enlarged Sylvian fissures, focally dilated sulci and an increased flow void signal in the aqueduct. 9 None of these signs have proved reliable as diagnostic markers – their presence merely supports the diagnosis. 9

Measurement of the circumference of the skull is also done to assess the progress of the disease. 3 Occipitofrontal circumference is a measurement of the circumference of the head around the occiput, or posterior aspect, of the skull, to the most anterior portion of the frontal bone. 3 The measurement should be taken with a device that cannot be stretched, such as a flexible metal tape measure. As everyone’s head is slightly different, the tape should be moved around the circumference of the head in order to obtain the ‘largest possible measurement’. 3

Ventricular CSF pressure monitoring is the only accurate way of assessing the activity of the hydrocephalus . 2 Until the anterior fontanel closes at 18 months , it is done by direct puncture of the ventricle via the fontanel. However, if repeated ventricular punctures should be required then a frontal ventricular access devise is inserted to the frontal horn of the right lateral ventricle to allow sequential pressure measurements . 2

Disturbed CSF dynamics induce metabolic and degenerative changes in the periventricular brain tissue. 9 It is well known that cerebral blood flow (CBF) is reduced globally, and regional reductions have been reported in frontal lobes and hippocampus, thalamus and basal ganglia and periventricularly. Oxygen metabolism is reduced in the basal ganglia and periventricular regions; in most cases above penumbra level with intact auto-regulation. 9CSF biomarkers have shown interesting changes in idiopathic normal pressure hydrocephalus.9 CSF TNF-α (a pro-inflammatory cytokine involved in apoptosis and toxic to oligodendrocytes) is very high before surgery and normal after surgery indicating that the altered CSF dynamics radically changed the inflammatory state. 9 Neurofilament protein an axonal marker has been reported as increased in several studies, indicating dysfunction or damage to the axons. 9 Sulfatide, a marker of demyelinisation, has been reported increased in patients with Binswanger’s disease but normal in NPH patients, potentially making it a good differentiating marker. The water content measured as apparent diffusion coefficient or fractional anisotropy is high in the periventricular tissue in acute hydrocephalus but normal in chronic or NPH patients. 9

Treatment.

Shunts and reservoirs
About 40 % of all the cases of hydrocephalus in infancy undergo spontaneous arrest, therefore surgical intervention is only confined to cases in which serial measurements of the skull circumference show progressive and rapid enlargement. 2 There are many surgical maneuvers devised for this disease, the most usual one where the CSF is drained by a one-way drainage system form the ventricles to another site. A shunt is a mechanical device designed to transport the excess CSF from or near the point of obstruction to a re-absorption site and it is implanted under the skin .10 There are numerous valves and shunt systems such as Spitz-Holter valve, Pudez-Hakim, the Denver . 2
A shunt system has two functions. It allows fluid to go only in one direction and the valve allows fluid to flow out only when the pressure in the head has exceeded some value (usually referred to as the “opening pressure”). This system regulates the amount of the CSF in the body so that not too much is taken, nor too little . 10
A shunt has 3 components. The first portion is the called the shunt catheter or proximal portion of the shunt. This is a small narrow tube (catheter), which is implanted into the ventricle of the brain, above where the obstruction has occurred. It is then connected to the valve and reservoir. 10 The valve controls how much fluid is withdrawn from the brain, it is then stored in the reservoir until it is released to drain down the distal (bottom) end. It is through the reservoir that the working condition of the shunt can be check and also samples of CSF can be obtained through it. The distal end is a small, narrow piece of tubing (catheter) which leads to the point where the excess CSF will drain and be absorbed by the body . 10
Shunts are composed of a silicone elastomer (plastic) and are often impregnated with barium. In general, there are fixed shunts or programmable shunts. A fixed shunt has fixed values for pressure adjustments while programmable shunts allows a greater range of choices in choosing the pressure at which the fluid drains.10 The pressure can be easily changed as the neurosurgeon has a magnetic device to change the setting, in the convenience of his office. 10 Newborns and infants often are implanted with a fixed shunt and when they are older the shunt can be replaced with valve and reservoir unit with a programmable shunt. 10
Various routes of drainage have been used. Among the popular drainage routes, the ventriculo-peritoneal drainage, the ventriculo-atrial drainage routes and the ventriculoazygous routes are the ones used.

The ventriculoatrial route was the earliest one to be used in which a tube was passed via the common facial vein to the right atrium 2 where the CSF was drained from the lateral ventricle into the superior vena cava and then into the atrium. 1 The most popular one is the ventriculo-peritoneal drainage 1 where the distal end of the shunt is placed in the peritoneum.

Patients may have active hydrocephalus (mean ICP above 12 mmHg), compensated hydrocephalus (mean ICP 5–12 mmHg) or even low-pressure hydrocephalus (< 5 mmHg). 9 In patients with active or compensated hydrocephalus, we recommend using low or very-low pressure opening ball-in-cone valves together with gravitational devices (GD). G-valves alone or adjustable valves plus GD are alternative options. 9

Fig – A ventriculo-peritoneal shunt.

Fig -A ventriculo-peritoneal and ventriculatrial shunts

Complications of CSF shunting
Shunt surgery, is the most common treatment for both pediatric and adult normal pressure hydrocephalus (NPH). However due to lack of clinical collaboration and because there is no robust evidence proving that any valve is superior, neurosurgeons face important dilemmas in choosing the most adequate shunt. 9 This step is essential for improving outcome and avoiding shunt-patient mismatch. The most frequent complications of shunt surgery are: over- and under drainage and infections. Over drainage presents as symptomatic subdural hygromas, haematomas and slit ventricles. Under drainage is either related to obstruction, disconnection, malpositioning, or migration of the shunt system or to a valve with, or set at, excessively high opening pressure, leading to functional under drainage. 9 Less frequent complications related to the surgical procedure are intracranial bleeding or pneumatocephalus, and in the case of adjustable valves, the likelihood for accidental readjustment. The type and rates of complications differ for pediatric and adult hydrocephalus. 9 During the first year after shunt surgery in pediatric hydrocephalus, 10–20% have a shunt infection and about 17% have shunt malfunction. In adult hydrocephalus, the complication rates for surgery are: infection 5–10%, mechanical malfunction 10–30%, and subdural haematoma, 10–15%.9

1. Shunt Blockage
Early complications occur when fontanels are still open, such as building fontanels, increasing head circumference, Poor feeding, Projectile vomiting, Impaired vision – sunset phenomenon, squint eyes. All are signs of the shunt not draining properly either due to a shunt blockage or malfunction.11 Survival analysis showed no significant relationship between the onset of the mechanical blockage and the type of the shunt, the age at reservoir insertion, the sex of the child, the etiology of hydrocephalus or the time relationship of the shunt insertion to reservoir insertion. 2 The complications are reduced by the introduction of a reservoir. It maybe due to the ability to measure the intracranial pressure directly and so reduce the number of unnecessary shunt revisions. 2

Complications follow later when the fontanels are closed such as headache, blindness, vision problems, developmental regression ( losing a skill that the child previously had), convulsions, vomiting and poor feeding leading to malnutrition. 11

2. Ventriculitis
Among the complications of cerebrospinal fluid shunting and intracranial pressure management by external ventricular drainage (EVD), infection is one of the most serious. 9 Shunt infections or Ventriculitis occur with fever, convulsions, signs of meningitis and redness along shunt track.11 Many factors influence the incidence of shunt infection, such as the length of the operation, the skin preparation and the type of shunt. 2 However shunt infections remain a problem in a significant number of children. 2 It is difficult to diagnose and there is still controversy about the optimal management. Several different treatment regimes have been suggested including vancomycin into the shunt and systemic therapy with oral trimethoprim and rafampicin. 2 The clinical consequences of ventriculitis include deterioration in cognition, which can result in decline in quality of life so that the patient becomes uneducable, unemployable and profoundly dependent. In ventriculoperitoneal shunts, infection often causes obstruction of the distal catheter and in some cases loss of absorptive capacity in the peritoneal cavity, requiring alternative routing of the shunt. In both shunting and EVD most infections are caused by staphylococci, but gram negative bacteria are also important, especially in EVD . 9

3. Slit Ventricle Syndrome
In patients with normotensive hydrocephalus the normal intracranial pressure in the sitting position is negative and approximately 5 mmHg. After a shunt insertion in the erect position, the pressures are approximately -18 mmHg.2 Therefore in most situations with the patient upright and mobile during the day, the pressures will be negative but when supine and in rapid eye movement sleep, there may be significant elevation of pressure. 2This has resulted in the concept of slit ventricles and the slit ventricular syndrome. 2

The slit ventricle syndrome incorporates three components : intermittent or chronic headache secondary to episodic ventricular catheter obstruction : a slit-like ( y shaped ) ventricles on the CT scan : and a slowed refill of the palpable valve mechanism. 2The pathogenesis of the slit ventricle syndrome involves a siphon effect of continuing CSF flow down a shunt tubing ( particularly with the ventriculoperitoneal route ), excessive drainage from thecoperitoneal shunts in patients who are predominantly in the upright posture and the possibility that with ventriculoatrial shunts the diastolic phase of blood flow may encourage CSF withdrawal from the distal end of the shunt. 2

The management of slit ventricle syndrome has involved several procedures such as the use of high pressure valves, an antisiphon device, a calve upgrade together with an antisiphon device, a sub temporal decompression, a volume-regulated shunt system and lastly the use of steroids and the head down position. 2

Shunts with adjustable valves enable the functioning pressure to be modified in situ and allow non-invasive management of complications such as over drainage and slit ventricles, and under drainage. 9 One problem with adjustable valves is that they can become re-set accidentally with magnetic fields, as in MRI, cell phones, headphones and home magnets. 9

Risk of infection can be reduced by shorter pre-operative hospital stay, less use of antibiotics with, where possible, shorter courses, locally targeted antibiotics (intraventricular route, antimicrobial catheters), and enhanced state spending on health care. Treatment of infection should include catheter removal, preferably with intraventricular antibiotics. Antimicrobial catheters have shown benefit in both shunting and EVD . 9

Alternative Treatment
Some patients can be treated with an alternative procedure called an Endoscopic Third Ventriculostomy (often referred to as an ETV, Third Ventriculostomy, or Third Vent). For this operation, a tiny burr hole is made in the skull and a neuroendoscope is utilized to enter the brain. A small hole (several millimeters) is made in the floor of the third ventricle. This allows the CSF to flow from the blocked ventricles into the open spaces surrounding the brain 10 via lamina terminalis . 2 If this procedure is successful, it will eliminate the need for a shunt. However, not everyone with hydrocephalus can qualify for this type of operation. It is also meant for patients older than 6 months of age.1
Choroid Plexestomy is also another operation done to treat hydrocephalus, but in most cases as hydrocephalus is due to an increased resistance to drainage rather than an over secretion of CSF and a reduction of over 50% of CSF production may not produce any substantial effect on the degree of hydrocephalus or pressure. 2

Various drugs have been shown to have an effect on the rate of production of CSF but it is unlikely that those drugs are a definitive management for progressive hydrocephalus. However various drugs can be used as additional measures to help control CSF pressure in various conditions as patients with external ventricular drainage due to ventriculitis. Drugs as Frusemide and Acetazolamide reduce CSF production by their ability to inhibit the action of Carbonic Anhydrase. 2 For any acute rise in intracranial pressure associated with hydrocephalus, Mannitol may reduce the pressure sufficiently to prevent coning. Other drugs with receptor sites on the choroid plexus may also reduce CSF production without diminishing the overall choroidal perfusion . 2

Conclusion
Universal guidelines in hydrocephalus have been absent through a lack of prospective and standardized trials to support recommendations for standards of care. As a consequence, prospective multicenter trials involving standardized reporting of diagnosis, treatment and outcome in a larger number of patients are evolving around the world.9 Therefore new experimental research programmes are conducted in experimental hydrocephalus and other aspects of the disease such as pharmaceutical modulation of the CNS ( CNS drug delivery), in order to underline and peruse the translational aspect of hydrocephalus research . 9

What is Hydrocephalus?
Hydrocephalus is a condition in which the primary characteristic is excessive
accumulation of fluid in the brain. Although hydrocephalus was once known as
“water on the brain,” the “water” is actually cerebrospinal fluid (CSF) — a clear
fluid surrounding the brain and spinal cord. The excessive accumulation of CSF
results in an abnormal dilation of the spaces in the brain called ventricles. This
dilation causes potentially harmful pressure on the tissues of the brain
Hydrocephalus may be congenital or acquired. Congenital hydrocephalus is
present at birth and may be caused by genetic abnormalities or developmental
disorders such as spina bifida and encephalocele. Acquired hydrocephalus
develops at the time of birth or at some point afterward and can affect
individuals of all ages. For example, hydrocephalus ex-vacuo occurs when
there is damage to the brain caused by stroke or traumatic injury. Normal
pressure hydrocephalus occurs most often among the elderly. It may result from
a subarachnoid hemorrhage, head trauma, infection, tumor, or complications of
surgery, although many people develop normal pressure hydrocephalus without
an obvious cause. Symptoms of hydrocephalus vary with age, disease
progression, and individual differences in tolerance to CSF[1];[2]. In infancy, the
most obvious indication of hydrocephalus is often the rapid increase in head
circumstance or an unusually large head size. In older children and
adults, symptoms may include headache followed by vomiting, nausea,
papilledema (swelling of the optic disk, which is part of the optic nerve),
downward deviation of the eyes (called “sunsetting”), problems with balance,
poor coordination, gait disturbance, urinary incontinence, slowing or loss of
development (in children), lethargy, drowsiness, irritability, or other changes in
personality or cognition, including memory loss. Hydrocephalus is diagnosed
through clinical neurological evaluation and by using cranial imaging
techniques such as ultrasonography, computer tomography (CT), magnetic
resonance imaging (MRI), or pressure-monitoring techniques[3].

Is there any treatment?
Hydrocephalus is most often treated with the surgical placement of a shunt
system. Thissystem diverts the flow of CSF from a site within the central
nervous system to another area of the body where it can be absorbed as part of
the circulatory process.A limited number of patients can be treated with an
alternative procedure called third ventriculostomy. In this procedure, a small
hole is made in the floor of the third ventricle, allowing the CSF to bypass the
obstruction and flow toward the site of resorption around the surface of the
brain.

What is the prognosis?
The prognosis for patients diagnosed with hydrocephalus is difficult to predict,
although there is some correlation between the specific cause of hydrocephalus and the
patient’s
outcome. Prognosis is further complicated by the presence of associated disorders, the
timeliness of diagnosis, and the success of treatment. The symptoms of normal pressure
hydrocephalus usually get worse over time if the condition is not treated, although some
people may experience temporary improvements. If left untreated, progressive
hydrocephalus is fatal, with rare exceptions. The parents of children with hydrocephalus
should be aware that hydrocephalus poses risks to both cognitive and physical
development. Treatment by an interdisciplinary team of medical professionals,
rehabilitation specialists, and educational experts is critical to a positive outcome. Many
children diagnosed with the disorder benefit from rehabilitation therapies and educational
interventions, and go on to lead normal lives with few limitations.
History
Hydrocephalus was first described by the ancient Greek physician Hippocrates, but it
remained an intractable condition until the 20th century, when shunts and other
neurosurgical treatment modalities were developed. Although 1 million Americans suffer
from hydrocephalus, it remains a lesser-known medical condition. Relatively small
amounts of research are conducted to improve treatments for hydrocephalus, and to this
day there remains no cure for the condition. Note: in the initial description of
hydrocephalus the text says 1 in 1,000 live births have hydrocephalus, when the actual
value is 1 or 2 per 1,000 births (1/500). There are many sources to confirm this.[1].

Epidemiology
There is no cure for hydrocephalus.
Hydrocephalus affects one in every 1000 live births, making it one of the most common
developmental disabilities, more common than Down syndrome or deafness [4];[5].
According to the NIH website, there are an estimated 700,000 children and adults living
with hydrocephalus, and it is the leading cause of brain surgery for children in the
United States. There are over 180 different causes of the condition, one of the most
common being brain hemorrhage associated with premature birth.
One of the most performed treatments for hydrocephalus, the cerebral shunt, has not
changed much since it was developed in 1960. The shunt must be implanted through
neurosurgery into the patient’s brain, a procedure which itself may cause brain damage.
An estimated 50% of all shunts fail within two years, requiring further surgery to replace
the shunts. In the past 25 years, death rates associated with hydrocephalus have decreased
from 54% to 5% and the occurrence of intellectual disability has decreased from 62% to
30% [5].
Pathology

Spontaneous intracerebral and intraventricular hemorrhage with hydrocephalus shown on CT scan.

The elevated intracranial pressure may cause compression of the brain, leading to brain
damage and other complications. Conditions among affected individuals vary widely.
Children who have had hydrocephalus may have very small ventricles, and presented as
the “normal case”.
If the foramina (pl.) of the fourth ventricle or the cerebral aqueduct are blocked,
cerebrospinal fluid (CSF) can accumulate within the ventricles. This condition is called
internal hydrocephalus and it results in increased CSF pressure. The production of CSF
continues, even when the passages that normally allow it to exit the brain are blocked.
Consequently, fluid builds inside the brain causing pressure that compresses the
nervous tissue and dilates the ventricles. Compression of the nervous tissue usually

aqueduct may be blocked at the time of birth or may become blocked later in life because
results in irreversible brain damage. If the skull bones are not completely ossified when
the hydrocephalus occurs, the pressure may also severely enlarge the head. The cerebral
of a tumor growing in the brainstem.
Internal hydrocephalus can be successfully treated by placing a drainage tube (shunt)
between the brain ventricles and abdominal cavity to eliminate the high internal
pressures. There is some risk of infection being introduced into the brain through these
shunts, however, and the shunts must be replaced as the person grows. A subarachnoid
hemorrhage may block the return of CSF to the circulation. If CSF accumulates in the
subarachnoid space, the condition is called external hydrocephalus. In this condition,
pressure is applied to the brain externally, compressing neural tissues and causing brain
damage. Thus resulting in further damage of the brain tissue and leading to necrotization[6].

Classification
Hydrocephalus can be caused by impaired cerebrospinal fluid (CSF) flow, reabsorption,
or excessive CSF production.
• The most common cause of hydrocephalus is CSF flow obstruction, hindering the
free passage of cerebrospinal fluid through the ventricular system and
subarachnoid space (e.g., stenosis of the cerebral aqueduct or obstruction of the
interventricular foramina – foramina of Monro secondary to tumors,
hemorrhages,
Infections or congenital malformations).
• Hydrocephalus can also be caused by overproduction of cerebrospinal fluid
(relative obstruction) (e.g., papilloma of choroid plexus).
Based on its underlying mechanisms, hydrocephalus can be classified into
communicating and non-communicating (obstructive). Both forms can be either
congenital or acquired.

Communicating [7]
Communicating hydrocephalus, also known as non-obstructive hydrocephalus, is
caused by impaired cerebrospinal fluid resorption in the absence of any CSF-flow
obstruction between the ventricles and subarachnoid space. It has been theorized that this
is due to functional impairment of the arachnoid granulations, which are located along the
superior sagittal sinus and is the site of cerebrospinal fluid resorption back into the
venous system. Various neurologic conditions may result in communicating
hydrocephalus, including subarachnoid/intraventricular hemorrhage, meningitis,
Chiari malformation, and congenital absence of arachnoidal granulations (Pacchioni’s
granulations).
Scarring and fibrosis of the subarachnoid space following infectious,
inflammatory, or hemorrhagic events can also prevent resorption of CSF, causing diffuse
ventricular dilatation.
• Normal pressure hydrocephalus (NPH) is a particular form of communicating
hydrocephalus, characterized by enlarged cerebral ventricles, with only
intermittently elevated cerebrospinal fluid pressure. The diagnosis of NPH can be
established only with the help of continuous intraventricular pressure recordings (over
24 hours or even longer), since more often than not, instant measurements yield
normal pressure values. Dynamic compliance studies may be also helpful. Altered
compliance (elasticity) of the ventricular walls, as well as increased viscosity of the
cerebrospinal fluid, may play a role in the pathogenesis of normal
pressure hydrocephalus.
normal pressure hydrocephalus
• Hydrocephalus ex vacuo also refers to an enlargement of cerebral ventricles and
subarachnoid spaces, and is usually due to brain atrophy (as it occurs in dementias),
post-traumatic brain injuries and even in some psychiatric disorders, such as
schizophrenia. As opposed to hydrocephalus, this is a compensatory enlargement of
the CSF-spaces in response to brain parenchyma loss – it is not the result of
increased CSF pressure.
Non-communicating [7]
Non-communicating hydrocephalus, or obstructive hydrocephalus, is caused by a CSF-
flow obstruction ultimately preventing CSF from flowing into the subarachnoid space
(either due to external compression or intraventricular mass lesions).
• Foramen of Monro obstruction may lead to dilation of one or, if large enough
(e.g., in colloid cyst), both lateral ventricles.
• The aqueduct of Sylvius, normally narrow to begin with, may be obstructed by a
number of genetically or acquired lesions (e.g., atresia, ependymitis, hemorrhage,
tumor) and lead to dilation of both lateral ventricles as well as the third ventricle.
• Fourth ventricle obstruction will lead to dilatation of the aqueduct as well as the
lateral and third ventricles.
• The foramina of Luschka and foramen of Magendie may be obstructed due to
congenital failure of opening (e.g., Dandy-Walker malformation).
Congenital
The cranial bones fuse by the end of the third year of life. For head enlargement to occur,
hydrocephalus must occur before then. The causes are usually genetic but can also be
acquired and usually occur within the first few months of life, which include 1)
intraventricular matrix hemorrhages in premature infants, 2) infections, 3) type II
Arnold-Chiari malformation, 4) aqueduct atresia and stenosis, and 5) Dandy-Walker
malformation.
In newborns and toddlers with hydrocephalus, the head circumference is enlarged rapidly
and soon surpasses the 97th percentile. Since the skull bones have not yet firmly joined
together, bulging, firm anterior and posterior fontanelles may be present even when the
patient is in an upright position.
The infant exhibits fretfulness, poor feeding, and frequent vomiting. As the
hydrocephalus progresses, torpor sets in, and the infant shows lack of interest in his
surroundings. Later on, the upper eyelids become retracted and the eyes are turned
downwards (due to hydrocephalic pressure on the mesencephalic tegmentum and
paralysis of upward gaze). Movements become weak and the arms may become
tremulous. Papilledema reduction of vision. The head becomes
so is absent but there may be enlarged that the child may eventually be bedridden.
About 80-90% of fetuses or newborn infants with spina bifida—often associated with
meningocele or myelomeningocele—develop hydrocephalus.[7]
Acquired
This condition is acquired as a consequence of CNS infections, meningitis, brain tumors,
head trauma, intracranial hemorrhage (subarachnoid or intraparenchymal) and is usually
extremely painful[7].
Symptoms
Symptoms of increased intracranial pressure may include headaches, vomiting, nausea,
papilledema, sleepiness, or coma. Elevated intracranial pressure may result in uncal
and/or cerebellar tonsill herniation, with resulting life threatening brain stem
compression. For details on other manifestations of increased intracranial pressure:

The triad (Hakim triad) of gait instability, urinary incontinence and dementia is a
relatively typical manifestation of the distinct entity normal pressure hydrocephalus
(NPH). Focal neurological deficits may also occur, such as abducens nerve palsy and
vertical gaze palsy (Parinaud syndrome due to compression of the quadrigeminal plate,
where the neural centers coordinating the conjugated vertical eye movement are located).

Effects [8]
Because hydrocephalus can injure the brain, thought and behavior may be adversely
affected. Learning disabilities including short-term memory loss are common among
those with hydrocephalus, who tend to score better on verbal IQ than on performance IQ,
which is thought to reflect the distribution of nerve damage to the brain. However the
severity of hydrocephalus can differ considerably between individuals and some are of
average or above-average intelligence. Someone with hydrocephalus may have
motivation and visual problems, problems with coordination, or may be clumsy. They
may reach puberty earlier than the average child (see precocious puberty). About one in
four develops epilepsy.
Because the problem resides inside the head, doctors rely heavily on
computer tomography scanning (CT scans), which may be used frequently to evaluate
the condition of the disorder throughout the patient’s life. Each CT scan exposes the
patient to many times the level of x-ray radiation of a chest x-ray. See CT
radiation exposure.
Treatment [9]
Hydrocephalus treatment is surgical. It involves the placement of a ventricular catheter
(a tube made of silastic), into the cerebral ventricles to bypass the flow
obstruction/malfunctioning arachnoidal granulations and drain the excess fluid into other
body cavities, from where it can be resorbed. Most shunts drain the fluid into the
peritoneal cavity (ventriculo-peritoneal shunt), but alternative sites include the
right atrium (ventriculo-atrial shunt), pleural cavity (ventriculo-pleural shunt), and
gallbladder. A shunt system can also be placed in the lumbar space of the spine and have
the CSF redirected to the peritoneal cavity (Lumbar-peritoneal shunt). An alternative
treatment for obstructive hydrocephalus in selected patients is the endoscopic
third ventriculostomy (ETV), whereby a surgically created opening in the floor of the
third ventricle allows the CSF to flow directly to the basal cisterns, thereby shortcutting
any obstruction, as in aqueductal stenosis. This may or may not be appropriate based on
individual anatomy.

Shunt complications
Examples of possible complications include shunt malfunction, shunt failure, and shunt
infection. Although a shunt generally works well, it may stop working if it disconnects,
becomes blocked (clogged), infected, or it is outgrown. If this happens the cerebrospinal
fluid will begin to accumulate again and a number of physical symptoms will develop
(headaches, nausea, vomiting, photophobia/light sensitivity), some extremely serious,
like seizures. The shunt failure rate is also relatively high (of the 40,000 surgeries
performed annually to treat hydrocephalus, only 30% are a patient’s first surgery)
and it is not uncommon for patients to have multiple shunt revisions within their lifetime.
The diagnosis of cerebrospinal fluid buildup is complex and requires specialist expertise.
Another complication can occur when CSF drains more rapidly than it is produced by
the choroid plexus, causing symptoms -listlessness, severe headaches, irritability light
sensitivity, auditory hyperesthesia (sound sensitivity), nausea, vomiting, dizziness,
vertigo, migraines, seizures, a change in personality, weakness in the arms or legs,
strabismus, and double vision – to appear when the patient is vertical. If the patient lies
down, the symptoms usually vanish in a short amount of time. A CT scan may or may not
show any change in ventricle size, particularly if the patient has a history of slit-like
ventricles. Difficulty in diagnosing overdrainage can make treatment of this complication
particularly frustrating for patients and their families.

Resistance to traditional analgesic pharmacological therapy may also be a sign of shunt
overdrainage or failure. Diagnosis of the particular complication usually depends on
when the symptoms appear – that is, whether symptoms occur when the patient is upright
or in a prone position, with the head at roughly the same level as the feet.

Shunts in Developing Countries
Since the cost of shunt systems is beyond the reach of common people in developing
countries, most people with hydrocephalus die without even getting a shunt. Worse is the
rate of revision in shunt systems that adds to the cost of shunting many times. Looking at
this point, a study done by Dr. Benjamin C. Warf compares different shunt systems and highlighting the role of low cost shunt systems in most of the developing countries. This study has been published in Journal of Neurosurgery: Pediatrics May 2005 issue. It is about comparing Chhabra shunt system to those of the shunt systems from developed countries. The study was done in Uganda and the shunts were donated by the International Federation for Spina Bifida and Hydrocephalus.
Exceptional case
One interesting case involving a person with past hydrocephalus was a 44-year old French man, whose brain had been reduced to little more than a thin sheet of actual brain tissue, due to the buildup of fluid in his skull. The man, who had a shunt inserted into his head to drain away fluid (which was removed when he was 14), went to a hospital after he had been experiencing mild weakness in his left leg.

DWS: All of the black in the middle is cerebrospinal fluid and the brain matter is the
rid of white along the outside of the skull. This is a screen shot from a Fox News
report.Dr.Lionel Feuillet of Hospital de la Timone in Marseille as saying: “The images
were most unusual… the brain was virtually absent.” [9] When doctors learned of the
man’s medical history, they performed a computed tomography (CT) scan and magnetic
resonance imaging (MRI) scan, and were astonished to see “massive enlargement” of the
lateral ventricles in the skull. Intelligence tests showed the man had an IQ of 75, below
the average score of 100 but not considered mentally retarded or disabled, either.Remarkably, the man was a married father of two children, and worked as a civil servant, leading a normal life, despite having little brain tissue. “What I find amazing to this day is how the brain can deal with something which you think should not be compatible with life,” commented Dr. Max Muenke, a pediatric brain defect specialist at the National Human Genome Research Institute. “If something happens very slowly over quite some time, maybe over decades, the different parts of the brain take up functions that would normally be done by the part that is pushed to the side.”[5]

What research is being done?
The NINDS conducts and supports a wide range of fundamental studies that explore the complex mechanisms of normal brain development. The knowledge gained from these studies provides the foundation for understanding how this process can go awry and, thus, offers hope for new means to treat and prevent developmental brain disorders such as congenital hydrocephalus [5].

What Is Lymphoma?
Lymphoma is a cancer of the lymphatic system. The lymphatic system carries lymph
fluid and white blood cells throughout body. The purpose of the lymphatic system is to
fight infections.1,2
Like all cancers, lymphoma happens when the body’s cells grow out of control, often
causing tumors to grow. Most lymphomas are made up of white blood cells called either
T cells or B cells.2
Lymphoma cells are sometimes found in the blood, but tend to form solid tumors in the
lymph system or in organs. These tumors can often be felt as a painless lump or swollen
gland almost anywhere in the body.
The lymphomas are commoner than the leukaemias and are increasing in insidence for

reasons wich are unclear.1

About the Lymphatic System
The lymphatic system helps to filter impurities, bacteria, and viruses from the body. The
lymphatic system is made up of the
lymph nodes, spleen, and special tubes that extend throughout the body like blood vessels.1
Swollen glands are actually enlarged lymph nodes. Lymph nodes act as alert centers which
activate the immune system to attack viruses, bacteria, or other foreign substances.12

Main functions of lymphatic system 9
1. To collect and return interstitial fluid, including plasma protein to the blood,
and thus help maintain fluid balance.
2. To defend the body against disease by producing lymphocytes.
3. To absorb lipids from the intestine and transport them to the blood.

Lymph nodes: Human lymph nodes are bean-shaped and range in size from a few millimeters to
about 1-2 cm in their normal state. They may become enlarged due to a tumor or infection.10
White blood cells are located within honeycomb structures of the lymph nodes. Lymph nodes are
enlarged when the body is infected due to enhanced production of some cells and division of
activated T and B cells. In some cases they may feel enlarged due to past infections; although
one may be healthy, one may still feel them residually enlarged.12

Lymphoma Causes
The exact causes of lymphoma are not known.1 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

• Medical conditions that compromise the immune system
o HIV
o Autoimmune disease
o Diseases requiring immune suppressive therapy, often used
o following organ transplant
o Inherited immunodeficiency diseases (severe combined
o
o immunodeficiency, ataxia telangiectasia, among a host of others)11,12

• Exposure to toxic chemicals
o Farm work or an occupation with exposure to certain toxic chemicals such
o 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

• Genetics: Family history of lymphoma 4

What Are Grading and Staging?
When a doctor has found cancer cells and is sure that they are from a lymphoma, it is
important to know the grade and the stage of the cancer. Lymphomas of different grades
and stages grow at different rates, and respond differently to treatment5
• The grade of a lymphoma refers to how quickly, or aggressively, it isgrowing
•
• The stage of lymphoma or any cancer depends on how far it has spread throughout the body.
•
• Grade and stage are the most important factors for predicting how a patient will do and for deciding on the best treatment.5,6

Classifications of lymphoma
Lymphoma can classify to two main categories. 1
▪ Hodgkin’s lymphoma
▪ Non Hodgkin’s lymphoma

Hodgkin’s Lymphoma (Hodgkin’s Disease)
Hodgkin’s Lymphoma or Hodgkin’s Disease is a malignant growth of cells in the
lymph system. Hodgkin’s Disease is the better known form of lymphoma. It is a
rare disease. (in UK- 2.5/100 000) (2) Hodgkin’s has a long and rich history. The
disease was named after Thomas Hodgkin (1798-1866), 3,6

What now differentiates Hodgkin’s lymphoma is the presence of Reed-Sternberg
cells (and variations on this cell) in the cancerous area, a cell specific to
Hodgkin’s Lymphoma. Hodgkin’s may be more prevalent in people who have
contracted infectious mononucleosis. 6

Hodgkin’s can occur in children and adults. It is more common in two age
groups – early adulthood (ages 15-40, usually around 25-30) and late adulthood
(after 55). This lymphoma is rare in children under 5. About 10% to 15% of
cases are diagnosed in children 16 years old and younger. 12
Hodgkin’s lymphoma is not contagious and the patient does not pose a risk to
others in any way. 10

Stages of Hodgkin’s Lymphoma
*Stage I involves one lymph node region
*Stage II involves two or more lymph node regions on the same side of the diaphragm
*Stage III involves lymph nodes on both sides of the diaphragm
*Stage IV involves other organs besides the lymph system

Survival Rates by Stage 3
Stage 5-year relative survival rate
I 90% to 95%
II 90% to 95%
III 85% to 90%
IV 80% to 85%
Pathological classification of Hodgkin’s Lymphoma 5,6
◘ Classical Hodgkin’s Lymphoma
◘ Nondular sclerosis Hodgkin’s Lymphoma
◘ Nondular lymphocyte predominant Hodgkin’s Lymphoma
◘ Lympho cyterich Hodgkin’s Lymphoma
◘ Mixed cellularity Hodgkin’s Lymphoma
◘ Lymphocyte depleted Hodgkin’s Lymphoma

Nodular sclerosis- (NS)-The lymph nodes in the lower neck, chest and collarbone usually
contain normal and reactive lymphocytes and Reed-Sternberg cells separated by bands of scar-
like tissues. NS accounts for 60-70% of Hodgkin’s cases. NS appears to account for the increase
in Hodgkin’s cases in recent years 6

Nodular lymphocyte predominant- (NLP) Hodgkin’s lymphoma – while the 4 types above are
“Classical” types, NLP is in a category of its own. Typical Reed-Sternberg cells are rare to non-
existent; instead variants called L & H cells (colloquially “popcorn cells”) are seen. 12

Diagnosis of Hodgkin’s Lymphoma
There are some symptoms for Hodgkin’s but they are not specific. Often a lymph
node swells, especially in the upper body area. Other times one feels they have a lack of
energy. More serious symptoms can include weight loss, fever, and drenching night
sweats. 12
Hodgkin’s is medically diagnosed by taking a tissue sample (biopsy) and
searching for the presence of Reed-Sternberg cells, a cell specific to Hodgkin’s
lymphoma

Treatment for Hodgkin’s Lymphoma

There are treatments for all patients with Hodgkin’s lymphoma. The main types of
treatment are:
1. Chemotherapy -(using drugs to kill cancer cells and shrink tumors).
2. Bone marrow and peripheral blood transplants – transplants (actually high
dose chemotherapy and/or radiotherapy with a “rescue” of the immune
system) are being used for certain patients, especially with recurrent disease.
3. Immunotherapy is being studied in Hodgkin’s treatment including monoclonal
antibody therapy (such as rituxan) and vaccine therapy may not be far off.
4. Radiation- therapy is the use of high-energy x-rays to kill cancer cells and
shrink tumors. 4,5,6

Non-Hodgkin’s Lymphoma
Non-Hodgkin’s lymphoma is a malignant (cancerous) growth of B or T cells in the
lymph system. What causes Non-Hodgkin’s lymphoma is still unknown. Incidence
of NHL has continued to increase over the years.7 The current thinking is that
there probably is a genetic factor and the cancer may not start without a “trigger”
such as environmental factors. NHL is not contagious and the patient does not
pose a risk to others in any way. 8

Grades of Non-Hodgkin’s Lymphoma
For Non-Hodgkin’s lymphoma, grade is the most important factor in predicting the likely
outcome with and without treatment. Lymphomas are usually divided into three main
grade categories: 8
1. Low-grade or indolent: slow-growing lymphomas that can go for many years
without treatment.
2. Intermediate-grade or aggressive: faster-growing lymphomas.
3. High-grade or highly aggressive: very fast-growing lymphomas. 5,8

Different Types of Non-Hodgkin’s Lymphoma 7,8
◘ lymphoplasmacytoid lymphoma
◘ Burkitt’s lymphoma
◘ monocytoid B-cell lymphoma
◘ anaplastic large-cell lymphoma
◘ mantle cell lymphoma
◘ adult T-cell lymphoma

Lymphoblastic lymphoma (LBL) – This form occurs more often in children than adults,
and accounts for about 30% of all lymphomas in children. It is an aggressive, fast-
growing form of lymphoma.7 In the past, it has been fatal for many patients. Today, intensive
chemotherapy has greatly improved the chance of surviving LBL 12

Burkitt’s lymphoma – This form of lymphoma has been found in Africa, where infection with
Epstein-Barr virus may play a role in its cause.8 Burkitt’s lymphoma is also seen in other parts
of the world, but in most of these cases a virus doesn’t seem to be involved. Burkitt’s usually
causes a large tumor either in the bone of the jaw, or in the abdomen 7

◙ Diagnosis of Non-Hodgkin’s Lymphoma
There are some symptoms for Non-Hodgkin’s but they are not specific. Often a
lymph node swells, especially in the upper body area. Other times one feels that they
have a lack of energy. More serious symptoms can include weight loss, fever, night
sweats, or unexplained itching.7
NHL is medically diagnosed by taking a tissue sample (in a surgical procedure called a
biopsy). A needle biopsy is sometimes used but a surgical biopsy, removal of a whole
node, is preferred in getting enough tissue for a definite diagnosis. 12

1. Physical Exam 5
This includes checking the lymph nodes in the neck, armpit, or groin and
checking for an enlarged liver or spleen.

2. Blood Tests 5
The blood will be checked to see if cancer cells or cancer-related enzymes
are present. Other factors in the blood, such as anemia may be looked at.
3. Imaging Tests 6
4. Biopsy 5

Treatments for Non-Hodgkin’s Lymphoma
1. Chemotherapy and Radiation Therapy
2. Bone Marrow Transplant
3. Biological Therapy

Chemotherapy and Radiation Therapy
Chemotherapy is the use of drugs to kill cancer cells.Chemotherapy for non-Hodgkin’s
lymphoma usually includes a combination of several drugs. 8
Radiation therapy uses high-energy x-rays to kill cancer cells and shrink tumors.
Chemotherapy and radiation therapy are the most common treatments for non-Hodgkin’s
lymphoma. Because of the risk that a lymphoma has spread beyond the original tumor
surgery alone isn’t usually enough. 12
Chemotherapy is called a systemic treatment because the drugs travel throughout the
body. This means that even those cancer cells that have not yet been found may be killed.
Patients may receive chemotherapy alone or in combination with radiation therapy. 10

Bone Marrow Transplant
One form of chemotherapy called high-dose chemotherapy (HDCT), uses very high doses
of toxic drugs to kill all possible tumor cells. Because these high doses also kill most of
the bone marrow, patients are then given a bone marrow transplant to restore their ability to
make new red and white blood cells.8
Bone marrow may be taken from the patient before chemotherapy begins and given back
to the patient after treatment is done. Or, bone marrow from another person may be used. 10

Biological Therapy
Biological therapy also called biological response modifier therapy (BRMT), uses
chemicals made by the body’s own cells in order to activate the body’s defenses against
cancer. 8
The different approaches to biological therapy include:
@ Immunotherapy
@ Angiogenesis inhibitors
@ Gene therapy

Immunotherapy
In one kind of immunotherapy chemicals called cytokines are used to activate white
blood cells. Sometimes, when the immune system is activated in this way, it will fight
and kill tumor cells. Two cytokines being used are called interferon and interleukin. 8,12
*Antibodies are proteins that help white blood cells fight off viruses and bacteria.
*Antibodies bind to foreign invaders and signal the immune cells to attack 10

Angiogenesis inhibitors
Angiogenesis inhibitors are chemicals that block the formation of new blood vessels.
Tumors need to create a whole new blood supply in order to keep growing, so they cause
new blood vessels to be formed.11 In mice, angiogenesis inhibitors have blocked the
growth of many types of cancer. This highly experimental form of treatment has been
successful in mice.5 Clinical trials are underway to test the treatment in people.

Gene therapy
In gene therapy pieces of DNA are placed into cells to correct something that has gone
wrong with those cells, or to make the cells self-destruct.1 Because most cancers are now
known to result from damage to genes that keep cells from growing out of control, gene
therapy of cancer cells may someday be able to correct the problem or force cancer cells
to destroy themselves.11 Gene therapy for cancer is still highly experimental.

Non-Hodgkin’s lymphomas in Asia.

The relative frequencies of the various histopathologic types of lymphomas are generally
similar among Asian countries. Hodgkin’s disease and follicular lymphomas are relatively
rare in Asia.9 Among NHL, the Asians have a higher rate of aggressive NHL, as compared
with the NCI data. Immunologic analysis revealed that PTCL is common in Asia. The
relative frequency of PTCL is comparable among Chinese in Taiwan, the east coast of
China, and Hong Kong, as well as in adult T-cell leukemia/lymphoma (ATLL)
nonendemic areas in Japan. The increased rate of T-cell lymphomas in Asia is attributed
to the low incidence of follicular lymphomas. The similar patterns of distribution in
histopathologic and immunologic subtypes of NHL in Asia suggest that a common ethnic
or geographic factor exists.12 To elucidate it, further detailed epidemiologic studies are
needed. Primary extranodal NHL is slightly more prevalent in Asia than in the United
States; the most frequent primary site is Waldeyer’s ring in Japanese patients and the GI
tract in Chinese patients.12 Primary small intestinal lymphoma in Asia showed the pattern
of the Western type. Primary cutaneous lymphomas are rare in Asia. The clinical features
of PTCL in Asia are comparable with those described in the United States, except for a
predilection for the nasal/paranasal region. In Asia, outside Japan, ATLL has been
reported only in Taiwan. The seroepidemiologic survey of carriers of ATLL showed the
rate of seropositivity for HTLV-I in Taiwan was similar to that in nonendemic areas in
Japan. The clinicopathologic features of ATLL in Taiwan and Japan are essentially9
identical. In children in Japan and Taiwan, Hodgkin’s disease is much less frequent than
in the West. However, the relative frequencies of the histopathologic and immunologic
subtypes of childhood NHL in Japan and Taiwan do not differ significantly from those of
the West.9 Although Burkitt’s lymphoma in Japan and Taiwan is of nonendemic type, in
India it may comprise both endemic and nonendemic types in almost equal number.

Side effects of treatments
Treatments for cancer are often quite toxic. Drugs or radiation must kill cancer cells and
in the process some normal cells are also damaged. 12 This leads to the development of side-
effects. Most side-effects of treatment are only temorary. They usually resolve soon after
treatment is complete. 6 Here is a list of common side effects and how to deal with them.

1. Fall in blood counts and infections

Often during a course of chemotherapy or radiotherapy, your blood counts may fall

below normal levels. The white cells in your blood are the most commonly affected.

When white cell counts drop, your body can develop an infection and you may have a

fever. 6,8 You should contact your doctor immediately if you have fever. You may need

treatment to increase your counts and tackle infections. A fall in red blood cells or

platelets may require transfusions. 12

2. Feeling sick

Some chemotherapy drugs can make you feel sick or nauseous. You may even have a few

episodes of vomiting. This may also occur during radiotherapy to the abdomen. Most of

the time the nausea is prevented or reduced by administering drugs (called anti-emetics)

before each cycle of chemotherapy or an exposure of radiotherapy is given. 11 With

excellent new medicines available, nausea and vomiting can usually be controlled quite

effectively. 4

3. Hair loss

Hair loss is common after chemotherapy. The extent of hair loss (also called ‘alopecia’)

depends on the drugs being used in the chemotherapy. Some highly effective drugs also

cause a lot of hair loss. 7 Hair almost always starts growing back within a few months of

completing treatment, though it may take up to a year before it can grow back to normal. 4

You should discuss issues like wearing wigs or turbans with your doctor or counselor,

during and after treatment. 11

4. Sore mouth

Radiotherapy to the neck, as well as some chemotherapy drugs may cause a sore mouth a

few weeks into treatment. 4 You may feel difficulty or pain in swallowing food or drinking

fluids. Usually these symptoms are controlled well with pain medicines and temporarily

switching to mashed food that is easier to swallow. This problem is always temporary,

and reduces soon after treatment is completed. 7

5. Sore skin

Radiotherapy to the neck or chest occasionally causes a short duration of soreness on

your skin. 11 This is rarely severe because the radiotherapy doses in lymphoma are usually

low. Consult your doctor if you have this problem. Often this requires no action. If severe

enough, your doctor may stop radiation for a couple of days or change the area being

treated. 12

6. Changes in taste and appetite

Many individuals on chemotherapy or radiotherapy develop a change in taste during

treatment. Taste usually returns to normal after completing treatment. 7 Most patients

develop a loss of appetite. You may need to take small meals more frequently and drink

plenty of fluids. It is very important to maintain your nutrition during treatment. Speak to

your doctors and nurses and work out a diet that suits you best. 12

7. Fatigue

Treatment related fatigue is common, though not well understood. Any sort of cancer

treatment may leave you feeling tired.2 This is sometimes aggravated by the loss of

appetite that leads to many patients eating less than required. It is very important that you

maintain a healthy diet and eat in sufficient quantity.6 Some light exercise on each day

may also help you feel better.

Acknowledgement
●Author wishes to special thanks to Dr.Amaranath Karunanayake to help and give advices to
success this project.
●Author also wishes to thanks group members D.V.K.Wijemanne, W.Wijenayeke, G.Wijekoon
and A.S.Wijeratne to help for this project.