Download Influenza is an acute respiratory disease of viral etiology, wh

Vinnytsya National Pirogov Memorial Medical University
Department of Children Infectious Diseases
1.
“Approved”
at sub-faculty meeting
28. 08. 2012 , protocol №_1_
Head of Department
prof. _______I.I. Nezgoda
Study guide for practical work of students
Topic: “Central nervous system infections in children. Emergencies and emergency
management”.
Course VI
English-speaking Students’
Medical Faculty
Duration of the class-150min
Composed by assoc. prof. L.M. Stanislavchuk
Vinnytsa
2012
I. The theme urgency.
The gram-negative diplococcus Neisseria meningitides is a major infectious cause of childhood death
in developed countries. The mortality rate remains around 10%. Isolated meningococcal meningitis (5%
mortality rate) has a better prognosis than meningococcal septicemia (10-40% mortality rate). Infection
with N meningitides is highest in children aged 6 months to 2 years; these children have lost the maternal
antibodies and have not yet developed mature humoral immunity.
Although many meningococcal infections rapidly improve when treated with antibiotics, meningococcal
disease may quickly progress in some cases; the time lag from the appearance of the first symptoms to
death may be only a few hours. Because the mortality rate in meningococcal disease is 10%, all patients
with fever and petechiae warrant urgent initial assessment and treatment and subsequent careful and repeated assessment. The initial assessment should be conducted to identify major clinical problems.
The following findings may help in the identification of severely ill patients whose condition may deteriorate and who are likely to need intensive care:
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Shock
Absence of meningitis
Rapidly extending rash
Low WBC count
Coagulopathy
Deteriorating level of consciousness
Shock and increased ICP, which are underlying processes in meningococcal disease that lead to death, may
coexist. However, increased ICP is more common in patients with only meningitis.
II. Primary aims of the study.
To teach students major methods of septic shock and cerebral edema diagnosis and treatment.
A student should know:
1) By definition “shock” and “cerebral edema”
2) Pathogenesis of septic shock and cerebral edema
3) Clinical manifestations of septic shock and cerebral edema
4) Emergency management of septic shock and cerebral edema
5) Prevention
A student should be able to:
1) Find out history
2) Interpret data of physical examination
3) Interpret data of laboratory studies
4) Formulate clinical diagnosis
5) Make differential diagnosis
6) Administer prehospital and in-patient treatment of septic shock and cerebral edema
III. Educative aims of the study.
To facilitate:
1) The formation of deontology concepts and practical skills related to patients with meningococcal disease.
2) To acquire the skills of psychological contact establishment and creation of trusting relations between
the doctor and the patient and his parents.
3) The development of responsibility sense for timeliness and completeness of patient’s investigation.
IV. The contents of the theme.
SHOCK
1. General
a. Definition: shock is characterized by vascular collapse and widespread hypoperfus of cells and
tissue due to reduced blood volume, cardiac output, or vascular tone
b. Cellular injury is initially reversible
c. If the hypoxia persists, the cellular injury becomes irreversible, leading to the death of cells and
the patient
2. Major causes of shock
a. Cardiogenic shock (pump failure)
i. Myocardial infarction
ii. Cardiac arrhytmias
iii. Pulmonary embolism
iv. Cardiac tamponade
b. Hypovolemic shock(reduced blood volume)
i. Hemorrhage
ii. Fluid loss secondsry to severe burns
iii. Severe dehydration
c. Septic shock (bacterial infection)
i. Gram-negative septicemia
ii. Release of endotoxins (bacterial wall lipopolysaccharides) into the circulation
iii. High levels of endotoxin results in
 Production of cytokines TNF, IL-1, IL-6, AND IL-8
 Vasodilatation and hypotension
 Acute respiratory distress syndrome (ARDS)
 DIC
 Multiple organ dysfunction syndrome
iv. Morality rate: 50 %
d. Neurogenic shock (generalized vasodilatation)
i. Anesthesia
ii. Brain or spinal cold injury
e. Anaphylactic shock (generalized vasodilatation) – type I hypersensitivity reaction
3. Stages of shock
a. Stage I: compensation, in which perfusion to viral organs is maintained by reflex mechanisms
i. Increased sympathetic tone
ii. Release of catecholamines
iii. Activation of the rennin-angiotensin system
b. Stage II: decompensation
i. Progressive decrease in tissue perfusion
ii. Potentially reversible tissue injury occurs
iii. Development of a metabolic acidosis, electrolyte imbalances, and renal insufficiency
c. Stage III: irreversible
i. Irreversible tissue injury and organ failure
ii. Ultimately resulting in death
4. Pathology
a. Kidneys
i. Acute tubular necrosis
ii.Oliguria and electrolyte imbalances occur
b. Lunges undergo diffuse alveolar damage(«shock lung»)
c. Intestines
i. Superficial mucosal ischemic necrosis and hemorrhages
ii. Prolonged injure may lead to sepsis with bowel flora
d. Liver undergoes centrilobular necrosis («shock liver»)
e. Adrenals undergo the Waterhouse-Friderichsen syndrome
i.Comonly associated with meningococcal septic shock
ii. Bilateral hemorrhagic infraction
iii. Acute adrenal insufficiency
Managing shock
After basic life support and antibiotics are administered, the next priority is treating shock. Basic life support should include the administration of oxygen at a rate of 10-15L/min by means of a facial mask.
Any patient with cool extremities, prolonged capillary refill time, and tachycardia should be considered to
have shock.
The initial therapy for shock is volume replacement at a rate of 20mL/kg. In the United Kingdom, the use
of 4.5% human albumin solution is generally recommended, although some US and UK centers use normal
saline. A satisfactory response to volume replacement is a reduction in heart rate and improved peripheral
perfusion. The first bolus of fluid may be repeated to achieve this response.
The patient's condition may stabilize with only volume replacement, but the patient requires close monitoring and reassessment to detect further signs of shock or pulmonary edema (due to capillary leak syndrome).
The goal of circulatory support is to maintain tissue perfusion and oxygenation.
Patients who do not respond to initial volume replacement require further volume replacement and may
need inotropic support, such as the use of dopamine or dobutamine (10-20 mcg/kg/min), which may be
administered via a peripheral vein until central venous access is established. Patients with persistent hypotension may need an infusion of adrenaline (0.1-5 mcg/kg/min), which must be administered via central
venous access.
Endotracheal intubation and ventilation are recommended in patients who still have signs of shock after
they have received volume replacement of more than 40mL/kg. Even patients who are apparently awake
and alert have a high risk of pulmonary edema.
Some patients require fluid replacement with as much as twice their circulating blood volume in the first
hours after presentation, but additional volume should be administered only after positive pressure ventilation is established.
Biochemical correction of acidosis, hypoglycemia, hypokalemia, hypocalcemia, and hypomagnesemia is
usually required. Correct coagulopathy and anemia with the use of fresh frozen plasma and blood, as appropriate.
Managing raised intracranial pressure
Suspect increased ICP if the patient has a decreased level of consciousness; focal neurological signs; unequal, dilated or poorly reacting pupils; abnormal posturing or seizures; or relative hypertension or bradycardia or if the patient is agitated or combative. Because papilledema is a late sign, its absence should not
reassure the treating team, because raised ICP can still be present.
After initiating basic life support measures and administering antibiotics, the therapeutic goal is to maintain
oxygen and nutrient delivery to the brain. For this reason, shock must be corrected in individuals with both
shock and increased ICP to maintain cerebral perfusion pressure. After correcting shock with volume replacement and inotropic support as necessary, cautiously manage the fluid balance to avoid further increasing the ICP.
Consider the use of mannitol (0.25 g/kg IV over 10 min), followed by furosemide (1 mg/kg IV), when increased ICP is suspected. These drugs can help to control the ICP during elective intubation.
Immediately institute measures to stabilize the ICP. These may include intubation and ventilation in order
to control PaCO2 between 4-4.5 kPa, sedation and muscle relaxation, and elevation of the patient's head by
30В°.
In addition, find and correct biochemical abnormalities and treat seizures, if present, using standard resuscitation guidelines; do not attempt lumbar puncture.
Treatment of patients with limited shock and no increased ICP
Reassess patients with limited shock and no increased ICP, as well as patients who respond rapidly to minimal volume replacement, for signs of deterioration during the first 48 hours following admission.
The use of corticosteroids in meningitis may be considered. Several studies revealed that adjunctive dexamethasone reduces sensorineural hearing loss (but not mortality or other neurologic sequelae) in children
and infants with H influenzae type B meningitis. Few adverse effects occur with dexamethasone administration. No reports of delayed CSF sterilization or treatment failure are known. A meta-analysis of findings from randomized, controlled trials suggested that such treatment has a benefit in preventing sequelae
in meningococcal meningitis and pneumococcal meningitis in childhood.
Although data are poor for meningococcal meningitis, the pathophysiologic events are likely to be similar
to those of other forms of bacterial meningitis. In some animal models, anti-inflammatory therapy was
beneficial. No evidence of the benefits of steroid use in patients with septic shock is known, and steroid use
is necessary only with meningitis.
If hypoadrenalism is suspected because of resistance to large doses of inotropic drugs, administer adrenal
replacement doses of hydrocortisone.
Steroids have not yet been proven helpful in septicemia. A phase 2, multicenter pilot study is underway in
the United Kingdom to examine the safety and endocrine/inflammation/coagulation profiles seen in lowdose replacement corticosteroid therapy for sepsis in children and to inform a large, multicenter trial. Replacement corticosteroids should not currently be used routinely in pediatric sepsis (and are now controversial in adult sepsis).
Pharmacologic Therapy
The most important measure in treating meningococcemia is early detection and rapid administration of
antibiotics. Penicillin G is the antibiotic of choice for susceptible isolates. A third-generation cephalosporin
(eg, cefotaxime, ceftriaxone) can be used initially in septic patients while the diagnosis is being confirmed
or in countries such as the United Kingdom or Spain, where penicillin-resistant strains of N meningitidis
have been isolated.
These cephalosporins penetrate sufficiently into CSF from blood and are useful in the treatment of bacterial
meningitis. They are known to have a potent action against meningococci, as do chloramphenicol, and rifampin. Meningococci have also been found to be susceptible to ciprofloxacin at low concentrations.
Meningococci resistant to sulfadiazine (MIC >0.128 Вµg/mL) have appeared. Surveillance studies indicate
that approximately one third of clinical isolates in the United States are resistant to sulfonamides.
Meningococci are not inherently susceptible to vancomycin, polymyxin, or achievable serum levels of
aminoglycoside antibiotics.
Intensive supportive care is required for patients with fulminant meningococcemia. Components of treatment include antibiotic therapy, ventilatory support, inotropic support, and IV fluids. Central venous access
facilitates the administration of massive amounts of volume expanders and inotropic medications needed
for adequate tissue perfusion. If disseminated intravascular coagulation (DIC) is present, fresh frozen
plasma may be indicated. Treatment is individualized depending on the severity of hemodynamic compromise of the patient.
Empiric therapy
Empiric antibiotic therapy ensures coverage of likely meningeal pathogens when no rash is present, when
the etiology of meningitis is uncertain, and when an immediate microbiologic diagnosis is unavailable.
This therapy can be modified in favor of appropriate specific therapy when the organism is grown or when
its antibiotic sensitivities are known.
A third-generation cephalosporin is the appropriate antibiotic until culture results are available. Although
meningococcal infection is the most common bacterial cause of a petechial or purpuric rash and meningitis,
other organisms (including H influenzae type B and Streptococcus pneumoniae) can cause shock and a
nonblanching rash.
Although H influenzae type B is now an uncommon cause of meningitis in developed countries with modern vaccination programs, antibiotic therapy should cover this organism. Most cases of bacterial meningitis
are due to N meningitides, and most other cases are due to S pneumoniae. In the United States, most cases
are due to S pneumoniae.
Empiric antibiotic therapy for meningitis based on age is as follows:
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Neonates - Ampicillin and cefotaxime
Infants aged 1-3 months - Ampicillin and cefotaxime
Older infants, children, and adults - Cefotaxime or ceftriaxone
In 2007 the US Food and Drugs Administration (FDA) issued an alert that led to changes in the prescribing
information for ceftriaxone. Dilution, mixing, or y-site infusion with calcium-containing IV solutions may
increase the risk for precipitant to formin vivo. Initially, the FDA recommended that ceftriaxone no longer
be administered within 48 hours of the completion of calcium-containing solutions, including parenteral
nutrition, regardless of whether the drugs were administered by different infusion catheters.
In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MRHA) issued a drug
safety bulletin stating that ceftriaxone should not be given simultaneously with calcium-containing infusions.
However, in April 2009, the FDA changed its advice; the agency no longer cautions against the use of
ceftriaxone and calcium-containing solutions, except in neonates younger than 28 days.The MRHA in the
UK has not yet changed its advice.
Experimental Therapies
Many experimental and alternate therapies for meningococcal infection have been tried with varying success.Currently under study are treatments to inhibit inflammatory mediators (eg, monoclonal antibodies to
endotoxin, TNF, IL-1, IL-2, and interferon-gamma).
Anecdotal reports show that the removal of inflammatory mediators by dialysis may offer some benefit.
Fibrinolytic treatment using recombinant tissue plasminogen activator may prove to be a helpful adjunct to
conventional therapy to improve tissue perfusion in the presence of DIC.
Activated protein C (drotrecogin alfa [Xigris]) was approved for the treatment of severe sepsis in the absence of bleeding but was withdrawn from the worldwide market on October 25, 2011.
Antiendotoxin agents
A randomized trial of the antiendotoxin monoclonal antibody HA1A in children with meningococcemia
showed a 32% reduction in mortality, but the result was not statistically significant.
A bactericidal/permeability-increasing (BPI) protein, a natural protein stored in neutrophil granules that
binds to and neutralizes the effects of endotoxin in vitro, in laboratory animals, and in humans, has shown
some promise in clinical trials in children with severe meningococcal sepsis.
Treatment of hyperglycemia in critically ill children
Currently, whether hyperglycemia in critically ill patients in the pediatric intensive care unit (PICU) should
be treated with insulin is under debate. A trial in adult surgical patients showed decreased mortality in ICU
patients with tight glycemic control (on insulin).In 2006, however, a repeat study showed no mortality benefit and a significantly increased risk of hypoglycemia.
Another study, in the United Kingdom, showed poorer outcomes in PICU patients with hyperglycemia (no
insulin therapy used). A large, multicenter trial is underway in the United Kingdom to further examine the
control of hyperglycemia in critically ill children in the PICU.
Surgical Treatment of Ischemic Complications
Patients who survive the initial acute phase of fulminant meningococcemia are at increased risk for serious
complications as a result of poor tissue perfusion.
Early in the course of tissue injury, conservative therapy is recommended until a distinct line of demarcation is apparent between viable and nonviable tissue.
Once the patient is stable, dГ©bridement of all necrotic tissue is essential and may necessitate extensive
removal of skin, subcutaneous tissue, and muscle. Large defects may be covered using microvascular free
flaps or skin grafts. The use of artificial skin can spare the patient immediate use of autograft sites, which
frequently are limited. Avoid early limb amputation, because significant tissue recovery may occur as the
disease progresses.
Poor tissue perfusion may also lead to dental complications that require extensive extraction of severely
affected teeth.
Anecdotally, fasciotomy may preserve limb and digit function in severe meningococcal septicemia when
impending peripheral gangrene and increased compartment pressures are present. Measure compartment
pressures and assess peripheral pulses with Doppler ultrasonography when patients have impaired limb
perfusion or severe edema.
Monitoring and Follow-Up
Pericarditis can occur while patients are recuperating from meningococcemia. Consider pericarditis in patients with fever and shortness of breath upon minimal exertion during the recovery period.
Late skeletal deformities are rare, but epiphyseal avascular necrosis and epiphyseal-metaphyseal defects
have been described. These usually occur in the lower extremities and result in angular deformity and inequality of leg length.
Observe patients for any late neurologic sequelae. Abnormal findings on electroencephalography or cerebral computed tomography (CT) scanning, as well as epileptogenic activity, sensorineural hearing loss, impaired vestibular function, and neuropsychological impairment, have been found in up to 30% of survivors
1 year after an episode of meningococcal disease. The frequency of serious neurologic sequelae in individuals who survive an episode is 3%.
Follow-up care at least 6 weeks after meningococcal infection should include the following:
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Ongoing management of specific complications such as amputations, skin grafting, or renal failure
Full physical examination
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Assessment of plasma complement levels - Eg, total hemolytic complement, C3, and C4, with or
without properdin
Serologic confirmation of the diagnosis if no diagnosis was made at the time of presentation
Audiologic function testing
Basic assessment of psychological status after intensive care, if relevant
Possible vaccination of contacts if an outbreak of group A, C, Y, or W-135 disease occurs
Vaccination
Meningococci are gram-negative diplococci. Pathogenic strains are enveloped in a polysaccharide capsule,
which facilitates invasion and which is an obvious target for candidate vaccines. The serogroup of the organism is assigned from the reaction of sera to the polysaccharide capsule.
Purified polysaccharide vaccines against encapsulated bacteria (which, in addition to meningococci, include Haemophilus and pneumococci) are poorly immunogenic in young children. In contrast, the conjugate vaccine for group C meningococci in which the serogroup C meningococcal polysaccharide is conjugated to the protein CRM197 appears to provide immunogenic protection to young children. It was administered to all children during 1999-2000 in the United Kingdom.
In January 2001, the short-term effectiveness of this vaccine in England was reported to be 97% for teenagers and 92% for toddlers. These early results confirmed the superiority of this vaccine to plain C polysaccharide vaccines.
The UK immunization schedule has since changed to include a meningococcal booster at 12 months (combined with Hib booster) because studies showed that the efficacy of the vaccine declined at 1 year to
around 80%.
In the United States, 2 meningococcal vaccines are available. MPSV4 (meningococcal polysaccharide vaccine), which is quadrivalent, is recommended for use only in individuals aged 2-10 years who are at increased risk for meningococcal disease, such as those with terminal complement deficiencies and asplenia.
A single dose of vaccine does not protect younger children, especially those younger than 2 years.
The conjugate vaccine MCV4, which is also quadrivalent, is approved for individuals aged 9 months to 55
years who are at increased risk In addition, MCV4 is given to all children aged 11-12 years or to unvaccinated students upon entry to high school or college. This vaccine has the advantage of producing a longer
duration of protective antibodies.
Vaccines against group B serotypes are difficult to make. Because the polysaccharide capsule of the group
B meningococcus is chemically and antigenically identical to human brain and fetal antigens, it is poorly
immunogenic in humans, and its use may induce autoimmunity.
Other bacterial components, such as bacterial outer membrane proteins, are being investigated for use in
vaccines. Vaccines have been prepared by using simple complexes of these proteins. These include vaccines involving outer membrane vesicles, containing outer membrane proteins in spheres of the bacterial
lipid membrane.
Although some serogroup B vaccine trials demonstrate an overall efficacy of more than 50%, protection for
the most vulnerable age group has not been demonstrated. In those individuals with a detectable immune
response, serum bactericidal activity after vaccination seems to be limited to the strain in the vaccine.
Safety considerations
The safety of meningococcal polysaccharide vaccine in pregnant women has not been evaluated, and it
should be avoided unless the risk of infection is high. The vaccine is also not routinely indicated for health
care workers in the United States.
The risk of Guillain-BarrГ© Syndrome (GBS) seems to be slightly increased among recipients of the
MCV4 vaccine.The CDC estimated the rate to be 0.2 per 100,000 person-months in individuals aged 11-19
years who received the vaccine. The background rate was estimated at 0.11 per 100,000 person-months in
this population group.
The CDC recommends that persons with a history of GBS not receive MCV4, although persons with a history of GBS at especially high risk for meningococcal disease (eg, microbiologists routinely exposed to
isolates of N meningitidis) might consider vaccination.
Prevention of Secondary Cases
Antimicrobial chemoprophylaxis of close contacts is the primary means of preventing secondary cases of
sporadic meningococcal disease. Person-to-person transmission can be interrupted by administration of an
antimicrobial that eradicates the asymptomatic nasopharyngeal carrier state. Sulfonamides, rifampin, minocycline, ciprofloxacin, and ceftriaxone are the drugs that have been shown to eradicate meningococci from
the nasopharynx.
Because the rate of disease in secondary contacts is highest immediately after the onset of the disease in the
patient, chemoprophylaxis should be administered as soon as possible, preferably within 24 hours. If
chemoprophylaxis is delayed by more than 14 days, it is probably of limited value, although it is still recommended until 4 weeks after the patient's presentation.
Infection risks
Meningococcal infection is probably introduced into families by asymptomatic adults and then spread
through 1 or more household contacts to infect younger family members. Household contacts are defined
as individuals who live in the same house with a person who has a meningococcal disease. An operational
definition commonly used by public health authorities includes persons eating and sleeping under the same
roof as the index case.
The attack rate of meningococcal disease among household contacts has been estimated to be several hundred times greater than that in the general population. The secondary attack rate is inversely proportional to
age and is estimated to be approximately 10% in household contacts aged 1-4 years.
The risk of acquiring meningococcal disease may also be increased in other closed populations, such as
those of daycare facilities and nursery schools.
Health care workers who are exposed to aerosol secretions from patients with meningococcal disease are
25 times more likely to contract the disease than is the general population.
The likelihood of acquiring infection is increased 100-1000 times in intimate contacts of individuals with
meningococcemia.
Chemoprophylaxis
The American Academy of Pediatrics recommends antimicrobial chemoprophylaxis for contacts of persons
with invasive meningococcal disease, including household members, individuals at daycare centers and
nursery schools, and persons directly exposed to the patient's oral secretions (eg, kissing, sharing of food or
beverages) within the 7 days preceding the onset of the illness in the index case.
The decision to administer chemoprophylaxis to other populations should be reached only after consultation with public health authorities, who have a better understanding of the patterns of disease that currently
exist in the community.
Consider antimicrobial chemoprophylaxis in hospital personnel who have had direct exposure to the oral
secretions of a patient with meningococcal disease from such activities as mouth-to-mouth resuscitation,
endotracheal intubation, or endotracheal tube management.
To further decrease the risk of infection in the clinical setting, staff caring for patients with known or suspected meningococcal infections should wear masks, in addition to taking standard precautions.
Patients with meningococcal disease who are hospitalized should be placed on respiratory precautions for
the first 24 hours of effective antimicrobial therapy. When this is done, the risk for hospital personnel with
casual or indirect contact is believed to be negligible. Antimicrobial chemoprophylaxis is not recommended in hospital personnel who have only casual or indirect contact with a patient with meningococcal disease.
For travelers, antimicrobial chemoprophylaxis should be considered for any passenger who had direct contact with respiratory secretions from an index patient or for anyone seated directly next to an index patient
on a prolonged flight (ie, one that lasts ≥8h).
Prophylactic drugs
Rifampin is commonly used for meningococcal prophylaxis of household contacts in the United States,
where one third of the prevalent strains are sulfadiazine resistant. A 2-day course of rifampin is recommended. The rapid emergence of rifampin-resistant meningococci precludes the use of this drug in large
populations. Chemoprophylaxis of sulfadiazine-resistant meningococci with rifampin should be accompanied by close observation of household contacts for signs of disease.
A single dose of ciprofloxacin has been found to provide an effective alternative to rifampin for the eradication of meningococcal carriage in adults. Ciprofloxacin is not recommended in persons younger than 18
years because it has caused cartilage damage in immature experimental animals.
A single IM injection of ceftriaxone has been found to eradicate meningococcal carriage. The chemoprophylactic dose of ceftriaxone is 250 mg IM in adults and 125 mg IM in children. Ceftriaxone is preferred in
children who refuse oral medication and may be used in pregnancy.
Meningococcal isolates that are susceptible to sulfadiazine can be eradicated with a 2-day course of sulfadiazine. The high incidence of adverse effects has limited acceptance of minocycline as a means of eradicating the carrier state.
Meningococcal disease can be prevented by vaccination with group-specific meningococcal capsular polysaccharides.Purified polysaccharides of groups A, C, Y, and W-135 meningococci have been used to
stimulate group-specific humoral bactericidal antibodies.
Cerebral Edema and its Management
Introduction
Surprising as it may sound cerebral edema is a fairly common pathophysiological entity which is encountered in many
clinical conditions. Many of these conditions present as medical and surgical emergencies. By definition cerebral
edema is the excess accumulation of water in the intra-and/or extracellular spaces of the brain.
Pathophysiology
Pathophysiology of cerebral edema at cellular levelis complex. Damaged cells swell, injured blood vessels leak and
blocked absorption pathways force fluid to enter brain tissues. Cellular and blood vessel damage follows activation
of an inj ury cascade. The cascade begins with glutamate release into the extracellular space. Calcium and sodium
entry channels on cell membranes are opened by glutamate stimulation. Membrane ATPase pumps extrude one calcium ion exchange for 3 sodium ions. Sodium builds up within the cell creating an osmotic gradient and increasing
cell volume by entry of water. Increase in water causes dysfunction but not necessarily
permanent damage. Finally, hypoxia depletes the cells’ energy stores disabling the sodium - potassium ATPase and
reducing calcium exchange. Because of failure of the energy-dependent sodium pump in the cellular membrane, sodium accumulates intracellularly and water moves from the extracellular to the intracellular space to maintain osmot-
ic equilibrium Calcium accumulates inside the cell activating intracellular cytotoxic processes. An inflammatory
response is initiated by the formation of immediate early genes such as c-foc and c-jun and cytokines and other intermediary substances. Microglial cells are activated and release free radicals and proteases which contribute
to the attack on cell membranes and capillaries. Once the membranes are disrupted recovery of the cells is impossible
.Free radicals are toxic to cells. Reactive oxygen
species such as superoxide ion, hydrogen peroxide and hydroxyl ion are produced by the arachidonic acid cascade.
Release of fatty acids such as arachidonic acid provides a supply of damaging molecules. Nitric oxide (NO) is also a
source of free radicals. Macrophages and activated microglial cells form NO through the action of inducible or immunological NO synthetase (iNOS) .During injury and ischaemia of the central nervous system (CNS) mediators like
glutamate, free fatty acids, or high extracellular potassium compounds are released or activated, which cause secondary swelling and damage of nerve cells. Other substances like histamine, arachidonic acid and free radicals including
NO may also be considered mediators of brain edema, but to each of these compounds evidence is less clear than for
bradykinin (BK) [4]. A variety of mediators may enhance each other in a cascading manner by various initiating reactions that might be amenable to pharmacologic inhibition. BK may be involved in edema
formation after cold lesion, concussive brain injury, traumatic spinal cord and ischaemic brain injury. In stroke, the
molecular cascade initiated by cerebral ischaemia includes the loss of membrane ionic pumps and cell swelling. Secondary formation of free radicals and proteases disrupts brain-cell membranes, causing irreversible damage .To explain the consequences of cerebral edema in the simplest terminology, it is best to take the help of Monro-Kelie hypothesis, which says that the total bulk of three elements (inside the skull) i.e. brain - 1400 ml, cerebral spinal fluid
(CSF) 150 ml and blood 150 ml is at all times constant. Since skull is like a rigid box which cannot be stretched - if
the volume of one of these components increases, it will force the reduction of volume of the other components. So if
there is excessive water, the volume of brain as well as blood inside the skull is compressed. Conversely, primary
blood flow disturbances also lead to brain edema As the brain, blood or CSF volumes continue to increase, the accommodative mechanisms fail and intracranial pressure (ICP) then rises exponentially. Greatly raised ICP eventually
causes a reduction in cerebral blood flow throughout the brain. In its most severe form the widespread ischaemia
produces brain death. Lesser degrees of increased ICP and reduced blood flow can cause correspondingly less severe
but still extensive cerebral infarction. The numerical difference between raised ICP and mean blood pressure within
the cerebral vessels, termed cerebral perfusion pressure and the duration of its reduction are the main determinants of
cerebral damage [7]. If these changes continue further, it leads to the disastrous condition of brain herniation, which
is the forerunner of irreversible brain damage and death. It must be clearly understood that though raised ICP is the
result of cerebral edema of significant magnitude, they are not synonymous as raised ICP can be caused by other
mechanisms also.
Types
Klatzo specified two categories of cerebral edema -vasogenic and cytotoxic edema. The term cellular edema refers to
cytotoxic edema and is preferable to the latter;
Fishman accepts these two categories but adds a third, which he calls interstitial cerebral edema. Rarely is the separation into distinct categories possible, there is often
overlap between the various types of edema.Vasogenic cerebral edema refers to the influx of fluid and solutes into
the brain through an incompetent blood-brain-barrier (BBB). This is the most common type of brain edema and results from increased permeability of the capillary endothelial cells, the white matter is primarily affected. Breakdown
in the blood-brain barrier allows movement of proteins from the intravascular space through the capillary wall into
the extracellular space.Cellular (cytotoxic) cerebral edema refers to a cellular swelling. It is seen in conditions like
head injury and hypoxia. It results from the swelling of brain cells, most likely due to the release of toxic factors
from neutrophils and /bacteria. Cytotoxic edema is caused by swelling of glia, neurons, endothelial cells and begins
within minutes after an insult. Cytotoxic edema affects predominantly the gray matter. Interstitial edema is seen in
hydrocephalus when outflow of CSF is obstructed and intraventricular pressure increases. The result is movement of
sodium and water across the ventricular wall into the paraventricular space [3]. Interstitial cerebral edema occurring
during meningitis is due largely to obstruction of normal CSF pathways, with a resulting increase in he resistance to
CSF outflow.
Etiology
Cerebral edema is seen in the following neurological and non-neurological conditions:
Neurological conditions Ischaemic stroke and intracerebral haemorrhage.
Brain tumours.
Meningitis and encephalitis of all etiologies.
Other brain infections like cysticercosis, tuberculosis and toxoplasma.
Non-neurological conditions Diabetic ketoacidosis, lactic acidotic coma.
Malignant hypertension, hypertensive encephalopathy.
Fulminant viral hepatitis, hepatic encephalopathy. Reye’s syndrome.
Systemic poisoning (carbon monoxide and lead).
Hyponatraemia, SIADH.
Opioid drug abuse and dependence.
Bites of certain reptiles and marine animals.
High altitude cerebral edema (HACO)
Clinical Features
A high index of suspicion is very important. The features of cerebral edema add on to and often complicate the clinical features of the primary underlying condition. Until the ICP reaches a level that produces local ischaemia, cerebral
edema alone will not produce clinical neurological abnormalities [1]. In a given clinical setting, alteration in level of
consciousness, appearance of bradycardia, rise in blood pressure, abnormal breathing patterns evidence of extra ocular movement abnormalities, alteration and inequality of pupillary size and extensor plantar response on the side of
the lesion should raise strong suspicion of cerebral edema. The most common cause of neurological deterioration and
death during acute ischaemic stroke is cerebral edema. It occurs in all ischaemic strokes. Ischaemic brain edema is
initially cytotoxic because of disturbances in cell membrane. Later vasogenic edema sets in due to disruption of
BBB. Cerebral edema usually begins to develop soon after the onset of ischaemia and peaks at 24-96 hours. Usually
this is confined to ischaemic region and does not appreciably affect adjacent brain. But, when it progresses it compresses brain regions
adjacent to ischaemic zone causing neurological worsening.
Investigations
CT scan provides an excellent tool for in vivo determination of abnormalities in brain water content. The areas of
edema appear as low density on unenhanced scan. This is due to the dilution of all the constituents of the white matter . The anatomical specificity of CT permits detection of not only the presence but also the type of brain edema.
This is helpful in differentiating nature of underlying lesion eg. infarction/tumour. In general, the more malignant
primary tumours of the brain and metastatic tumours
entail the greatest incidence of cerebral edema, although presence of brain edema does not rule out benign lesions.
CT is an excellent method for following the resolution
of brain edema following therapeutic intervention.Cerebral edema in acute vascular lesions can be seen in both the
cortex and the underlying white matter. The cerebral edema in an epidural and intracerebral haematoma is typically
limited to white matter. MRI appears to be more sensitive than CT at detecting brain abscess in the cerebritis phase
of its development as well as at detecting associated cerebral edema. ICP monitoring is an important tool to monitor
cases where cerebral edema is present or anticipated and is routinely done in all Neurology and Neurosurgery ICUs.
Unfortunately, the direct measurement of ICP and aggressive measures to counteract high pressures have not yielded
uniformly beneficial results, and after two decades of popularity - the routine use of ICP monitoring remains controversial. The problem may be partly a
matter of the timing of monitoring and the proper selection of patients for aggressive treatment of raised ICP. Only if
the ICP measurements are to be used as a guide to
medical therapy and the timing of surgical decompression, is the insertion of a monitor justified .Whether ICP monitoring adds much to the management of patients of stroke is still open to question, clinical signs and imaging data on
shift of brain tissue are probably more useful. EEG is not very helpful in the management of cerebral
edema, because the changes which are noted are the sum total of changes due to cerebral edema, raised ICP and the
primary lesion superimposed upon each other.
Treatment
Treatment of brain edema has not kept up with the advances in understanding of the mechanism producing the edema.
Medical treatment
1. Osmotherapy
The most rapid and effective means of decreasing tissue water and brain bulk is osmotherapy. Osmotic therapy is
intended to draw water out of the brain by an osmotic gradient and to decrease blood viscosity. These changes would
decrease ICP and increase cerebral blood flow (CBF).
Mannitol is the most popular osmotic agent. Osmotic therapy using mannitol reduces ICP by mechanisms that remain unclear. Mannitol is thought to decrease brain
volume by decreasing overall water content, to reduce blood volume by vasoconstriction, to reduce CSF volume by
decreasing water content. Mannitol may also improve
cerebral perfusion by decreasing viscosity or altering red blood cell rheology. Lastly, mannitol may exert a protective
effect against biochemical injury.
There is some evidence that lower dosage is quite effective with less chances of inducing hyperosmolar problems
that have been noted with frequent high-dose
therapy. IV Mannitol is given in the dosage of 1.0 g/kg, then 50 g every 2-3 hours (for adult). When Mannitol is
used, one should aim for plasma osmolality 300-310mOsm/L with maintenance of adequate plasma volume. Prolonged administration of Mannitol results in an electrolyte imbalance that may override its benefits and
that must be carefully monitored [2]. Nursing care of the patient receiving Mannitol requires vigilant monitoring of
electrolytes and overall fluid balance and observation
for the development of cardiopulmonary complications in addition to neurological assessment . Glycerol is another
useful agent given in oral doses of 30 ml every 4-6 hour or daily IV 50g in 500 ml of 2.5% saline solution although
its effectiveness appears to decrease after few days. It is used in a dose of 0.5- 1.0 g/kg body weight. In unconscious
or uncooperative patients it is given by nasogastric tube.
2. Diuretics - The osmotic effect can be prolongedby the use of loop diuretics (Furosemide) after the osmotic agent
infusion. Loop diuretics (Furosemide) can be used as an adjunct. Furosemide (0.7 mg/kg) has been shown to prolong
the reversal of blood brain osmotic gradient established with the osmotic agents by preferentially excreting water
over solute.
3. Corticosteroids - Corticosteroids lower intracranial pressure primarily in vasogenic edema because of their beneficial effect on the blood vessel. They have been less effective in cytotoxic edema, and are not recommended in treatment of edema secondary to stroke or haemorrhage. In fact, systemic complications of steroids can worsen the patient’s condition. Corticosteroids have not proven effective in stroke unless stroke is caused by documented cerebral
vasculitis. Inj Dexamethasone 4-6 mg IM every 4-6 hours may be useful in these cases. They have also been used in
chronic meningitis and in acute bacterial meningitis under cover of antibiotics. Glucocorticoids are used for the management of malignant brain tumours, either primary or secondary, as adjuvant chemotherapy of some CNS tumours
and perioperatively in brain surgery.
Edema surrounding brain tumours particularly metastatic brain tumours responds dramatically to treatment with high
doses of Dexamethasone. Glucocorticoids are believed to exert their influence on brain tumours mainly by reducing
tumor-associated vasogenic edema, probably by decreasing the increased capillary permeability of
BBB. The role of corticosteroids in head trauma is uncertain.
4. Hyperventilation - Controlled hyperventilation is helpful in reducing the raised ICP. The cerebral vasculature is
most sensitive to arterial pCO2 changes around the normal level of 40 mm Hg. ICP falls within minutes of onset of
hyperventilation and although the buffering mechanisms in the CSF and extra cellular fluid soon restore pH to normal the effect may last for many hours. It is important to monitor the effects of ventilation carefully by blood gas
analysis and chest radiograph.The pCO2 should not be reduced below 25 mm Hg. At this point vasoconstrictor effect
of hypocarbia itself will cause hypoxia and ischaemic cell damage.
5. Other agents - Barbiturates, Procaine derivatives, Indomethacin, Propofol and THAM (Thrometamine) are some
other agents which have been tried and used in
the past but are not being used routinely in present practice. Barbiturates produce a marked decrease in metabolic
rate and it seems likely that the fall in cerebral blood
flow and ICP is secondary. Complication of barbiturate therapy, in particular systemic hypotension and pulmonary
failure, have caused concern and careful monitoring with a Swan Ganz catheter is recommended. Lidocaine will prevent a rise in ICP during intubation. It may act directly on brain stem vasomotor centre.However, there is no present
evidence that it reduces ICP already raised. THAM has been used to regulate the acidotic impairment of cerebral autoregulation and the response of the vascular system to hypocapnia can be improved.
Surgical treatment
Surgical treatment is occasionally recommended for large hemispherical infarcts with edema and life threatening
brain-shifts. Temporary venticulostomy or craniectomy may prevent deterioration and may be lifesaving. Decompressive craniectomy in the setting of acute brain swelling from cerebral infarction is a life saving procedure and
should be considered in younger patients who have a rapidly deteriorating neurological status. Also, in large cerebellar infarcts with cerebral edema surgical decompression is life saving. The surgical removal of lesions responsible for
cerebral edema results in resolution of cerebral edema. In cases of severe hydrocephalus VP shunt is very
helpful .
General measures
When signs of elevated ICP are present certain measures for management should be initiated. Position of the patient Elevation of head end of bed 15-30 degrees to promote cerebral venous drainage is advisable and head is kept in
midline to limit neck vein compression. However, in acute carotid or basilar artery occlusion bed is not tilted to
avoid hypoperfusion distal to occlusion. Correction of contributory factors - Correction of factors increasing ICP e.g.
hypercarbia, hypoxia, hyperthermia, acidosis, hypotension and hypovolaemia is helpful. Endotracheal intubation and
mechanical ventilation to hyperventilate to PaCO2 of 25 mm Hg is helpful in impending herniation .
Fluid restriction - Fluid restriction minimally affects cerebral edema and, if pursued to excess, may result in episodes
of hypotension, which may increase ICP and is associated with worse neurologic outcome. Glucose containing solutions should be avoided; euvolaemia should be maintained, N or N/2 saline should be used; urinary losses should be
replaced with N saline in patients receiving Mannitol . Hypothermia - Multiple mechanisms for reduced brain temperature-induced neuroprotection have been
identified and include reduced metabolic rate and energy depletion, decreased excitatory transmitter release, reduced
alterations in ion flux, reduced vascular
permeability, edema and BBB disruption. Recent studies have led to the hypothesis that changes in postischaemic
cerebral temperature can critically modulate
encephalopathic processes which are initiated during the primary phase of hypoxia-ischaemia, but which extend into
the secondary phase of cerebral injury. Randomised
clinical trials are in progress to establish the safety and efficacy of prolonged cerebral hypothermia. Suarez JI has
shown that a body temperature >37.5°C and blood
glucose >150 mg/dl are related to worsening of the cerebral edema. The measures necessary for good cerebral reanimation are the following : evaluation of the airway, controlled hyperventilation, maintenance of the cerebral perfusion pressure >70 mm Hg, suitable position of the head, administration of hypertonic solutions, Dexamethasone, and
possibly barbiturates. Blood pressure needs to be monitored carefully in cases with cerebral edema. When cerebral
edema causes raised ICP, systemic blood pressure rises as a compensatory phenomenon to ensure adequate cerebral
perfusion. Hence, under these circumstances bringing down the raised blood pressure will increase the extent of cerebral ischaemic damage and will be counter productive.
Management of cerebral edema in specific conditions
Stroke
In stroke 5% - 10% patients develop symptomatic cerebral edema resulting in obtundation with its attendant consequences or brain herniation. Edema peaks on the
second or third day but causes mass effect for 10 days. The larger the infarct, the more likely edema will be a problem. Even small amounts of edema from a cerebellar
stroke can raise intracranial pressure in the posterior fossa. Restriction of free water and intravenous Mannitol may
be useful. As the molecular events become clearer, novel treatments that block different stages of the injury cascade
will be available for clinical testing.
Cerebral edema in bacterial meningitis
Initial management of increased ICP is intubation and controlled hyperventilation to reduce pCO2 to 25 mm Hg .
However, the effect of hyperventilation is transient. Hypotension should be avoided to maintain cerebral perfusion.
Mannitol may enter brain through partially open BBB and therefore is less effective. Corticosteroids have shown no
benefit in 24 hours over non-corticosteroid treated patients. Lasix and fluid restriction produces dehydration, fall of
blood pressure, low cerebral perfusion pressure and increased risk of cerebral thrombosis. If severe hydrocephalus is
present VP shunt should be considered.
Tuberculous Meningitis and Tuberculoma
Glucocorticoids are a useful adjunct to chemotherapy, clinical trials have demonstrated that patients treated with adjunctive glucocorticoids experience a significantly
faster resolution of CSF abnormalities and elevated CSF pressure. Adjunctive glucocorticoids enhance survival and
reduce the frequency of neurologic sequelae especially in cases with cerebral edema.
Toxoplasmosis
Glucocorticoids are recommended for the management of patients with cerebral edema.
Cryptococcosis
Daily lumbar puncture or CSF shunting has been advocated in the hope of averting permanent blindness for patients
with marked cerebral edema who have incipient blurred vision.
Diabetic Ketoacidosis
When the plasma glucose level falls to about 17 mmo1/L (300 mg/dL), 5% glucose solutions should be added, both
as a source of free water and as a prophylactic
measure to prevent the late cerebral edema syndrome. In children, cerebral edema is a common cause of death (less
frequent in adults). The exact cause of the brain
swelling is not known, however, in a recent study Glaser et al found that children with diabetic ketoacidosis with low
partial pressures of arterial carbon dioxide and high
serum urea nitrogen and treatment with bicarbonate therapy are at an increased risk of cerebral edema.Theories include osmotic disequilibrium between brain and plasma as glucose is rapidly lowered, decreased plasma oncotic
pressure due to infusion of large amounts of saline, and insulin-inducted ion flux across the BBB. Whatever the
mechanism, mortality rates are high. Treatment involves the bolus infusion of 1 g Mannitol per kilogram of body
weight in the form of 20% solution. The major nonembolic complication of DKA therapy is cerebral edema, which
most often develops in children as DKA is resolving. The etiology and optimal therapy for cerebral edema are not
well established but over replacement of free water should be avoided.
Reye’s syndrome (Fatty Liver with Encephalopathy)
Fatty changes of the renal tubular cells, cerebral edema, and neuronal degeneration of the brain are the major extra
hepatic changes in Reye’s syndrome. Therapy consists of infusion of glucose and fresh frozen plasma, as well as intravenous. Mannitol to reduce the cerebral edema.
Cirrhosis of Liver
Cerebral edema is frequently present and contributes to the clinical picture and overall mortality in patients with both
acute and chronic encephalopathy. Hemoperfusion to remove toxic substances and therapy directed primarily towards coincident cerebral edema in acute encephalopathy are also of unproven value.
High Altitude Cerebral Edema
High altitude cerebral edema is a clinical diagnosis, defined as the onset of ataxia, altered consciousness, or both, in
someone with acute mountain sickness or high altitude pulmonary edema. Global encephalopathy rather than focal
findings, characterizes high – altitude cerebral edema.Despite normal cerebral oxygenation and normal global cerebral metabolism, vasogenic edema develops in humans (and sheep) who become moderately ill with acute mountain
sickness /high altitude cerebral edema during 24 hour or more of hypoxic exposure. The exact cause of high altitude
cerebral edema is not known. Possible mediators, some triggered by endothelial activation, include vascular endothelial growth factor, inducible nitric oxide synthase and bradykinin.
Treatment requires descent and gradual acclimatization provides the most effective prevention. Acetazolamide is an
effective preventive aid and can be used in certain conditions as treatment. Simulated descent with portable hyperbaric chambers, now commonly used in remote locations, is also effective. Education should include information
about rate of ascent, diet, alcohol intake, physical activity, and preventive medications, including Acetazolamide,
Nifedipine, and Dexamethasone in selected cases.
Conclusion
Though there has been good progress in our understanding of pathophysiological mechanisms associated with cerebral edema more effective treatment is required and is still awaited. Certainly, the “ideal” agent for the treatment of
cerebral edema- one that would selectively mobilize and / or prevent the formation of edema fluid with a rapid onset
and prolonged duration of action, and with minimal side effects, remains to be discovered. Probably in the days to
come we can look forward to newer agents specifically acting on the various chemical mediators involved in the
pathogenesis of cerebral edema.
V. Revision of the basic knowledge of the earlier studied themes and disciplines.
Discipline
The student should know
The student
Microbiology
Description of infectious agents
To interpret the results of tests: culture an
petechial or papular lesions specimens; l
fluid or urine); polymerase chain reaction
Epidemiology
Spread of infectious agents
Administer prevention of the central nervou
Pathophysiology Pathogenesis of septic shock and cerebral ede- Administer treatment of septic shock and ce
ma
Neurology
Symptoms of CNS disorders
Clinical manifestations of cerebral edema
VI. Algorithm of practical work of students.
First stage
1) To find out epidanamnesis, anamnesis of life and disease
2) To interpret data of physical examination of patient
3) To interpret data of laboratory studies
4) To formulate clinical diagnosis
5) To make differential diagnosis
Second stage
To
administer prehospital and in-patient treatment of septic shock and
cerebral edema
Third stage
To administer prevention
of the central nervous system infections
VII. Sources of information.
Basic literature:
№
Author(s)
№
1. Mikhailova
1
A.M., Minkov
I.P., Savchuk
A.I.
2 E. Nikitin,
M. Andreychin
Name of the source
(textbook, manual, monograph, etc)
Infection diseases in children
Infectious diseases
City,
Publishing house
Year of
edition,
vol.,
issue
Number
of pages
Odessa
2003
124-131
Ukrmedkn
iga
2004
Additional literature:
№
Author(s)
№
Robert
1
M.
Kliegman, MD,
Richard E. Behrman, MD, Hal
B. Jenson, MD
and Bonita F.
Stanton, MD
Name of the source
(textbook, manual, monograph, etc)
Nelson Textbook of pediatrics
City,
Publishing
house
W.B.Saun
ders company
Year of
edition,
vol.,
issue.
2007,
18 th
edition
Number
of pages
747751