Management of Cyanotic spells in children

                MANAGEMENT OF CYANOTIC SPELLS

                                          Dr.Shashikant Dewangan

Definition-

Cyanotic spell is also known as ‘tet’ spell or hypercyanotic spell. This is a sudden onset, occasionally progressive event seen in infants with Tetralogy of Fallots. It is associated with progressive cyanosis, hyperpnea (increased rate and depth of breathing) and disappearance of heart murmur. If not treated in time it may ultimately lead to altered sensorium, neurological complications and death.

Other cardiac causes of cyanotic spells-
(A) Tricuspid atresia with pulmonary stenosis
(B) Transposition of Great arteries with pulmonary stenosis
(C) Single ventricle physiology with PS or pulmonary atresia.
Mechanism of Cyanotic spells-

                         ?Spasm of RVOT,Anxiety,Crying

Pathophysiology-

In a typical case of Tetralogy of Fallot the pressures in the right ventricle and left ventricle are equal. Hence the level of cyanosis and onset of cyanotic spell is determined the systemic vascular resistance and the level of pulmonary stenosis component. In case of mild pulmonary stenosis the right ventricular pressures are usually less than the left ventricle and hence the shunt is usually left to right. However, if the pulmonary stenosis is severe (due to any of the causes described later) then the right ventricular after load becomes high and hence the right ventricular pressures become high. If the systemic vascular resistance is low (which is usually the case in TOF with cyanotic spells) then the shunt flow becomes right to left. This results in progressive cyanosis. Low arterial pO2s lead to stimulation of the carotid receptors and the brain stem nuclei respectively which then leads to increased rate and depth of breathing which further increases the venous return to the right side of the heart and further right to left shunt of deoxygenated blood, thus leading to a vicious cycle. If not broken then it would ultimately lead to death.

Certain theories have also been postulated as possible explanation for the cause of cyanotic spells. These theories have basically compared the onset of cyanotic spells to exercise in normal individuals where there is fall in systemic arterial oxygen saturation during exercise and which reverses once exercise stops. In cyanotic spells this process of low systemic oxygen saturation continues and ultimately leads to progressive metabolic acidosis. These theories are:

a) Woods et al (1) - Postulated that hypoxemic spells are caused by spasm of the infundibulum of the right ventricle which precipitates a cycle of progressively increasing right to left shunting and metabolic acidosis.

b) Surge in Catecholamine release leads to increased myocardial contractility and infundibular stenosis. (Both these theories don’t explain the cause of cyanotic spells in patients with TOF with Pulmonary atresia)
c) Guntheroth et al (1) – episodes of paroxysmal hyperpnea are the cause rather than the effect of cyanotic spells. Hyperpnea increases the systemic venous return leading to right to left shunt as well as oxygen consumption through increase work of breathing.

d) Kothari et al (1) – argued against the commonly held views mentioned above and suggested the role of stimulation of mechanoreceptors in the right ventricle to be the cause of spells.

Increased contractility (due to catecholamine) and decreased right ventricular size (due to various factors) can trigger a reflex resulting in hyperventilation, some peripheral vasodilation without bradycardia, and this may initiate a spell. This mechanism he argued, explains most of the precipitating events and many other issues about cyanotic spells more satisfactorily.
PEAK AGE GROUP- 2-4 months

CLINICAL MANIFESTATIONS-

The spells occur most frequently in the morning or initially awakening or after episode of vigorous crying.The infant becomes hyperpneic and restless ,cyanosis increases and gasping respiration ensues,and syncope may follow.The spells may last from a few minutes to a few hours but are rarely fatal.The onset is usually spontaneous and unpredictable.Infants who are mildly cyanotic at rest are often more prone to the development of hypoxic spells because they have not acquired the homeostatic mechanism to tolerate rapid lowering of arterial oxygen saturation.

 MANAGEMENT OF HYPOXEMIC SPELLS -

A) Knee chest position-.Placment of the infant on the abdomen in knee-chest position while making certain that infant’s clothing is not to constrictive(4). Three mechanisms may be involved(3).

·        First, reduction of systemic venous return by trapping venous blood in the lower extremities reduces right to left shunt at the ventricular level (evidenced by reduced arterial lactate levels)

·        Second,reduced arterial blood flow to the legs reduces venous wash out from the  leg muscles.

·        Third ,squatting may also increase SVR a known mechanism to reduce right to left ventricular shunt. 

          Calming and holding the infant in a knee-chest position may abort progression of an early spells.
If  the child is very agitated it is difficult to achieve to knee-chest position.In this situation it is favourable to hold the child in parents shoulder with knees bent and oxgen is administered by another person from behind.
B) Oxygen- Oxygen to improve oxygenation. It is better given in nebulized form .
C) Morphine- Depresses respiratory center→abolishes hyperpnea→ decreases Systemic Venous Return. While giving this, facilities for ventilation should be available.
D) Inj Metoprolol- 0.1mg/kg over 5 min, repeat every 5 min to max 3 doses , then start infusion 1-5 mcg/kg/min. The mode of action of metoprolol is similar to Propranolol. Another short acting B-blocker that can be used is Inj Esmolol(0.5mg/kg over 1 min then 50mcg/kg/min over 4 min.
E) Propanolol- 0.1-0.2 mg/kg intravenously over 5 min. Reduces dynamic RV outflow obstruction and slow the heart rate thereby decreasing R→L shunting.More important propanolol may increase Systemic Vascular Resistance by antagonizing the vasodilating effects of  β2 adrenergic stimulation.   
Propanolol reduces platlet aggregation and propanolol also shift the oxyhemoglobin dissociation curve to the right thereby helping in cyanotic spells.(6)
F) Ketamine- 0.25- 1.0 mg/kg. IV or IM→ has dual benefit causes sedation and ↑ SVR(3).
G) Phenylephrine Hydrochloride- 0.01 mg/kg IV (slowly) or 0.1 mg/kg SC or IM (↑ SVR – dose to be titrated to BP response).
H) Methoxamine- 0.10mg/kg IV over 5-10 min. Leads to ↑ Systemic Vascular Resistance.
I) IV fluids- preferably initially as bolus of 10-20cc/kg which may be increased to 60cc/kg. Bolus fluid should be isotonic saline or colloid. Extra volume can be given in cyanotic spell as the physiology is not inductive to CCF and also because of a restrictive RV physiology.
J) Inj NaHCO3-(1-2 meq/kg intravenously slowly). To correct metabolic acidosis(MUST BE GIVEN)thereby eliminates the respiratory center –stimulating effects of acidosis.
K) Transfuse PRBC’s- 5-10 ml / kg IV over 5 hrs.
L) Correct Tachyarrhythmia- Improve diastolic filling and cardiac output.
M)Premature attempts to obtain blood samples may cause further agitation and counterproductive and should be avoided.

Long Term Management –

 Medical-

1.It is important to educate parents to recognize the spell and know what to do.

2.Oral propanolol therapy ,0.5-1.5 mg/kg every 6 hours,is used to prevent hypoxic spells(4).Propanolol effectively abolishes spells for at least 3 months in 80% patients(4).

3.Maintenance of good dental hygiene and practice of antibiotic prophylaxis against SBE are important.

4.Ballon dilatation of the right ventricular outflow tract and pulmonary valve has been attempted to delay repair for several months.

5.A relative iron deficiency state should be detected and treated.Iron deficient children are more susceptible to cerebrovascular complications.Hemoglobin and hematocrit values are usually normal so RBC indices and peripheral smear examination should be done.

Surgical-

Palliative Shunt Procedures-

Shunt procedures are performed to increase pulmonary blood flow-

Indications-

1.     Neonates with TOF and pulmonary atresia

2.     Infants with hypoplastic pulmonary annulus

3.     Infants younger than 3-4 months with medically unmanageable hypoxic spells

4.     Infants weighing less than 2.5 kg

A.   Classic Blalock-Taussing shunt-(SA-PA)-Usually performed for infants older than 3 months because the shunt is often thrombosed in younger infants.

B.   Modified  Blalock-Taussing shunt-A Gore-Tax interposition is placed between the subclavian artery and the ipsilateral PA.The surgical mortality rate is less than 1%.

C.   Potts operation-anastomosed between the descending aorta and left  pulmonary artery.No longer recommended because it may result in heart failure and pulmonary hypertension.

D.   Waterson Shunt-anastomosed between ascending aorta and right PA.

Complications include CHF,Pulmonary hypertension and kinking of PA at the site of anastomosis.

       Complete Repair Surgery-

          Indications-

1.     Oxygen saturation less than 75 to 80%.

2.     Occurrence of hypoxic spell

3.     Mildly cyanotic infants who have had previous shunt surgery

4.     Asymptomatic children with coronary artery anomalies.  

Timing-

Symptomatic infants may have primary repair at any time after 3-4 months.Most  centers prefer primary elective repair by 1 to 2years of age . 

Procedure- Total repair of defect is carried out under cardiopulmonary bypass,circulatory arrest and hypothermia.The procedure include –

·        Patch closure of VSD

·        Widening of the RVOT

·        And Pulmonry valvotomy

Surgical mortality rate is 2-3%

Complications-

1.     Bleeding problem during the post-operaitve period

2.     Pulmonary valve regurgitation

3.     CHF,usually transient

4.     RBBB over 90% pts and well tolerated

5.     Complete heart block <1%                                                      
   

References:

¹⁾       Neches W., Park S., and Ettedgui J., Tetralogy Of Fallot and Tetralogy of Fallot with Pulmonary Atresia In : Garson A., Bricker J., Fisher D., and Neish S.(Eds), The Science and Practice of Pediatric Cardiology, 2^{nd edition Vol.1, 1999, Williams and Wilkins.}

^{2)     Nelson Textbook of  PEDIATRICS 18th EDITION.}

^{3)     Park Pediatric Cadiology for Practitioners 5th Edition.}

^{4)     Garson A,Gillette P.C. and McNamara,D.G. Propranolol the preferred         palliation for tetralogy of Fallot. Am. J. cardiology,47:1098,1981}

^{5)     Ponce,F.E.et al Propanolol palliation of tetralogy of fallot,experience with long term drug treatment in pediatric pts. Pediatrics 52: 100,1973}

^{6)     Drug therapy in Infants and Children with Cardiovascular disorder by Lea & Febiger}

^{7)     Pediatric cardiac intensive care by Williams & wilkins. 2nd edition.}

^{8)     Internet references.}

Management of Severe Malaria in Children

Management of Severe Malaria in children

Shashikant Dewangan

Malaria is the most important vector borne disease worldwide. Globally it results in an estimated 400 million infections and more than 1 million deaths each year. Severe malaria is caused by Plasmodium falciparum infection and usually occurs as a result of delay in treating an uncomplicated attack of falciparum malaria. Sometimes, however, especially in children, severe malaria may develop very rapidly. Recognizing and promptly treating uncomplicated P. falciparum malaria is therefore of vital importance.

In a child with P. falciparum asexual parasitaemia and no other obvious cause of symptoms, the presence of one or more of the following clinical laboratory features classifies the child as suffering from severe malaria.¹

Clinical features:

─       Severe P. falciparum with cerebral manifestations, usually including coma (Glasgow coma scale < 11, Blantyre coma scale <3). Malaria with coma persisting for >30 minutes after a seizure is considered to be severe malaria

─       Prostrations, i.e. generalized weakness so that child is unable to walk or sit up without assistance

─       Failure to feed

─       Multiple convulsions – more than two episodes in 24 h

─       Deep breathing, respiratory distress (acidotic breathing )

─       Circulatory collapse or shock, systolic blood pressure <70 mm Hg in adults and <50 mm Hg in children

─       Clinical jaundice plus evidence of other vital organ dysfunction

─       Hemoglobinuria

─       Abnormal spontaneous bleeding

─       Pulmonary edema (radiological)

Laboratory findings:

─       Hypoglycemia (blood glucose <2.2 mmol/l or <40 mg/dl)

─       Metabolic acidosis (plasma bicarbonate <15mmol/l)

─       Severe normocytic anemia (Hb <5g/dl, packed cell volume < 15%)

─       Hemoglobinuria

─       Hyperparasitemia (>2% or 100000/µl in low density transmission area or >5% or 250000/µl in areas of high stable malaria transmission intensity)

─       Hyperlactatemia  ( plasma lactate > 5 mmol/L)

─       Renal impairment (serum creatinine > 3 mg/dL)

High risk: Immediate risk of dying and urgent need for supportive treatment²

• Depressed conscious level (any degree)
• Active seizure activity
• Irregular respirations or obstructed airway (pooling saliva or vomit in mouth)
• Hypoxia (oxygen saturations < 95%)
• Evidence of shock (systolic blood pressure < 80 mm Hg or < 70 mm Hg if child aged < 1 year) or two or more of the following: tachycardia, increased work of breathing, cool peripheries, capillary refill time ≥ 3 seconds, temperature gradient)
• Clinical evidence of dehydration
• Hypoglycemia (blood glucose < 40 mg/dL)
• Metabolic acidosis (base deficit > 8 mmol/L)
• Severe hyperkalemia (potassium > 5.5 mmol/L)

Intermediate risk: Need for high dependency care

• Hemoglobin < 7 g/dL
• History of convulsions during this illness
• Hyperparasitemia > 5%
• Visible jaundice
• Plasmodium falciparum in a child with sickle cell disease

Low risk: Need admission for parenteral medication

• Vomiting
• Unable to take or comply with oral medication

Low risk: Need for observation

• None of the above
• observe on oral treatment

Who is at risk?

In high-transmission areas, the risk of severe falciparum malaria developing is greatest among young children, and visitors (of any age) from non-endemic areas. In non-transmission and low-transmission areas the risk is greatest among travellers returning, with undiagnosed malaria infection, from any area where P. falciparum transmission occurs.

TABLE 1

Differences between severe malaria in children and in adults

Sign or symptoms	Adults	Children
History of cough	Uncommon	Common
Convulsions	Common	Very common
Duration of illness	5-7 days	1-2 days
Resolution of coma	2-4 days	1-2 days
Neurological sequel	< 5%	>10%
Jaundice	Common	uncommon
Pretreatment hypoglycemia	Uncommon	Common
Pulmonary edema	Uncommon	Rare
Renal failure	Common	Uncommon
CSF opening pressure	Usually normal	Usually raised
Respiratory distress	Sometimes	Common
Bleeding or clotting disorder	Upto 10%	Rare
Abnormalties of brain stem reflexes(e.g. oculovestibular or oculocervical)	Rare	More common

 

General management²

The following measures should be applied to all patients with clinically diagnosed or suspected severe malaria:

• Make a rapid clinical assessment with special attention to level of consciousness, blood pressure, rate and depth of respiration and pallor.

• Admit child to an intensive care unit if this is available.

• If parasitological confirmation of malaria is not readily available, make a blood film and start treatment on the basis of the clinical presentation.

• Give antimalarial chemotherapy intravenously. If intravenous infusion is not possible, an appropriate drug may be given intramuscularly. Suppository formulations of artemisinin and its derivatives are becoming available and should be given if parenteral administration is not possible. Oral treatment should be substituted as soon as reliably possible (once child can swallow and retain tablets).

• Calculate doses as mg/kg of body weight. Therefore, weigh the patient.

• Do not confuse the doses of salt and base. Quinine doses are usually prescribed as the quinine salt (10 mg of quinine dihydrochloride salt = 8.3 mg of quinine base). Chloroquine and quinidine are commonly prescribed as base.

• Provide good nursing care. This is vital, especially if the child is unconscious.

• Pay careful attention to fluid balance, if fluids are being given intravenously, in order to avoid over- and underhydration.

• Make a rapid initial check of the blood glucose level, and monitor frequently for hypoglycemia. If this cannot be done, give glucose.

• Examine the optic fundi by ophthalmoscope. This may help in differential diagnosis, and rarely will reveal papilloedema, which is a contraindication to performing a lumbar puncture. Retinal haemorrhages may be seen, but these do not influence management.

• Make sure you look for other treatable causes of coma. Meningitis should be excluded (by lumbar puncture) or covered by treatment.

• Look for and manage any other complicating or associated infections.

• Record urine output and look for the appearance of black urine (hemoglobinuria) or oliguria which may indicate acute renal failure.

• Monitor the core temperature (preferably rectal temperature), respiratory rate and depth, blood pressure, level of consciousness and other vital signs regularly. These observations will allow to identify the late onset of important complications such as hypoglycemia, metabolic acidosis, pulmonary edema and shock.

• Reduce high body temperatures (>39 ºC) by tepid sponging and fanning. Administer paracetamol as an antipyretic if necessary (controversial).

• If the child goes into shock, take blood cultures but start antibiotics without waiting for blood culture results.

• Monitor the therapeutic response, both clinical and parasitological, by regular observations and blood films.

• Carry out regular checks on packed cell volume (hematocrit) or hemoglobin concentration, glucose, urea or creatinine, and electrolytes.

• Avoid drugs that increase the risk of gastrointestinal bleeding (aspirin, corticosteroids).

• Remove an indwelling urinary catheter as soon as it is no longer necessary or if the child becomes anuric.

• Clean insertion sites for intravenous lines at least twice daily with iodine and alcohol.

More sophisticated monitoring (e.g. measurement of arterial pH, blood gases, central venous pressure) may be useful if complications develop.

Specific antimalarial chemotherapy

The drugs appropriate for the treatment of severe falciparum malaria are given in following tables. Response should be monitored by frequent clinical examination including recording of fluid balance, temperature, pulse, respiratory rate and depth, level of consciousness, blood pressure, jugular venous pressure, and parasitaemia (in blood films) every 4–6 hours for the first 48 hours. Chloroquine resistance is now virtually global and it is therefore advisable to treat all children with severe malaria with quinine or, where appropriate, an artemisinin derivative.

 RECOMMENDED TREATMENT IN FAILURE WITH ARTEMISININ COMBINATION THERAPY (ACT)⁹

Quinine + Tetracycline or Doxycycline or Clindamycin for 7 days. (Dosage are given in Table1)

(i) Treatment failure within 14 days of receiving an ACT is unusual. It should be confirmed parasitologically by blood slide examination. It is important to determine whether child has vomited previous treatment or did not complete a full course.

(ii) Failure after 14 days of treatment can be re-treated with first line ACT.

 DRUG AND DOSAGE OF ANTIMALARIALS IN COMPLICATED AND SEVERE MALARIA⁹

Quinine salt 20mg salt/kg (loading dose) diluted in 10mL of isotonic fluid/kg by infusion over 4 hours→ Then 12 hours after the start of loading dose give a maintenance dose of 10mg salt/kg over 2 hours→ This maintenance dose should be repeated every 8 hours, calculated from beginning of previous infusion, until the child can swallow→ then quinine tablets, 10mg salt / kg 8 hourly to complete a 7 day course of treatment (including both parenteral and oral). Tetracycline or doxycycline or clindamycin is added to quinine as soon as the child is able to swallow and should be continued for 7 days. If controlled IV infusion cannot

be administered then quinine salt can be given in the same dosages by IM injection in the anterior thigh (not in buttock).

The dose of quinine should be divided between two sites, half the dose in each anterior thigh. If possible IM quinine should be diluted in normal saline to a concentration of 60-100mg salt/ml. (Quinine is usually available as 300mg salt/ml). Tetracycline or doxycycline or clindamycin should be added as above. (Dosage are given in Table 2)

OR

Artesunate 2.4 mg/kg IV then at 12 and 24 hours, then once a day for total 7 days. If the child is able to swallow, then the daily dose can be given orally. Tetracycline or doxycycline or clindamycin is added to artesunate as soon as the child can swallow and should be continued for 7 days. (Dosage are given in Table 2)

OR

Artemether 3.2 mg/kg (loading dose) IM, followed by 1.6 mg/kg daily for 6 days. If the child is able to swallow, then the daily dose can be given orally. Tetracycline or doxycycline or clindamycin is added to artemether as soon as the child can swallow and should be continued for 7 days. (Dosage are given in Table 2)

TABLE 2

Tetracycline (above 8 years) 4mg/kg/dose 4 times daily for 7 days OR Doxycycline (above 8 years) 3.5mg/kg once a day for 7 days OR Clindamycin 20mg/kg/day in 2 divided doses for 7 days

  

Intravenous artesunate versus intravenous quinine

Ø  Intravenous artesunate should be used in preference to quinine for the treatment of severe P. falciparum malaria in adults (Strong evidence, high quality evidence).

─       Intravenous artesunate has been shown to significantly reduce the risk of death from severe malaria compared to intravenous quinine (6 trials, 1938 participants; high quality evidence)

─       Intravenous artesunate was associated with a lower risk of hypoglycemia (2 trials, 185 participants; low quality evidence)

─       No difference has been shown in the risk of serious neurological sequelae.

Ø  Artesunate offers a number of programmatic advantage over quinine such as

not requiring rate controlled infusion or cardiac monitoring and can be given safely in vital organ dysfunction esp. renal failure.

Respiratory patterns of severe malaria

Irregular breathing or drooling—The presence of respiratory depression or irregular breathing should alert the clinician to the presence of complex seizures, iatrogenic respiratory depression (because of multiple anticonvulsant medications), or the presence of raised intracranial pressure. High flow oxygen and appropriate airway management are as important as the administration of anticonvulsants. Hypoglycemia (blood sugar < 40mg/dL) may precipitate seizures or posturing and should be considered in such cases.

 Respiratory distress—Tachypnea and increased work of breathing are common complications of severe malaria in children. Studies conducted in Kenya have shown that these signs are usually associated with underlying metabolic acidosis (base deficit > 8 mmol/l) (grade 3 evidence). Moreover, more recent studies show that this metabolic acidosis is often associated with hypovolemia (grade 2) and can safely be treated with volume resuscitation by using colloid or crystalloid (grade 2-3).

Circulation

Hypovolemic shock needs to be identified and managed if present.

• Acidosis (base deficit > 8 mmol/l) is a common feature of severe malaria and in children is often accompanied by features of compensated shock (grade 3 evidence). These include hypoxia, increased work of breathing, tachycardia, altered peripheral pulse volume, cool peripheries, prolonged capillary refill time (≥ 2 seconds), and altered consciousness (grade 3).

• Hypotension (systolic blood pressure < 80 mm Hg) complicates about 25% of cases presenting with severe acidosis (base deficit > 15 mmol/l).

• Delayed capillary refill time (≥ 2 seconds) is a reasonable prognostic indicator, especially in children with a decreased conscious level (grade 3).

Treatment

In the absence of coma (children's Glasgow coma score ≤ 3) volume resuscitation with 20-40 ml/kg of either 0.9% saline or 4.5% human albumin solution safely corrects the hemodynamic features of shock and improves renal function in Kenyan children with severe malaria (grade 2 evidence), and that pulmonary edema is a rare complication (< 0.5%; grade 2)³.

Hypovolemic shock and coma

In children presenting in coma (inability to localise pain; children's Glasgow coma score ≤ 3) a more cautious approach to volume expansion is advised. A recent phase II trial has shown that volume expansion with human albumin solution may result in a lower mortality (5%) than with saline (46%) in children with shock and coma (grade 2)³. Until further data become available from larger trials, it is recommended that human albumin solution should be considered the resuscitation fluid of choice in the subgroup of children who present with coma and features of shock (grade 2-4).

Further management

Volume resuscitation should proceed cautiously in children with shock and should be stopped once the signs of circulatory failure have been reversed.

• Urine output of <1 ml/kg/hour, in the absence of urinary retention or established renal failure, indicates impaired renal perfusion secondary to hypovolemia and is a good non-invasive guide to fluid management (grade 3 evidence).

• For any child with persisting features of shock despite 40 ml/kg of fluid, elective intubation and ventilation, and placement of a central venous catheter should be done to guide further fluid management (grade 2).

• Inotropes (Dopamine and Dobutamine) can be added.

•  Children with severe acidosis may self ventilate their partial pressure of carbon dioxide (pCO₂) to very low levels, as compensation for the metabolic acidosis (grade 3).

• When initiating ventilation, great care should therefore be taken to avoid a rapid rise of pCO₂, even to normal levels, before acidosis has been partly corrected (grade 4).

• If the child is still shocked or if the shocked state returns then treatment of shock should take priority, since cerebral perfusion depends on an adequate blood pressure (grade 4).

Cerebral malaria

Clinical features-

• A child who loses consciousness after a febrile convulsion should not be classified as having cerebral malaria unless coma persists for more than 30 minutes after the convulsion. Antimalarial treatment must not be delayed.

• The depth of coma may be assessed either AVPU scale (Alert, responds to Voice, responds to Pain, or Unresponsive) or  according to the coma scale for children (Blantyre coma scale⁴) by observing the response to standard vocal or painful stimuli (rub knuckles on child’s sternum; if there is no response, apply firm pressure on thumbnail bed with horizontal pencil).

Best motor response:
Localizes painful stimulusa Withdraws limb from painb   Nonspecific or absent response	2 1 0
Verbal response:
Appropriate cry Moan or inappropriate cry None	2 1 0
Eye movements:
Directed (e.g. follows mother’s face) Not directed	1 0

                                                                                                Total 0-5

 A state of unrousable coma is reached at a score of <3.

This scale can be used repeatedly to assess improvement or deterioration.

^a Rub knuckles on patient’s sternum.

^b Firm pressure on thumbnail bed with horizontal pencil.

• Convulsion may present in a very subtle way – important signs include intermittent nystagmus, salivation, minor twitching of a single digit or a corner of the mouth and an irregular breathing pattern.

• In children with profound coma, corneal reflexes and “doll’s eye” movements may be abnormal.

• About 10% of children who survive cerebral malaria have neurological sequelae which persist into the convalescent period. Sequelae may take the form of cerebellar ataxia, hemiparesis, speech disorders, cortical blindness, behavioural disturbances, hypotonia or generalized spasticity.

 • Other infections of the central nervous system or intracranial hemorrhage, rather than malaria, should be considered as alternative diagnoses in a child with neck stiffness or a full fontanel.

• Hypoglycemia (blood sugar <40mg/dL) may precipitate coma and should be excluded.

• The cardinal features of cerebral malaria are impaired consciousness, convulsions, abnormal neurological signs, and opisthotonic posturing. Only in a small proportion of children do these features suggest raised intracranial pressure (grade 3 evidence).   

 • Recent studies in children in Malawi have shown a retinopathy that is peculiar to severe malaria and consists of patchy whitening of the retina in the macular and extramacular areas, pale opacification of retinal vessels, and white centred hemorrhages. In children who die, a correlation between the density of hemorrhages in the retina with their density in the brain has been found.

Treatment

• Initial management should include maintenance of the airway, support of breathing, and immediate correction of hypoglycemia and volume deficits.

• Children who remain unconscious or have features suggestive of raised intracranial pressure warrant elective intubation and ventilation.

• For children with seizures, the decision to ventilation should be delayed if they are in a postictal state, as long as the airway is patent and respiration is not compromised.

• No adjunctive therapies have shown any benefit in treatment of children in coma.

• Repeated seizures and motor posturing movements are common in children in coma. Their relation to raised intracranial pressure has not been established (grade 3 evidence); nevertheless, because of the potential risk of raised intracranial pressure, ventilation should aim to optimise the pCO₂ in the normal range, as there is no evidence that hyperventilation is beneficial in raised intracranial pressure (grade 4). Most children will regain full conscious level over the following 48 hours.

Management of seizures

Seizures are common in severe childhood malaria. Most present as tonic-clonic convulsions, but 25% are subtle or subclinical (grade 2-3 evidence), commonly manifesting as eye deviation, an irregular respiratory pattern, or drooling.

 • Initiating high flow oxygen and appropriate airway management are as important as the administration of anticonvulsant drugs.

• Hypoglycemia may precipitate seizures or posturing and should be considered in such cases (grade 3).

• Seizure prophylaxis is not recommended.

• A recent trial of prophylactic phenobarbital, at a loading dose of 20 mg/kg given intramuscularly, increased mortality in Kenyan children with cerebral malaria. Mortality was greatest in those receiving two or more doses of diazepam, which may have caused respiratory depression in these unventilated children (grade 2). Nevertheless, the safe use of anticonvulsants in the setting of a modern pediatric intensive care setting is likely to differ greatly from that in African centres where ventilatory support is unavailable.

Raised intracranial pressure

• Brain swelling is a major feature in fatal cases (grade 3 evidence).

• Nevertheless, in most cases, signs suggestive of raised intracranial pressure developed in the later stages of the illness (grade 3). Signs include a declining conscious level, focal neurology including unequal, dilated, or poorly responsive pupils, and abnormal posturing.

•  Papilloedema and the combination of hypertension and relative bradycardia are late findings in acute raised intracranial pressure.

• Unilateral sluggish or absent pupillary responses are the only reliable signs (grade 3).

• Caution should be exercised in the diagnosis of raised intracranial pressure in children in the peri-ictal state, where pupillary signs and conscious level may be misleading (grade 4).

Treatment

The development of features suggestive of raised intracranial pressure should be considered a medical emergency and should be treated by the rapid induction of anaesthesia, tracheal intubation, mechanical ventilation, and close, and frequent monitoring of blood gases (grade 4 evidence).

 • To stabilize cerebral blood flow, pCO₂ should be kept within the normal range. However, in children with hyperventilation and low initial pCO_2, ventilation should allow the pCO₂ to rise to a normal range more gradually.

• Mannitol (0.5 mg/kg) infused rapidly over five to 10 minutes may be effective in lowering the intracranial pressure, but its short term effect means that repeated doses are often necessary (grade 3)⁵.

• Other forms of osmotherapy for the management of raised intracranial pressure, such as hypertonic saline, have not been evaluated in children with severe malaria.

• Steroids are not recommended as their effect on raised intracranial pressure remains unclear and their use may adversely affect outcome (grade 3).

Pulmonary edema

Clinical features

Pulmonary edema is a grave complication of severe malaria, with a high mortality (over 80%). It may appear several days after chemotherapy has been started and at a time when the patient’s general condition is improving and the peripheral parasitaemia is diminishing. In most cases there are features of acute respiratory distress syndrome (ARDS), implying increased pulmonary capillary permeability. Pulmonary edema may also arise iatrogenically from fluid overload. The two conditions are difficult to distinguish clinically and may coexist in the same patient. Pulmonary edema is often associated with other complications of malaria and may also occur in vivax malaria. The first indication of impending pulmonary edema is an increase in the respiratory rate. The arterial pO2 is reduced.

Hypoxia may cause convulsions and deterioration in the level of consciousness and the child may die within a few hours.

Management

• Keep the child upright; raise the head of the bed or lower the foot of the bed.

• Give a high concentration of oxygen by any convenient method available, including mechanical ventilation.

• Give the child a diuretic, such as furosemide (frusemide), 40 mg, by intravenous injection. If there is no response, increase the dose progressively to a maximum of 200 mg.

• Last resort is mechanical ventilation with high PEEP.

If there is pulmonary edema due to overhydration in addition to the above:

• Stop all intravenous fluids.

• Use hemofiltration immediately, if available.

• If there is no improvement, withdraw 250 ml of blood by venesection into a blood transfusion donor bag so that it can be given back to the child later if necessary.

Circulatory collapse (“algid malaria”)

Clinical features

Some childrens  are admitted in a state of collapse, with a systolic blood pressure less than 50 mmHg in the supine position; a cold, clammy, cyanotic skin; constricted peripheral veins; rapid feeble pulse. This clinical picture is often associated with a complicating Gram-negative septicemia. Circulatory collapse is also seen in children with pulmonary edema or metabolic acidosis, and following massive gastrointestinal hemorrhage or ruptured spleen. Dehydration with hypovolemia may also contribute to hypotension. Possible sites of associated infection should be sought, e.g. lung, urinary tract (especially if there is an indwelling catheter), meninges (meningitis), intravenous injection sites, intravenous lines.

Management

• Correct hypovolemia with an appropriate plasma expander (fresh blood, plasma, dextran 70 or polyglycans). If these are not available give isotonic saline.

• Take a blood culture and start the children broad spectrum antibiotics immediately, e.g. a penicillin or cephalosporin combined with a single dose of gentamicin.

• Once the results of blood culture and sensitivity testing are available, give the appropriate antibiotic.

• Monitor central venous pressure .

Abnormal bleeding and disseminated intravascular coagulation

Clinical features

Bleeding gums, epistaxis, petechiae and subconjunctival hemorrhages may occur. Disseminated intravascular coagulation, complicated by clinically significant bleeding, e.g. hematemesis or melena, occurs in fewer than 10% of children. It is more common in non-immune children with imported malaria in the temperate zone. Thrombocytopenia is very common in falciparum malaria, usually without other coagulation abnormalities. In most cases it is unaccompanied by bleeding. The platelet count usually returns to normal after successful treatment of the malaria.

Management

• Transfuse fresh blood, clotting factors or platelets as required.

• Give vitamin K, 10 mg, by slow intravenous injection.

Hyperparasitaemia

Clinical features

In general, and especially in non-immune subjects, high parasite densities (above 5%) and peripheral schizontemia are associated with severe disease; however, in highly endemic malarious areas, partially immune children can tolerate surprisingly high densities (20–30%) often without clinical symptoms.

Management

• Antimalarial therapy should be initiated immediately, preferably by a parenteral route

 even if the child can take medication by mouth.

• If parasitemia exceeds 10% in severely ill children, especially those deteriorating after optimal chemotherapy, exchange transfusion with screened blood can be considered.

Malarial hemoglobinuria

Clinical features

Children with glucose-6-phosphate dehydrogenase (G6PD) deficiency may develop intravascular hemolysis and hemoglobinuria precipitated by primaquine and other oxidant drugs, even in the absence of malaria. Hemoglobinuria associated with malaria (“blackwater fever”) is uncommon in children and malarial hemoglobinuria usually presents in adults as severe disease with anemia and renal failure.

Management

• Continue appropriate antimalarial treatment if parasitaemia is present.

• Transfuse screened fresh blood if needed.

• Monitor central venous pressure to avoid fluid overload and hypovolemia.

• If oliguria develops and blood urea and serum creatinine levels rise (i.e. if acute renal failure develops), peritoneal dialysis or hemodialysis may be required.

Other complications

Very common

·   Hypoglycemia (blood glucose < 40mg/dL): often correlates with disease severity. Maintenance fluids containing 5-10% glucose should prevent this complication.

·   Hyperpyrexia: increases the risk of convulsions in children and should be treated with antipyretics or tepid sponging. Ibuprofen is superior to paracetamol for reducing fever (grade 3 evidence); the dose should be reduced in cases complicated by impaired renal function. Ibuprofen should be avoided if there is abnormal bleeding.

Common

•Electrolyte derangement:

Hyperkalemia may complicate cases with severe metabolic acidosis at admission.

Hypokalemia, hypophosphatemia, and hypomagnesemia are often apparent only after admission after metabolic derangements have been corrected (grade 3). Serial monitoring of plasma electrolytes is suggested, correction should follow the recommendations given by the Advanced Paediatric Life Support guidelines.

TABLE 3

Glucose/electrolyte	Treat if less than	Correct with
Glucose	3 mmol/L	5 ml/kg of 10% dextrose
Potassium	3.5 mmol/L	0.25 mmol/kg over 30 min
Total calcium	2 mmol/L	0.3 ml/kg 10% Ca gluconate over 30 min
Magnesium	0.75 mmol/L	0.2 ml/kg 50% MgSO4 over 30 min
Phosphate	0.7 mmol/L	0.2 mmol/kg of NaPO4 over 30 min

• Metabolic acidosis: Resolves with the correction of hypovolemia and treatment of anemia by adequate blood transfusion. No evidence to support the use of sodium bicarbonate (grade 3). Dichloroacetate reduces lactic acidosis in African children, but effect on mortality unknown (grade 2).

• Severe malaria anemia: Most children will experience some reduction of hemoglobin and do not require transfusion.

─       In general, a packed cell volume (hematocrit) of 15% or less, or a hemoglobin concentration of 5 g/dl or less, is an indication for blood transfusion, whatever the clinical condition of the child. In some children, an initial transfusionis required with the utmost urgency (10 ml of packed cells or 20 ml of whole blood per kg of body weight).

─       In children with less severe anemia (i.e. packed cell volume 15–21%, Hb 5–7 g/dl), transfusion should be considered for high-risk children with any one of the following clinical features: (i) respiratory distress (acidosis); (ii) impaired consciousness; (iii) hyperparasitaemia (>20%).

─       Anemic children with respiratory distress are, contrary to usual belief, rarely in congestive cardiac failure. More commonly their dyspnea is due to acidosis, resulting from tissue hypoxia, often associated with hypovolemia. The sicker the child the more rapidly the transfusion needs to be given.

─       A diuretic is usually not indicated as many of these children are hypovolemic. However, if there is fluid overload, furosemide (frusemide), 1–2 mg/kg of body weight up to a maximum of 20 mg, may be given intravenously.

─       WHO recommendations

·         In high-transmission settings, blood transfusion is generally recommended for children with a hemoglobin level of <5g/100ml (hematocrit <15%).

·         In low-transmission settings, a threshold of 20%(hemoglobin 7 g/100ml) is recommended. 

Uncommon

·   Secondary bacterial infection may occur (grade 3) and empiric broad spectrum antibiotics are warranted—such as ceftriaxone 100 mg/kg/day.

·   Coagulation activation: Bleeding is rare despite the customary thrombocytopenia of severe malaria (platelet counts often < 50×10⁹/l; grade 3).

Role of exchange transfusion

·   Exchange transfusion has been advocated for hyperparasitemia (> 10%) in adult intensive care settings, despite little evidence to indicate an improved outcome (grade 2 evidence)⁷. Even when parasitaemia exceeds 25%, most children respond rapidly to the management outlined above. In children with persistent acidosis and multiorgan impairment who are not responsive to these resuscitation treatments, exchange transfusion may be considered as a means of rapidly reducing the level of abnormally rigid red cells, or parasite toxins (grade 2). This treatment, however, remains experimental.

Conclusions from Cochrane database⁸

Ø  There is insufficient data to confirm or refute an impact of antipyretic measures on parasitaemia or malarial illness.

Ø  There is insufficient data to be sure whether routinely giving blood to clinically stable children with severe anaemia in endemic malarious areas reduces death, or results in higher haematocrit measured at one month.

Ø  There are insufficient data to draw any conclusions for desferroxamine  and deferiprone. There are nonsignificant trends towards fewer seizures but overall harm (death) with desferroxamine, and results from one small trial of deferiprone suggest shorter coma recovery and parasite clearance.

Ø  Iron does not increase the risk of clinical malaria or death, when regular malaria surveillance and treatment services are provided. There is no need to screen for anemia prior to iron supplementation.

Ø  Routine phenobarbitone in cerebral malaria is associated with fewer convulsions but possibly more deaths.

Ø  There is currently no evidence of benefit from corticosteroids.

References ;

1.      Guidelines for treatment of Malaria. 2^nd Edition, World Health Organization 2010.

2.      Management of severe malaria in children: proposed guidelines for the United Kingdom by K. maitland et al. BMJ 2005;331 337

3.      Maitland K, Pamba A, English M, Peshu N, Marsh K, Newton CRJC, et al. Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit. Clin Infect Dis 2005;40:538-45

4.       Molyneux ME. Taylor TE, Wirima JJ, Bargstein J. Clinical features and prognostic indicators in pediatric cerebral malaria. A study of 131 comatose malarial children. Q J Med 1989;71:441-59

5.      Newton CR, Chokwe T, Schellenberg JA, Winstanley PA, Forster D, Peshu N, et al. Coma scales for children with severe falciparum malaria. Trans R Soc Trop Med Hyg 1997; 91: 1615

6.      Severe falciparum malaria. World Health Organization, communicable diseases cluster. Trans R Soc Trop Med Hyg 2000; 94:S1–90.

7.      Riddle MS, Jackson JL, Sanders JW, Blazes DL. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis 2002; 34:119-28

8.      Cochrane reviews

9.      Guidelines for management of malaria in children: Update 2008. INFECTIOUS DISEASE CHAPTER, INDIAN ACADEMY OF PEDIATRICS

10.  Nelson textbook of pediatrics 18^th edition

11.  Ghai Essential Pediatrics 7^th edition

12.  Manson’s textbook of tropical medicine