UNDERSTANDING THE PATHOPHYSIOLOGY OF MENINGOCOCCAL INFECTION AND THE PRINCIPLES OF MANAGEMENT

The management of meningitis and septicaemia are best understood by having a basic knowledge of the pathophysiology of meningococcal infection. The section below is a summary. For more detailed information see references at the end of this section.

CLINICAL PATHOPHYSIOLOGY OF SEPTICAEMIA

CAPILLARY LEAK SYNDROME

When meningococci enter the bloodstream endotoxin is released from the bacteria. This triggers an intense inflammatory response, damaging the endothelium lining the blood vessels so that it becomes ‘leaky’. Plasma then leaks out of the blood into interstitial tissues. This is called the ‘capillary leak syndrome’. The patient becomes hypovolaemic as fluid is lost from the blood stream. Hypovolaemia results in diminished venous return to the heart, and reduced filling of the ventricles decreases cardiac output. The patient increases the heart rate and the force of contraction of the heart, in order to maintain the blood pressure and cardiac output (‘cardiac compensation’). Blood is also diverted away from non vital organs such as the limbs and kidneys. Early in sepsis children have tachycardia, cool peripheries and normal blood pressure. They are also alert as blood flow to the brain is being maintained at the cost of the other organs. Continuing capillary leak results in tissues becoming underperfused and hypoxic. Hypoxia is exacerbated by capillary leak into the lung vascular beds causing pulmonary oedema. Cardiac compensation becomes increasingly difficult in the presence of acidosis, hypoxia and severe hypovolaemia and eventually the blood pressure falls. This is a very late sign in septic shock in children.

DISSEMINATED INTRAVASCULAR COAGULATION

Endotoxin causes activation of the coagulation cascade together with down-regulation   of anticoagulant pathways. There is also up-regulation of antifibrinolytic proteins leading to a procoagulant state. This is demonstrated by prolongation of clotting times and thrombocytopaenia. Micro-vascular thrombosis is a major contributing factor to multiple organ failure and purpura fulminans.

MYOCARDIAL DYSFUNCTION

Endotoxin and inflammatory cytokines together with poorly characterised myocardial depressant factors reduce myocardial contractility despite adequate fluid resuscitation. This may also cause a relative inotrope unresponsiveness.

SPECIFIC ORGAN DYSFUNCTION IN SHOCK

Respiratory failure

(arterial PO2 <10kPa in air or PCO2 >6)  Common in shock.

Capillary leak into lung parenchyma causing acute pulmonary oedema.

Clinically: tachypnoea, chest wall retraction, hypoxia.

Metabolic derangement 

Septicaemia causes profound acidosis and derangements in metabolism, which may affect myocardial function and need correcting. Hypoglycaemia is common. Hypokalaemia, hypocalcaemia, hypomagnesaemia and hypophosphataemia all occur.

Coagulopathy (purpuric rash)

Coagulopathy occurs early in patients with septicaemia. The laboratory findings of disseminated intravascular coagulation (DIC) are common in such patients: increased PT (prothrombin time), APTT (activated partial thromboplastin time), TT (thrombin time) and decrease in plasma fibrinogen with elevation of fibrin degradation products and thrombocytopaenia. The coagulopathy is generally associated with the presence of a purpuric rash, but significant coagulopathy may infrequently occur in the absence of purpura.

Neurological dysfunction

In septicaemia, patients may be alert until late in the illness. Falling conscious level results from impaired cerebral blood flow and disturbed brain metabolism due to hypotension, hypoxia and acidosis.

Myocardial failure

Depressed myocardial function is multifactorial, including endotoxin cytokines and multiple metabolic derangements, hypoxia, and hypovolaemia.

Clinically: tachycardia, gallop rhythm, cool peripheries and eventually hypotension.

Renal failure

Little or no urine output (<1ml/kg/hour) is a very early sign in septic shock, initially due to hypovolaemia. If shock persists then renal failure may occur.

CLINICAL PATHOPHYSIOLOGY OF MENINGITIS

Meningococcal meningitis usually carries a better prognosis than the septicaemic form of the illness. Deaths do occur, however, due to the severity of the inflammatory process within the brain. Bacteria invade through the nasopharynx, multiply in the bloodstream and then penetrate the blood brain barrier. Bacterial products, including endotoxin, initiate inflammatory changes in the CSF and blood brain barrier. Changes in the integrity and permeability of the blood-brain barrier together with alteration of brain cell function causes cerebral oedema. As a consequence there is an increase in total brain water content leading to an increase in intracranial pressure. In addition, the inflammatory process causes micro-vascular thrombosis in blood vessels of the meninges and brain substance. Both the cerebral oedema and micro-vascular thrombosis lead to a reduction in cerebral blood flow. The aim of this section is to outline the principles of management of septicaemia and meningitis which are based on understanding the pathophysiology. A fuller explanation of the management of meningococcal disease can be found in Archives of Disease in Childhood, July 2003, Volume 88, No 3, p 608-614 by SB Welch and S Nadel. The protocol from this article has been published as ‘Early Management of Meningococcal Disease in Children’ and you can refer to it here.

ANTIBIOTICS - Cefotaxime or Ceftriaxone

 -All children with fever and a haemorrhagic rash 

-Children with shock with or without a rash 

- Children with clinical evidence of meningitis. If lumbar puncture is contraindicated (see), treat immediately with antibiotics and lumbar puncture when safe.

For prophylaxis of contacts speak to Public Health department. Close family contacts often are treated by the clinicians caring for the ill child with Rifampicin, Ciprofloxacin (not in children) or Ceftriaxone. See protocol, Early Management of Meningococcal Disease in Children for doses.

Children with evidence of shock need immediate resuscitation: 

A- assess airway for patency.

B- give oxygen to all patients even if oxygen saturations are normal in order to optimise tissue oxygenation. 

C- secure good venous access. The goal of circulatory support in shock is the maintenance of tissue perfusion and oxygenation. Remember in shocked children the intra-osseous route may be the most effective way of giving large volume replacement.

 Fluid boluses should be initiated. Boluses of 20ml/kg should be given whilst monitoring the clinical response (HR, RR, BP, CRT, urine output). Unless the clinical response is excellent, up to 40-60 ml/kg should be given over the first hour. If there is still evidence of shock at this stage the patient will need further management, preferably on a paediatric intensive care unit.

Advice should be sought early. Intensive care is required in order to monitor and treat the patient adequately, which will require central venous and arterial access. Elective intubation and ventilation of shocked patients who have received 40-60 ml/kg is recommended to reduce the risk of pulmonary oedema and reduce the work of breathing and myocardial workload. If shock persists once the circulating volume has been restored (as measured by central venous monitoring) then inotropic support of the heart is indicated.

Metabolic derangements of calcium, magnesium and potassium are common, and need frequent checking and correction.  Renal replacement therapy may be necessary in patients with incipient or established renal failure.

Remember – Call for senior help early. Sick septic children need experienced doctors. This is not the time to ‘have a go!’

References