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Plasmodium
falciparum malaria is the cause of all the mortality and most of
the morbidity in malaria, although, rarely, P. vivax or P. ovale
also produce serious complications, debilitating relapses, and even death.
Go to
Treatment of P. vivax
/ P. ovale / P. malariae |
Treatment of Uncomplicated
P. falciparum
Severe malaria is a medical emergency and may rapidly progress to death
without prompt and appropriate treatment.[1] The main objective of the
treatment of severe malaria is to prevent the patient from dying; prevention of recrudescence, transmission or emergence of resistance and
prevention of disabilities are secondary objectives.
The mortality of untreated severe malaria can be 100%, but with antimalarial
treatment, the overall mortality falls to 15–20%.[2]. As death from severe malaria can
occur within hours of admission to hospital or clinic, it is essential that
therapeutic concentrations of antimalarial are achieved as soon as possible[2]
with intravenous antimalarials. Further, gastrointestinal intolerance and erratic intestinal
absorption make the oral route of administration unreliable in these
patients.[1] As resistance to antimalarial drugs
can complicate matters further, proper choice of antimalarials to
start the treatment is of utmost importance; changing the drugs or
adding of drugs half-way through the treatment only complicates the
issue and adds to the adverse effects of treatment.
Management of severe malaria comprises four main areas:
clinical assessment
of the patient, specific antimalarial treatment
(regimen,
follow-on treatment,
pre-referral treatment,
artimisinin, quinine/quinidine),
adjunctive therapy and
supportive
care.[2]
Clinical assessment:[2]
A
detailed clinical examination should be conducted, with particular
note of the level of consciousness (the Glasgow coma scale is
suitable for adults, and the simple Blantyre modification or
children’s Glasgow coma scale for children). The airway should be secured in
unconscious patients and breathing and circulation assessed. Body weight of the patient
should be measured or estimated so as to calculate the dose of antimalarial drugs and fluids. An intravenous cannula should be inserted and
blood should be taken for cross-match, full blood count, platelet
count, clotting studies, blood culture and full biochemistry; immediate measurements of blood glucose
(stick test), haematocrit/haemoglobin, parasitaemia and, in adults, renal
function should also be done. Unconscious patients should have a
lumbar puncture for cerebrospinal fluid analysis to exclude bacterial meningitis.
The degree of acidosis is an important determinant of outcome; the plasma
bicarbonate or venous lactate level should therefore be measured if possible.
If facilities are available, arterial or capillary blood pH and gases should be
measured in patients who are unconscious, hyperventilating or in shock.
The assessment of fluid balance is critical in severe malaria.
Respiratory distress, in particular with acidotic breathing in severely anaemic
children, often indicates hypovolaemia and requires prompt rehydration and,
where indicated, blood transfusion.
Specific antimalarial
treatment:
After rapid clinical assessment and confirmation of the
diagnosis, full doses of parenteral antimalarial treatment should be
started without delay with whichever effective antimalarial that is first available.[2] Two classes of drugs are currently available for the parenteral treatment
of severe malaria: the cinchona alkaloids (quinine and quinidine) and the artemisinin derivatives (artesunate, artemether and
artemotil). Although there are a few areas where chloroquine is still effective,
parenteral chloroquine is no longer recommended for the treatment of severe
malaria because of widespread resistance. Intramuscular sulfadoxine–
pyrimethamine is also not recommended.[2]
The
WHO recommends intravenous artesunate as the treatment of choice for severe malaria in adults and children in areas
of low transmission.[2,3] Data on children in high-transmission regions are limited, and the WHO recommends treatment with artesunate, artemether, or quinine. For severe malaria during pregnancy, additional data regarding the risks of artemisinins
are needed. The WHO recommends artesunate or quinine during the first trimester and artesunate as the first-line therapy
during the second and third trimesters.[2,3]
|
Treatment of
Severe P. falciparum Malaria [1,2,4] |
|
Regimen |
First Drug |
Second Drug |
|
Regimen 1a |
Artesunate 2.4 mg/kg bw iv or im on admission; then at 12 h
and 24 h, then once a day for 7 days |
Doxycyclined
100mgs BID (2.2mg/kg BID for <45kgs[4]) for 7 days OR |
|
Mefloquine 15 mg/kg (750 mg)
base, then 10 mg/kg (500 mg) base at 6–8 hours and (if >60 kg)
followed by 5 mg/kg (250 mg) at 16 hours (Total 1500 mg) OR |
|
Clindamycin 20mg base/kg/day divided in three doses for 7
days[4] in pregnancy |
|
Regimen 2b |
Artemether
3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg bw per day
for 7 days |
Same as above |
|
Regimen 3b,c |
Quinine
20 mg salt/kg bw on admission (iv infusion or divided im injection), then 10 mg/kg bw every 8 h; infusion rate should not exceed 5 mg salt/kg bw
per hour; course for 3 days for malaria acquired in Africa and
South America, 7 days for malaria acquired in SE Asia[4] |
Doxycycline OR Clindamycin as above |
|
Regimen 4c |
Quinidine gluconate 10 mg salt/kg
(equivalent to 6.2 mg base/kg) iv infused over 1–2 hours, followed immediately by
0.02 mg/kg/min salt (equivalent to 0.0125 mg/kg/min base) continuous iv infusion;
course for 3 days for malaria acquired in Africa and South
America, 7 days for malaria acquired in SE Asia[4] |
Doxycycline OR Clindamycin as above |
-
Recommended by WHO in low transmission areas or outside malaria endemic areas.[2]
-
Recommended by WHO for children in high transmission areas;
regimen 1 can also be used.[2]
-
For areas where artesunate or artemether are not available,
mainly the US.[1] National Vector Borne Disease Control
Programe in India recommends quinine as the treatment for
severe malaria in pregnancy.[5] Loading dose should not be administered to
patients who received quinine, quinidine, halofantrine, or mefloquine within
the preceding 12 hours.[1]
-
Not for children below 8 years of age and pregnant women
-
Mefloquine has important neuropsychiatric and cardiac adverse
effects; not an ideal drug for pregnancy[4]; cannot be used
concomitantly with quinine or quinidine.
-
For pregnant women.
Clindamycin 5 mg/kg (usually 300 mg) po or iv
every 8 hours can be administered if the patient is unable to take
doxycycline.
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Treatment response should be assessed by
parasite count daily until clearance of all trophozoites is
achieved. Parasitemia may rise during the first 12–24 hours,
because available drugs do not inhibit schizont rupture and
release of merozoites. Rising parasitemia beyond 36–48
hours after the start of antimalarial treatment indicates treatment
failure, usually because of high-level drug resistance. Because nonimmune hosts may exhibit a high pretreatment
total parasite burden , it may take
up to 6 days to achieve complete elimination of P. falciparum
trophozoites from the blood, even with fast-acting antimalarial
agents (e.g. quinine, artemisinin derivatives). A rising gametocyte
count does not indicate treatment failure.[1]
Follow-on treatment:[2]
Following initial parenteral treatment, once the patient can
tolerate oral therapy, it is essential to continue and complete treatment with an
effective oral antimalarial. Current practice is to continue the same medicine orally as
given parenterally to complete a full 7 days of treatment. In
non-pregnant adults, doxycycline is added to either quinine, artesunate or artemether
and should also be given for 7 days. Doxycycline is preferred to other
tetracyclines because it can be given once daily, and does not accumulate in renal
failure. But as treatment with doxycycline only starts when the patient has
recovered sufficiently, the doxycycline course finishes after the quinine,
artemether or artesunate course. Where available, clindamycin may be
substituted in children and pregnant women, as doxycycline cannot be given to these
groups. Although following parenteral treatment with a full course of oral ACT (artesunate
+amodiaquine or artemether-lumefantrine) is theoretically a good
alternative, this has not been evaluated in clinical trials. The recommendation from experts’ opinion is to complete
treatment in severe malaria following parenteral drug administration by giving a
full course of combination therapy, ACT or quinine + clindamycin or doxycycline.
Regimens containing mefloquine should be avoided if the patient presented
initially with impaired consciousness. This is because of an increased
incidence of neuropsychiatric complications associated with mefloquine following cerebral malaria.
Pre-referral treatment:[2]
The risk of death from severe malaria is greatest in the first
24 h, yet in most malaria endemic countries, the transit time between referral and
arrival at appropriate health facilities is usually prolonged thus delaying the
commencement of appropriate antimalarial treatment, during which time the
patient may deteriorate or die. It is recommended that patients are treated
with the first dose of one of the recommended treatments by the parenteral
route if possible or by the intra-rectal route before referral (unless the
referral time is very short).
This could be intramuscular artemether, artesunate or quinine,
or a rectal formulation of artemisinin or artesunate.
The following may be given:
Pre-referral and continued treatment with rectal artemisinins
The administration of an artemisinin by the rectal route as
pre-referral treatment is feasible even at the community level. There is insufficient evidence to show whether rectal artesunate
is as good as intravenous or intramuscular options in the management of severe
malaria. The recommendation, therefore, is to use artesunate or
artemisinin suppositories only as pre-referral treatment and to refer the patient to a
facility where complete parenteral treatment with artesunate, quinine or artemether can be instituted. If, however, referral is impossible, rectal
treatment should be continued until the patient can tolerate oral medication, at
which point a full course of the recommended ACT for uncomplicated malaria in
the locality can be administered. Definitive therapy for malaria should be
followed as soon as possible after the initial rectal administration.
Dosing for antimalarials given by suppository
Artemisinin derivatives
Artemisinin suppositories are not widely available. Doses used
have been variable and empiric: 10–40 mg/kg bw (at 0, 4 or 12, 24, 48 and
72 h). Some studies have given a maintenance dose of one- to two-thirds of
the initial dose. Artesunate suppositories (data relate to a single
suppository formulation) are given in a dose of 10 mg/kg bw daily. The individual suppositories contain either 50, 100 or 400 mg of
artesunate.
Initial (pre-referral) treatment with rectal artesunate
The appropriate single dose of artesunate given by suppository
should be administered rectally as soon as the presumptive diagnosis of
severe malaria is made. In the event that an artesunate suppository is expelled
from the rectum within 30 min of insertion, a second suppository should be
inserted and, especially in young children, the buttocks should be held
together, for 10 min to ensure retention of the rectal dose of artesunate.
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Dosage
for initial (pre-referral) treatment in adult patients (aged ≥16 years)
(WHO, 2006)2 |
|
Weight (kg) |
Artesunate dose |
Regimen (single dose)
|
|
<40
|
10 mg/kg bw |
Use appropriate no. of 100-mg rectal suppositories |
|
40–59 |
400 mg |
One 400-mg suppository |
|
60–80 |
800 mg |
Two 400-mg suppositories |
|
>80 |
1200 mg |
Three 400-mg suppositories |
For children: one or more
artesunate suppositories inserted in the rectum as indicated in Table 6. The dose should be given once and followed
as soon as possible by definitive therapy for malaria.
|
Dosage for
initial (pre-referral) treatment in children (aged 2–15 years) and weighing at least 5 kg |
| Weight (kg) |
Age |
Artesunate dose (mg) |
Regimen (single dose) |
|
5–8.9 |
0–12 months |
50 |
One 50-mg
suppository |
|
9–19 |
13–42 months |
100 |
One 100-mg
suppository |
|
20–29 |
43–60
months |
200 |
Two 100-mg
suppositories |
|
30–39 |
6–13 years |
300 |
Three 100-mg
suppositories |
|
>40 |
>14 years |
400 |
One 400-mg
suppository |
Quinine
The intrarectal dose used in treatment trials in Africa was
either 12 mg/kg bw quinine base every 12 h without a loading dose, or 8 mg/kg bw
every 8 h, also without a loading dose. The retention and absorption of quinine
is dependent on pH. Results with gluconate salts (pH 4.5) cannot be
extrapolated to more acidic solutions (such as the dihydrochloride salt, pH 2).
Antimalarial drugs used in severe malaria:
Artemisinin Derivatives:
Artemisinins,
the most important new class of antimalarial agents, have the key advantage of rapid action against all of the erythrocytic
stages of the parasite, including transmissible gametocytes, resulting in a rapid clinical benefit and decreased
transmission of malaria.[3] Intravenous and intramuscular artemisinins
have been highly efficacious for the treatment of severe malaria.
Rectal administration is also effective and may be of value in
settings with limited resources. In addition, there is currently limited, if any, resistance to artemisinins
in malaria parasites. Although all artemisinins have rapid antiparasitic activity, they have short half-lives,
such that the standard 3-day treatment course is commonly followed by recrudescence of infecting parasites and
recurrent illness within days to weeks. To help prevent late recrudescences
and the emergence of resistant parasites, these drugs should always
be used in combination with a longer-acting agent.[3]
The first artemisinin to be studied in large clinical trials of severe malaria
was artemether. Large randomized comparisons of intramuscular artemether and quinine in Gambian
children and Vietnamese adults and a meta-analysis of individual data from 1919 patients in 11
trials of parenteral therapy identified no significant difference in efficacy between these agents.
However, in the meta-analysis, the subgroup of adults had lower mortality when treated with artemether.[3]
Artesunate is dispensed as a powder of artesunic acid. This is
dissolved in sodium bicarbonate (5%) to form sodium artesunate. The solution
is then diluted in approximately 5 ml of 5% dextrose and given by
intravenous injection or by intramuscular injection to the anterior thigh.
The solution should be prepared freshly for each administration and should
not be stored. Artemether and artemotil are dispensed dissolved in oil
(groundnut, sesame seed) and given by i.m. injection into the anterior thigh.[2]
The efficacy of intramuscular artemether in severe malaria may be limited by
varied absorption of this fat-soluble artemisinin derivative. Artesunate, which is water-soluble, has
more reliable pharmacokinetic characteristics. A large, randomized comparison of intravenous artesunate
and quinine in 1461 patients in Asia showed a significant survival benefit with artesunate. Mortality was
22% with quinine, as compared with 15% with artesunate, a risk reduction of 34.7%. Treatment with artesunate
had a relatively mild side-effect profile; hypoglycemia was significantly more common with the use of quinine.
A systematic review of five randomized trials comparing the efficacy of intravenous quinine with that of artesunate
and one additional trial of intramuscular artesunate demonstrated the superiority of artesunate,
with significant reductions in the risk of death (relative risk, 0.62),
incidence of hypoglycemia, and parasite clearance time, as compared with
quinine.[3] The Cochrane review on the Artemisinin derivatives for treating severe malaria
concluded that the artemisinin drugs are no worse than quinine in preventing death
in severe or complicated malaria and that no artemisinin derivative appears to be better than the others.[6]
However, Artemisinin-based combination therapies are not yet available in the
United States.
Cardiac monitoring is not mandatory during treatment with artesunate,
and no serious toxic effects due to the drug are anticipated. Hypoglycemia is
also less common with artesunate than quinine or quinidine;
nonetheless, it is important to monitor the patient's blood glucose level and provide supplementary glucose as needed. Artesunate dosages need not be changed because of hepatic or renal failure or concomitant
or previous therapy with other medications, including previous therapy with mefloquine, quinine, or quinidine.
There are no known interactions between artesunate and other drugs.[3]
The dosage of artemisinin derivatives does not need adjustment in vital organ
dysfunction.[2]
After the acute stage of the illness, when the patient can
tolerate oral medication, long acting antimalarials like doxycycline or, in children or pregnant women, clindamycin, or full courses of treatment with atovaquone–proguanil
or mefloquine (although the neuropsychiatric toxic effects of mefloquine may be
increased after cerebral malaria) should be given.[3]
Toxic effects have been reported less frequently with the artemisinins than with other antimalarial agents.
The most common toxic effects that have been identified are nausea, vomiting, anorexia, and dizziness; these are
probably due, in many patients, to acute malaria rather than to the drugs. More serious toxic effects, including neutropenia, anemia, hemolysis, and elevated levels of liver enzymes, have been
noted rarely. Neurotoxicity is the greatest concern regarding artemisinins, since
the administration of high doses in laboratory animals has led to severe and
irreversible changes in the brain. Although neurologic findings are fairly common with acute malaria,
there is no convincing evidence of neurotoxic effects resulting from standard
oral or intravenous therapy with artemisinins.Limited data are available on the
use of intravenous artesunate for severe malaria during pregnancy.[3]
Quinine
and Quinidine: In most of the world, standard therapy for severe malaria
has been intravenous or intramuscular quinine. In the United States, intravenous quinidine has been the standard therapy since 1991. That year, parenteral
quinine was withdrawn by the CDC because quinidine had been shown to be more potent in vitro and highly effective against
P. falciparum
when used orally for uncomplicated disease or intravenously for severe falciparum
malaria. However,
quinine and quinidine are associated with considerable toxic effects, including tinnitus, reversible hearing loss,
nausea, vomiting, dizziness, hypoglycemia, and visual disturbances. As compared with quinine, intravenous quinidine
is associated with greater risks of cardiotoxic effects and hypotension and
therefore requires continuous cardiac monitoring, with slowing or
discontinuation of the infusion for prolongation of the QT interval. As the use of quinidine as an antiarrhythmic agent has decreased, its decreasing
availability has also become a problem. The antimalarial efficacy of quinine has
diminished in some areas, in particular Southeast Asia, suggesting partial resistance that may limit the drug's efficacy
against severe malaria.[3]
Whereas many antimalarials are prescribed in terms of base, for
historical reasons quinine doses are often recommended in terms of salt
(usually sulfate for oral use and dihydrochloride for parenteral use).
Therefore, one should be clear whether the salt or base is being referred to
while recommending the dose (doses with different salts must have the same
base equivalents).[2]
Quinine must never be given by intravenous injection, as lethal
hypotension may result. Quinine dihydrochloride should be given by
rate-controlled infusion in saline or dextrose solutions at a rate not exceeding
5 mg salt/kg bw per hour. If this is not possible then it should be given by
intramuscular injection to the anterior thigh, not the buttock (to avoid
sciatic nerve injury). The first dose should be split, 10 mg/kg bw to each thigh.
Undiluted quinine dihydrochloride at a concentration of 300 mg/ml is acidic (pH 2)
and painful when given by intramuscular injection, so it is best either
formulated or diluted to concentrations of 60–100 mg/ml for intramuscular injection. Gluconate salts are less acidic and better tolerated than the
dihydrochloride salt when given by the intramuscular and rectal routes.[2]
As the first dose (loading dose) is the most important in the
treatment of severe malaria, this should be reduced only if there is clear evidence
of adequate pretreatment before presentation. Although quinine can cause hypotension if administered rapidly, and overdose is associated with blindness
and deafness, these adverse effects are rare in the treatment of severe
malaria. The dangers of insufficient treatment (i.e. death from malaria) exceed those
from excessive treatment initially.
After the second day of parenteral
treatment, if there is no clinical improvement the maintenance
doses of quinine given by infusion should be reduced by one-third to avoid
accumulation.[2]
In renal failure
(clearance <10 ml/min) and in dialysis patients a normal
loading dose should be administered, but the maintenance
dose should be reduced by 30–50%. If hemodialysis is performed,
quinine or quinidine should be administered after
dialysis. Electrocardiographic monitoring is mandatory with
quinidine infusion and with quinine infusion if the patient has
acute renal failure. If the QRS complex lengthens by more
than 25% beyond baseline or the QTc interval increases to more than 500 ms, the
infusion should be slowed or discontinued.[1] Dosage adjustment by one-third is
necessary in patients with hepatic dysfunction.[2]
Adjunctive treatment
Various
adjunctive treatments for the complications of malaria
may
be
needed
to
reduce the unacceptably high mortality of severe malaria.[2,3]
Patients with severe malaria often require care in an intensive
care unit. Aggressive supportive care, including mechanical ventilation and hemofiltration or hemodialysis,
can be instrumental in successful management of severe malaria. In technologically limited settings, high-quality
nursing care, management of fluid balance, and control of seizures are helpful, although anticonvulsant agents that are
respiratory depressants should be used with caution if mechanical ventilation is unavailable. Aggressive fluid
resuscitation, blood transfusion for moderate anemia, exchange transfusion, and specific treatment for acidosis are
of uncertain value. Bacterial infections can coexist with severe malaria, so blood cultures should be obtained from
patients with shock or other signs of sepsis despite appropriate antimalarial therapy, and these patients should receive
broad-spectrum antibiotic therapy. Although hypoglycemia is less common when artesunate is used rather than quinine or quinidine, it is important to monitor the patient's blood glucose level and provide supplementary glucose as needed.[3]
|
Immediate
clinical management of severe manifestations and complications of falciparum malaria
(WHO, 2006)2
|
|
Manifestation/complication |
Immediate management (in addition to antimalarial treatment) |
|
Coma (cerebral malaria) |
Maintain airway, place patient on his or
her side, exclude other treatable causes of coma (e.g. hypoglycaemia, bacterial meningitis); avoid harmful ancillary treatment such as corticosteroids, heparin and adrenaline; intubate
if necessary
|
|
Hyperpyrexia |
Administer tepid sponging, fanning, cooling blanket and
antipyretic drugs
|
|
Convulsions |
Maintain airways; treat promptly with intravenous or rectal
diazepam or intramuscular paraldehyde
|
|
Hypoglycaemia (blood glucose concentration of<2.2
mmol/l; <40
mg/100ml)
|
Check blood glucose, correct hypoglycaemia and maintain with
glucose-containing infusion
|
|
Severe anaemia (haemoglobin <5
g/100ml or packed cell volume <15%)
|
Transfuse with screened fresh whole blood |
|
Acute pulmonary oedema |
Over-enthusiastic rehydration should be avoided so as to prevent
pulmonary oedema. Prop
patient up at an angle of 45o,
give oxygen, give a diuretic, stop intravenous fluids, intubate and add positive end-expiratory pressure/continuous positive airway pressure in life-threatening hypoxaemia
|
|
Acute renal failure |
Exclude pre-renal causes, check fluid
balance and urinary sodium; if in established renal failure add haemofiltration or haemodialysis, or if unavailable, peritoneal dialysis. The benefits of diuretics/dopamine in acute renal failure
are not proven
|
|
Spontaneous bleeding and coagulopathy
|
Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma and platelets if available);
give vitamin K injection
|
|
Metabolic acidosis |
Exclude or treat hypoglycaemia, hypovolaemia
and septicaemia. If severe add haemofiltration or haemodialysis
|
|
Shock |
Suspect septicaemia, take blood for cultures; give parenteral antimicrobials, correct haemodynamic
disturbances
|
|
Hyperparasitaemia |
Treat with artemisinins, intravenously or orally (See below) |
Supportive care:[1,2]
Vital signs, with an accurate assessment of respiratory rate
and pattern, coma score, and urine output should be recorded as frequently as
possible. Blood glucose should be checked, using rapid stick tests every 4 h if
possible, particularly in unconscious patients.
Comatose patients should be placed in a semirecumbent position
to reduce the risk for aspiration. Serum sodium concentration,
arterial carbon dioxide tension, blood glucose, and arterial
lactate concentration should be monitored frequently. The efficacy of hypertonic mannitol
in treatment of cerebral edema is not proven.[1]
Seizures
are common in cerebral malaria, particularly in
children. Convulsions should be treated promptly with
intravenous or rectal diazepam or intramuscular paraldehyde. In a large double-blind
placebo-controlled evaluation of a single intramuscular injection of 20 mg/kg bw of
phenobarbital (phenobarbitone) in children with cerebral malaria there was a reduction in
seizures but a significant increase in mortality in phenobarbital
recipients, resulting from respiratory arrest. Prophylactic
anticonvulsants are not recommended.[2]
Fluid requirements should be assessed individually. Adults with
severe malaria are very vulnerable to fluid overload and there is a thin
dividing line between underhydration, and thus worsening renal impairment, and
overhydration, with the risk of precipitating pulmonary oedema.[2]
The intravascular volume should be maintained at the lowest level sufficient for
adequate systemic perfusion.[1] If the patient
becomes oliguric (<0.4
ml of urine/kg bw per hour) despite adequate rehydration, and the blood urea or creatinine are rising or already high, then fluids
should be restricted to replace insensible losses only. Children, on the other hand,
are more likely to be dehydrated and may respond well to a bolus of fluid. The
fluid regimen must also be tailored around infusion of the antimalarial drugs.
Central venous pressure should be maintained at 0–5 cm. If the venous pressure
is elevated (usually because of excessive fluid administration), the patient
should be nursed with the head raised at an angle of 45o and,
if necessary, intravenous furosemide should be given. If available, heamofiltration should
be started early for acute renal failure or severe metabolic acidosis
unresponsive to rehydration. [2]
In hypotension early use of inotropic support is indicated rather than
overhydration. Negative fluid balance is critical to avoid exacerbating acute
lung injury, but is balanced against the risk for precipitating acute renal
failure[1]
Early institution of renal replacement therapy may
avoid the development of ARDS. Patients with hypotension tolerate
continuous renal replacement therapy better than conventional
intermittent hemodialysis. In addition, a continuous
regulation of body fluid avoids periods of volume overload
and depletion.[1]
If blood glucose is <2.2 mmol/l (<40mg/dL), then hypoglycaemia should be treated immediately (0.3–0.5 g/kg bw of glucose). Hypoglycaemia should
be suspected in any patient who deteriorates suddenly. Stick tests may
overestimate the frequency of hypoglycaemia, so laboratory confirmation may be
necessary.
Patients with acute pulmonary oedema should be nursed in an
upright position and given oxygen, and filling pressures on the right side of the
heart should be reduced with whichever treatments are available (loop
diuretics, opiates, venodilators, venesection, haemofiltration, dialysis). The
right-sided pressure should be reduced to the lowest level compatible with an
adequate cardiac output.[2] The patient may need to be intubated because of impaired consciousness or because
of acute lung injury. Mechanical ventilation with lower tidal
volume improves the clinical outcome. A higher positive
end-expiratory pressure may be needed to maintain optimal
arterial oxygenation. In respiratory acidosis, the plateau pressure
should be in excess of 25 cm H2O and the ventilator rate
should be increased. Surfactant therapy, inhaled nitric oxide,
and corticosteroids have no effect on survival or duration of
ventilation in patients with ARDS .[1]
Fewer than 5% of patients with severe malaria develop clinically
significant disseminated intravascular coagulation. These patients should be
given fresh blood transfusions and vitamin K.
Patients with secondary
pneumonia should be given empirical treatment with a third-generation
cephalosporin, unless admitted with clear evidence of aspiration, in which case
penicillin or clindamycin is adequate.
Unexplained deterioration may result from a
supervening bacterial infection. Children with persistent fever despite parasite
clearance may have a systematic
Salmonella
infection, although in the majority of cases of persistent fever no other pathogen is identified after parasite
clearance. Urinary tract infections are common in catheterized patients. Antibiotic
treatments should take account of likely local antibiotic sensitivity patterns.
Other treatments:[2]
Many other supportive strategies and interventions have been
proposed in severe malaria, but very few are supported by evidence of
benefit, and many have proved harmful. Heparin, prostacyclin, deferoxamine, pentoxifylline, low
molecular weight dextran, urea, high-dose corticosteroids, acetylsalicylic acid,
deferoxamine, anti-tumour necrosis factor antibody, cyclosporin,
dichloroacetate, adrenaline and hyperimmune serum have all been suggested – but none of
these is recommended.
One
systematic review on the use
of corticosteroids in severe malaria found no significant difference in mortality
but increased risk of gastrointestinal
bleeding; therefore, corticosteroids should not be used in severe malaria.
Severe metabolic acidosis is common but apart from correction of
hypovolaemia and anaemia, no specific treatment is of proven value.
Significant electrolyte abnormalities are relatively unusual, and potassium
supplementation is often not required in the acute phase. The optimum fluid resuscitation
regimens, the thresholds for blood transfusion, the role of exchange
transfusion, and the management of seizures remain areas of uncertainty. It is generally agreed that early
ventilation for respiratory abnormalities and early management of renal failure or severe
metabolic acidosis are beneficial. In acute renal failure, haemofiltration is
associated with a lower mortality, and more rapid correction of biochemical
abnormalities compared with peritoneal dialysis.
Blood transfusion:[2]
In high transmission settings, blood transfusion is recommended for children with a haemoglobin level of <5
g/100 ml (haematocrit <15%). In
low-transmission settings, a threshold of 20% (haemoglobin 7 g/100ml) is recommended. These
general recommendations still need to be tailored to the individual, as
the pathological consequences of rapid development of anaemia are worse than
those of acute on chronic anaemia, where there has been adaptation and a
compensatory right shift in the oxygen dissociation curve.
Exchange blood transfusion (EBT)[2]
There have been many anecdotal reports and several series
claiming benefit for EBT in severe malaria but no comparative trials, and there
is no consensus on whether it reduces mortality or how it might work. It requires intensive nursing and a relatively large volume of
blood, and carries significant risks. There is no consensus on the indications,
benefits and dangers involved, or on practical details such as the volume of
blood that should be exchanged. Therefore no
recommendation regarding the use of EBT has been made by the WHO.
Treatment during pregnancy
Pregnant women, particularly in the second and third trimesters
of pregnancy are more likely to develop severe malaria than other adults,
often complicated by pulmonary oedema and hypoglycaemia. Maternal mortality is
approximately 50%, which is higher than in non-pregnant adults. Fetal death
and premature labour are common. The role of early Caesarean section for the
viable live fetus is unproven, but is recommended by many authorities. Obstetric
advice should be sought at an early stage, the paediatricians alerted, and
blood glucose checked frequently. Hypoglycaemia should be expected and is
often recurrent if the patient is receiving quinine. Severe malaria may also present immediately following delivery.
Postpartum bacterial infection is a common complication in these cases. Falciparum malaria has also been associated with severe mid-trimester
haemolytic anaemia in Nigeria. This often requires transfusion, in addition
to antimalarial treatment and folate supplementation.
Parenteral antimalarials should be given to pregnant women with
severe malaria in full doses without delay. Artesunate or artemether
are preferred over quinine in the second and third trimesters because quinine is
associated with recurrent hypoglycaemia. Recent evidence shows that in non
pregnant adults with severe malaria in areas of low transmission,
artesunate was superior to quinine, reducing mortality by 35% compared to
quinine, which makes artesunate the preferred option in the second and third
trimesters. In the first trimester, the risk of hypoglycaemia associated with
quinine is lower, and the uncertainties over the safety of the artemisinin
derivatives are greater. However, weighing these risks against the above evidence in
favour of the efficacy of artesunate, and until more evidence becomes
available, both artesunate and quinine may be considered as options. Treatment
must not be delayed, so if only one of the drugs artesunate, artemether or
quinine is available, it should be started immediately. The National vector
Borne Disease Programme in India recommends quinine for the treatment of severe
malaria in pregnancy.[5]
Management in epidemic situations:[2]
In epidemic situations, staff shortages and high workloads make intensive care monitoring difficult. Drug
treatment should therefore be as simple and safe as possible, with simple dosing
schedules and a minimum need for monitoring.
As reconstitution of artesunate is a two step procedure and the dosing is twice
a day, and as parenteral quinine requires either
intravenous infusions or a three times a day intramuscular regimen, plus
monitoring of blood glucose, the simple once a day regimens of intramuscular artemether is a suitable
alternative for severe malaria in most epidemic situations, including in
pregnant women in all trimesters. Artesunate suppositories may
be appropriate in severely ill patients who are unable to swallow oral
medication when intramuscular artemether (or quinine by intravenous infusion) is
unavailable and in such cases, the patients should be moved
as soon as possible to a facility where intramuscular or intravenous
therapy can be started. When the patient cannot be moved, continued treatment with
rectal artesunate is appropriate until oral drugs can be taken.
Hyperparasitaemia:[2]
Patients with high parasite counts are known to be at increased
risk of dying, although the relationship between parasite counts and prognosis
varies at different levels of malaria endemicity. Many hyperparasitaemic
patients have evidence of vital organ dysfunction but there is a large
subgroup in which no other manifestations of severe disease are present. These
patients have symptoms and signs compatible with a diagnosis of uncomplicated
malaria in association with a high parasite count (sometimes termed
uncomplicated hyperparasitaemia). The relevance for treatment is firstly the
increased risk of progressing to severe malaria, and secondly the generally
higher treatment failure rates. This is of particular concern as resistance to
antimalarials is most likely to arise in patients with heavy parasite burdens and
little or no immunity. In a low-transmission area in north-west Thailand, the overall
mortality of uncomplicated falciparum malaria was 0.1%, but in patients with
parasitaemia of >4%
it was 3%. In areas of moderate or high transmission, much higher parasitaemias are often well tolerated, however. There is not
enough evidence to provide a firm recommendation on the definition of
hyperparasitaemia, although ≥5%
parasitaemia in a low-transmission setting and ≥10%
in a higher transmission setting are commonly used.
The rapidity of
action of the artemisinin derivatives makes them ideal drugs for the treatment
of hyperparasitemia. Available evidence indicates that use of oral treatment under
close supervision is effective in the treatment of patients with hyperparasitaemia
who have no other features of severe malaria. Patients must be monitored closely
for the first 48 h after the start of treatment and if there is concern or if the patient does not retain oral medication, parenteral treatment should be given without delay.
Non-immune patients with parasitaemia of >20%
should receive parenteral antimalarial treatment. Alternatively, the first dose of artemisinin derivative can be given parenterally or rectally to ensure adequate absorption,
followed by a full course of ACT. Mefloquine, if used, should be
given on days 2 and 3, rather than day 1, when it is better tolerated, with a
lower incidence of early vomiting. The optimum duration of treatment for hyperparasitaemia is still
unresolved. Data to support the suggestion that patients should be treated
conservatively with 7 days of an artemisinin derivative, plus a full course of
partner medicine (e.g. artesunate 7 days + mefloquine 25 mg/kg bw divided over 2
days) are lacking.
Treatment of severe vivax malaria:[2]
Although P. vivax malaria is considered to be a benign
malaria, with a very low case-fatality ratio, it may still cause a severe and
debilitating febrile illness. It can also very occasionally result in severe
disease as in falciparum malaria. Severe vivax malaria manifestations that have
been reported are cerebral malaria, severe anaemia, severe thrombocytopenia and
pancytopenia, jaundice, spleen rupture, acute renal failure and acute
respiratory distress syndrome. Severe anaemia and acute pulmonary oedema are not
uncommon. The underlying mechanisms of severe manifestations are not well
understood. Prompt and effective treatment and case management should be the
same as for severe and complicated falciparum malaria.
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