healthmedicinet

In many parts of the world malaria incidence has declined, in part due to substantial
donor investment targeting the scaling up of insecticide-treated nets (ITN) and other
vector control measures. Nevertheless, in 2010 it was estimated that there were 500
million episodes of Plasmodium falciparum malaria each year 1],2]. In the same year, the World Health Organization (WHO) estimated that there were
approximately 650,000 deaths directly attributed to malaria worldwide 3]. The heaviest burden of P. falciparum malaria falls on sub-Saharan Africa (sSA), where children under five years old are
disproportionately affected by this parasite (Figure 1). Today, 57% of Africa’s populations still live in areas with moderate to high malaria
transmission. Ten countries account for 87% of people exposed to the highest malaria
endemicities globally, where the P. falciparum rates in children two- to ten-years old exceed 50%. Malaria, therefore, remains a
very common cause of hospital admission in sSA, and where severe malaria is mainly
a disease of children under five years of age. It has been estimated that approximately
90% of the world’s severe and fatal malaria affects young children in sSA 4],5].

Figure 1. 2010 World MapPlasmodium falciparumparasite rate in 2-10 year olds.

Severe malaria is a complex multisystem disorder with a clinical presentation that
has many similarities to severe bacterial sepsis, despite distinctive differences
in pathogenesis. Children typically present when they are critically ill with life-threatening
complications yet, in most African hospitals, few will ever be managed on an intensive
care unit or in a high dependency facility. The high, and frequently seasonal, burden
of cases of severe malaria presents a unique challenge to health services and clinicians
working in resource-limited hospitals. This review intends to provide an overview
of the spectrum and complications of severe malaria, highlighting treatment priorities
for children managed within low-resource settings in Africa and re-examining what
has been learnt from clinical trials to outline a future research agenda. In order
to contextualise the current and future relevance of this review and the continued
necessity to prioritise research funding for this condition, I will briefly summarise
the current status of malaria eradication efforts, aimed at reducing the disease burden
and mortality, and accordingly, if successful and sustained, negating the necessity
for future investment in this clinical disease.

Malaria control: are we nearly there yet?

The global strategy towards gradual malaria eradication which has been developed and
ratified into policy was reviewed in 2010 in a four-part Lancet series 6]-9]. It focuses on aggressive control of transmission and investment in vaccine development,
insecticides, new treatments and diagnostics. Hospital admissions and deaths due to
malaria are, therefore, important barometers for the effectiveness of these measures
to control and eliminate malaria. Substantial reductions have been witnessed in several
African countries, in some cases directly or plausibly linked to the scaling up of
control efforts 10]-14]. However, many of the encouraging reports have tended to be from areas with relatively
low baseline malaria transmission intensities. In some cases, the greatest decline
in malaria hospitalisation preceded the scale-up of ITN use or the introduction of
artemisinin combination therapies 13], suggesting that more complex mechanisms are involved. Other sSA countries have documented
either no decline in severe or fatal malaria 4], an increase in hospitalisations during the same period 15],16] or a resurgence following sustained control 17]. The downstream effects on the spectrum of severe malaria are uncertain, although
there are reports that cerebral malaria is now being witnessed in children over five
years old, in areas where it was previously rare (KM verbal communication).

With regard to vaccine development, immunological and clinical data from large Phase
III multicentre vaccination trials of the most promising candidate on the market to
date (RTS,S), a vaccine which is directed against the pre-erythrocytic stage of P. falciparum malaria, were encouraging. However, longer term follow-up indicated these responses
were imperfect and short-lived. In the 18 months following vaccination with RTS,S,
vaccine efficacy (VE) against clinical malaria in children was 46% (95% confidence
interval (CI) 42% to 50%) but only 27% (95% CI 20% to 32%) in infants vaccinated between
6- and 12-weeks old 18],19]. VE waned with time in both groups and VE was more notable at sites with a lower
baseline incidence of malaria 20]. Although further results of the long term follow up are expected, in essence, this
is the status of malaria vaccine research and the culmination of over 20 years of
development and clinical trials.

Severe malaria

Formerly, severe malaria in African children was considered to comprise two distinct
clinical syndromes: cerebral malaria and severe malarial anaemia. This paradigm was
supported by clinical, molecular, immunological and genetic studies and, indeed, substantially
influenced their experimental design. As a consequence, it was held that most malaria
deaths were attributable to cerebral malaria and, thus, were primarily neurological
in origin, with a smaller number resulting from severe malarial anaemia, which could
be mitigated by an immediate blood transfusion. Over the last three decades substantial
research funding has enabled much clearer and detailed clinical phenotyping of severe
malaria in African children, its pathophysiology and complications. What has been
determined is that severe malaria encompasses a complex syndrome affecting many organs
resulting in biochemical and haematological derangements which have many features
in common with the pathophysiological derangements complicating children with severe
sepsis. Moreover, in-hospital deaths, most occurring within 24 hours of admission,
appear to be a consequence of a wide spectrum of pathophysiological determinants.
At the clinical level, a key challenge for health services in Africa, owing to the
large burden of paediatric admissions with P. falciparum malaria infection, is distinguishing those who are at greatest risk of poor outcome,
using largely clinical criteria, in order to target parenteral antimalarials and supportive
therapies 21]. This is reviewed in the next section.

Case definitions and defining those at greatest risk

Differentiating ‘true cases’ of severe malaria from other acute infections remains
both a clinical and epidemiological challenge, as most symptoms of malaria are indistinguishable
from other major causes of morbidity, in malaria-endemic sSA where parasite carriage
is the norm rather than the exception. For example, a child with severe respiratory
distress and P. falciparum malaria could either have severe malaria or very severe pneumonia, an issue that
has been covered in a number of publications 22]-26]. Determining the cases at greatest risk of poor outcome has been helped by a number
of seminal papers. A prospective study of 1,844 paediatric hospital admissions with
P. falciparum malaria in Kenya established that two clinical features, impaired consciousness (defined
as coma or prostration) and respiratory distress (a clinical sign of metabolic acidosis),
identified 84% of fatal cases. Prostration (the inability to sit upright in children
over eight months or breast feed), any respiratory distress, hypoglycemia, jaundice,
or any combination of these, predicted 92% of fatal cases. Relevant to the traditional
severe malaria paradigm was that severe malarial anaemia (defined as a haemoglobin
(Hb) 5 g/dl) in the absence of these two clinical signs had a very low mortality
(1.3%) 27]. Similar findings were reported in Gambian children with severe malaria where neurological
status (coma with or without extensor posturing), tachycardia, tachypnoea, hypoglycemia
and hyperlactatemia (plasma lactate level, 5 mmol/L) were found as independent indicators
of a fatal outcome 28]. Using data from six research units in Africa (SMAC network) the Lambaréné Organ
Dysfunction Score was developed, which combines three variables: coma, prostration
and deep breathing. The scores ranged from 0 to 3. Sixty-one percent of the children
had none of the three signs, 26% had one, 10% had two and 3% had all three signs (case
fatality rate 36%). However, it was unclear how the score was constructed since, at
an individual level, prostration and coma are mutually exclusive, thus impossible
to score 3 29]. Probably one of the most comprehensive descriptions of the clinical and laboratory
complications of severe malaria (and a subsequent evaluation of prognostic markers)
comes from the large Phase III randomised clinical trial comparing artesunate and
quinine (African Quinine Artesunate Malaria Trial: AQUAMAT) 30]. AQUAMAT included 5,425 participants and was conducted in 11 centres across nine
countries, spanning East, West and Central sSA, thus covering a range of malaria transmission
intensities. Baseline characteristics included severe acidosis (base excess?????8;
43%), coma (37%), convulsions (32%), severe anaemia (Hb 5 g/dl; 30%), hypoglycaemia
(blood sugar level 3 mmol/L; 10%) and compensated shock (9%). In a subsequent sub-analysis
of the AQUAMAT data which investigated predictors of poor outcome, four parameters
(out of 20 indicators of severity) were identified that were independently associated
with fatality in a multivariate analysis 31]. These were base deficit (8 mmol/L), coma, elevated blood urea nitrogen (BUN, 20 mg/dL)
and underlying chronic illness. In those with coma and acidosis, case fatality was
23%, in children with a combination of coma, acidosis and raised BUN, mortality was
43% (Figure 2). Finally, since asymptomatic carriage of parasites is common in endemic areas, a
further refinement aimed at improving the specificity of the case definition for either
epidemiological or research purposes proposed the addition of a parasitaemia threshold
32]. The malarial-attributable case fraction (MAF) for children with clinical evidence
of severe disease increased from 85% to 95% with the inclusion of a parasitaemia threshold
of over 2,500c parasites/ml and with the exclusion of those presenting with malaria
parasites but had a primary diagnosis of gastroenteritis with severe dehydration,
pneumonia, culture-proven bacteraemia, or meningitis.

Figure 2. Combinations of presentations and the associated mortality in children in the AQUAMAT
trial. Venn diagram illustrating the combinations of presentations and associated mortality
from von Seidlein et al. 2012 31].

The latest WHO guidelines 21], informed by systematic reviews by the expert advisory group, have drawn on these
resources to inform clinical and therapeutic management recommendations and provided
a comparison of the clinical spectrum of malaria in adults and children largely using
the AQUAMAT data set 30] and adult data from the corresponding artesunate-quinine trial (SEAQUAMAT) conducted
in southeast Asia 33] (Table 1).

Table 1. Comparison of the typical signs and symptoms of severe malaria in South East Asian
adults and in African children

Severe malaria: the clinical syndromes and complications

Cerebral malaria

Neurological involvement is common in African children. Typically, children with cerebral
malaria present with a history of a febrile illness lasting one to three days with
convulsions, impaired consciousness, with or without brain-stem signs. This is strictly
defined as an unrousable coma that persists for more than one hour following a seizure
(irrespective of anticonvulsant medication) since many children with malaria regain
full consciousness after a brief convulsion. The most widely used paediatric classification
of impaired consciousness in sSA is the Blantyre Coma Scale (BCS), a practical tool
developed for children who are too young to speak 34],35]. Coma is classified as a BSC of 2 (out of a possible 5) or less. The precision of
the clinical diagnosis of cerebral malaria, optimal for intervention studies, has
been shown to be considerably improved by ophthalmoscopy (in temporarily-dilated pupils)
to assess for malaria retinopathy 36]. The observation of a specific malaria retinopathy is supported by autopsy evidence
of intracerebral parasite sequestration in a study of 27 Malawian children with fatal
cerebral malaria 37].

Neuroimaging data describing the changes associated with cerebral malaria in African
children remains very limited. The only prospective study using magnetic resonance
imaging (MRI) involved 120 Malawian children with cerebral malaria (strictly defined
as a BCS???2 plus positive retinopathy on ophthalmoscopy) 38]. It identified the most common pathological finding as an abnormal T2 signal in the
basal ganglia (84%). In addition, cerebral volume was moderately-severely increased
in nearly 50%, supporting evidence from previous autopsy data, which until this study
remained inconclusive owing to the possibility that the findings could not exclude
post-morbid changes. Potential mechanisms for increased volume suggested including
parasite sequestration 37], venous congestion 39] or ischemic (due to seizures) and cytotoxic oedema. The MRI imaging indicated evidence
of uncal or cerebellar herniation in nearly 10% 38], an unexpected finding since previous autopsy studies indicated that evidence of
herniation was uncommon 37]. Clinically, papilloedema (a putative clinical sign of raised intracranial pressure)
is considered uncommon in children with severe malaria. This is supported by a review
of ophthalmoscopic findings from 436 children prospectively recruited into several
studies of cerebral malaria in Kenya, Malawi and The Gambia 36]. Bilateral swelling of the optic nerve heads occurred in only 6% in marked contrast
to the very prevalent retinal changes. Of note, in over 50% of children with papilloedema
there was no other abnormality in the fundus; however, prognosis with this sign was
very poor.

Seizures are the most common neurological complication of acute P. falciparum malaria, manifesting as either simple tonic-clonic or partial convulsive episodes
40] to clinically silent electrical status 41], which may or may not be clinically detected as excess salivation and/or an irregular
respiratory pattern 42]. Overall, 38% of Kenyan children had a history of seizures or evidence of seizures
at admission to hospital. Multiple seizures occurred in over 50% of these cases, with
22% having a prolonged seizure episode (30 minutes). The peak prevalence of seizures
(49%) occurred in children 27- to 33-months old and were generally associated with
a shorter duration of illness and higher P. falciparum malaria parasitaemia 43]. Whilst short-lived seizures frequently occur in young children with febrile illnesses,
and have limited prognostic significance, whether these are specifically related to
acute malarial illness was explored in a paper examining the MAF. Children admitted
with two or more seizures in 24 hours prior to admission had very high MAFs, suggesting
that acute malaria was the chief cause of convulsions 44].

In addition to seizures, abnormal motor posturing (AMP) is also a common complication
of children with cerebral malaria, manifesting as generalised extension of the trunk,
increased muscular tone and posturing in the upper and lower limbs and clinically
characterised as de-corticate, de-cerebrate or opisthotonic posturing. Whilst the
aetiology and pathogenesis remains poorly understood, Idro and colleagues attempted
to define the burden and the prognosis of each type of posturing. In 417 Kenyan children
with cerebral malaria, 163 (39.1%) had posturing during hospital stay, with 50% developing
AMP after admission 45], indicating a higher prevalence than previously described since previous studies
mainly reported this complication at the point of admission. De-corticate posturing
was the commonest manifestation occurring in 80 (49%), de-cerebrate AMP in 61 (37%)
and opisthotonic posturing in 22 patients (14%). Case fatality rate was high in those
with AMP (31; 19%), with the terminal mode of death in 19 (61%) suggestive of trans-tentorial
herniation. Posturing was associated with age over three years but not with any of
the markers of severity, except for opisthotonic posturing which was independently
associated with severe metabolic acidosis. Seizures after admission were more common
in those with de-cerebrate and opisthotonic manifestations.

Outcome for cerebral malaria remains poor with high in-hospital mortality and neurological
sequalae in survivors. In the AQUAMAT trial the subgroup with the greatest mortality
were children with coma, with an overall mortality of 359/1,825; 19.6% 30]. Outcome was no better in the artesunate-treated children (18%) than in the quinine-treated
children (21%). Estimates of the prevalence of neurological sequelae deficits in survivors
of cerebral malaria vary 46]-48]. To counter this, a meta-analysis was conducted including studies which had similar
case definitions of cerebral malaria, indicating that sequelae occurred in approximately
11% 49]. The most common neurological sequelae reported were ataxia (43%), hemiplegia (39%),
speech disorders (39%), blindness (30%), and cognitive 50],51] and behavioural abnormalities 52]. Some of the deficits were transient (for example, ataxia) and fully resolved, whereas
others showed improvement over months (for example, hemiparesis) but did not fully
resolve 53]. A history of previous seizures, deep coma and focal neurological signs observed
during admission were independent risk factors associated with persisting impairments
54].

Severe anaemia

Severe anaemia in children in sSA remains a leading cause of hospital admission 55] and a major factor in the 800,000 malaria deaths/year 56]. It is a common presenting feature of severe P. falciparum malaria in African children, particularly young infants in high transmission settings.
It is caused by haemolysis of both infected and uninfected erythrocytes and exacerbated
by impaired erythropoiesis 57]. Within international guidelines (WHO) and across different African countries there
are some discrepancies with respect to the definition of severe anaemia (and, thus,
the threshold haemoglobin or haematocrit level at which transfusion is recommended),
some defining severe anaemia as Hb 5 g/dl whereas others use Hb 6 g/dl. For research
definitions, severe malarial anaemia is defined as Hb 5 g/dl in recent guidelines
(with parasitological evidence of malaria infection) 58].

In terms of prognosis, since the prevalence of pre-morbid chronic mild to moderate
anaemia is very common in these populations, presentation in the absence of any other
complications has a lower MAF 32] and carries a good prognosis with a case-fatality of 1% 27]. However, if combined with a parasitaemia of ?2,500 the MAF increases to over 90%
32]. It is also important to note that, in addition to those presenting with severe anaemia,
this complication may also develop during hospital admission especially in children
with hyperparasitaemia 59], hence the frequent need to monitor Hb. The presence of respiratory distress increases
case fatality (approximately 15%) rising to 40% if also complicated by impaired consciousness
27],60]. Although timely transfusion can be life-saving, access to adequate supplies of blood
for transfusion remains a key challenge in sSA. In order to preserve this scarce resource,
guidelines developed by the WHO encourage the rational use of blood transfusion and
recommend that transfusion be reserved for children with profound anaemia (Hb ?4 g/dL)
or for those with a Hb between 4 to 6 g/dL who have additional severity critieria
in areas where malaria is hyperendemic but suggest a higher transfusion threshold
of 7 g/dl in areas of low malaria transmission 21]. Guideline-adherence remains poor and hampered by the lack of clinical evidence that
this policy is safe in both the short and long term. It has been shown that 63% of
the early deaths occur in children awaiting transfusion 61]-63]. Furthermore, WHO guidelines recommend a standard volume of 20 ml/kg of whole blood
(or 10 ml/kg packed cells) for any level below 5 g/dl; however, in practice this results
in only a modest Hb rise of mean 2.5 to 3.3 g/dl following initial transfusion with
approximately 25% remaining severely anaemic (5 g/dL) 61]. High case fatalities of children with severe malaria anaemia has resulted in recommendations
that the current transfusion guidelines be evidence-based and tested in a clinical
trial 64],65].

Metabolic acidosis and respiratory distress

Improved diagnostic capabilities have led to a better understanding of the importance
of metabolic acidosis as a common complication of severe malaria, despite its clinical
correlates (deep ‘Kussmaul’ breathing) being recognised for decades 10],19]. Historically, respiratory distress in children with severe malaria has been considered
synonymous with congestive cardiac failure 66], although recent work suggests that heart failure is rare, whereas deep breathing
or metabolic acidosis 67] is central to the pathophysiology. Moreover, clinical examination findings and chest
radiographs are usually normal, providing further evidence that pulmonary oedema or
‘acute respiratory distress syndrome’ is rare in children, although common in adult
severe malaria 21].

Despite being a common complication of severe malaria, the aetiology of malarial acidosis
is not well understood. At a clinical level metabolic acidosis is more frequent in
children with severe anaemia 23], hypovolaemia 21], altered rheological properties of non-parasitised red blood cells (npRBCs) 24] and hepatic or renal dysfunction (due to decreased elimination) 16],25],68]. Both increased production and impaired metabolism of lactate 20] and ketoacids 14],21],22] have been implicated as causes; however, other unidentified organic acids also contribute
21],69],70]. Use of sodium bicarbonate to correct acidosis has fallen out of favour, largely
since it failed to address the underlying processes and conferred no clinical benefit
27]. Treatment of acidosis with signs of hypovolaemic shock is covered later in the clinical
trials section (see Fluid and vasopressin use for correction of acidosis and shock).
Current management guidelines recommend prompt correction of hypoglycaemia, severe
anaemia with a blood transfusion, intravenous fluids at 3 to 4 ml/kg/hour (maintenance)
and careful monitoring 21].

Hypoglycaemia

Hypoglycaemia is an important complication of severe P. falciparum malaria, especially in children and pregnant women. Ten percent of children enrolled
in the AQUAMAT trial had hypoglycaemia (glucose 3 mmol/L) at the point of admission
30] whereas other studies in African children report higher frequencies at and during
the course of admission 71]-74]. Hypoglycaemia is independently associated with poor outcome 27],53],75], specifically an increased mortality 28],71],76],77], predominantly when accompanied by acidaemia (pH 7.3) or hyperlactataemia (lactate
5 mmol/l) 60],73]. If not carefully monitored, hypoglycaemia can go unnoticed leading to neurological
impairment and neurological sequelae 47],54],75]. The aetiology is incompletely understood and is likely to be multifactorial. Depletion
of glucose stores due to starvation, parasite utilisation of glucose and cytokine-induced
impairment of gluconeogenesis have been implicated 78]. Hyperinsulinaemia, secondary to quinine therapy, has been advanced as an iatrogenic
cause and is well established in adults 79],80]. Data on its relationship in African children with severe malaria are relatively
few, but what does exist indicates that insulin levels are appropriately low during
episodes of hypoglycaemia, either at admission or during quinine treatment 74],81].

In clinical practice there are several definitions of hypoglycaemia, each targeting
a different blood glucose threshold. In adults and children hypoglycaemia defined
as a blood glucose of 2.2 mmol/L has been shown to be associated with a poor outcome
81] and, hence, this definition is incorporated as the research case definition of severe
malaria (for epidemiological and research purposes) 21]. Paediatric treatment guidelines indicate a blood glucose of 3 mmol/L 82], which is now incorporated in the latest 2012 WHO severe malaria guidelines as the
threshold for intervention 21]. A retrospective study examining the outcome across the range of blood glucose in
418 Malian children with severe malaria found a 61.5% case fatality at a glucose level
of 2.2 mmol/L and 46.2% in those with low glycaemia (blood glucose 2.2 to 4.4 mmol/L)
compared to 13.4% in those with normoglycaemia (4.5 to 8.2 mmol/L) 83]. The authors concluded that 6.1 mmol/L is an optimum threshold for intervention,
which is substantially higher than currently recommended 58]. The poor outcomes of children at higher glucose levels (up 4.0 mmol/L) were also
noted in a general admission population of Kenyan children in whom this was found
associated with increased odds of mortality compared to all levels of glucose concentration
above this threshold 84]. Risk factors associated with hypoglycaemia (glucose ?3 mmol/l) at baseline and subsequent
development of hypoglycaemia was examined in a retrospective review of 1,234 cases
of severe P. falciparum malaria 85]. Included in the study were 952 children admitted to hospital before and 282 children
admitted after the introduction of the new WHO quinine regimen (when a loading dose
of quinine was increased from 10 mg/kg to 20 mg/kg). At baseline (and before use of
quinine) hypoglycaemia was present in 16% of the initial cohort and 9% of the second
cohort. Following admission (and initiation of intravenous quinine therapy), 15% developed
one or more episodes of hypoglycaemia, with over 70% of episodes occurring within
24 hours of admission. There was no evidence of a relationship between quinine dose
and any degree of hypoglycaemia after admission. Admission characteristics that predicted
later hypoglycaemia were hypoglycaemia, severe anaemia and temperature gradient (a
marker of impaired perfusion). Hypoglycaemic episodes were more common during transfusions
or periods of disruption of intravenous glucose infusion. Overall, fatal outcome was
more common in children developing hypoglycaemia after admission (case fatality 24%)
than their euglycaemic counterparts (8%) 85].

As in sepsis, dysregulation of the cortisol, insulin, mitochondrial, or other metabolic
pathways have been implicated in the aetiology of hypoglycaemia and deserve further
investigation. The evidence supporting the current threshold suggests that intervention
at a higher cutoff maybe warranted but this needs to be tested in an adequately powered
clinical trial directly investigating the optimum threshold for treating hypoglycaemia
and the best mode of treatment (dextrose loading or infusion).

Evidence for renal involvement in African paediatric severe malaria

Renal involvement in severe malaria is common in adult non-immune case series and
semi-immune cases in south- and southeast Asia (around 25% to 50% across various series).
Patients may progress to acute kidney injury with anuric or oliguic renal failure
86]. However, in paediatric severe malaria acute renal impairment has been assumed to
be minimal 87], but the piecemeal accumulation of data now suggests this problem has been under-recognised.
Studies examining prognostic risk factors in Gambian children with severe malaria
noted that biochemical evidence of hepatic and renal dysfunction were important additional
markers of a poor prognosis, but, contrary to the adult experience in severe malaria,
none developed acute renal failure 28]. Several large clinical studies have confirmed the independent significance of raised
BUN (20 mg/dl) or creatinine (80 mmols/L) and acidosis as poor prognostic signs
in severe malaria in African children 31],60]. BUN and pH are measures of hypovolaemia or dehydration but also reflect decreased
elimination due to impaired renal function. These measures are key laboratory parameters
incorporated in the Risk Injury Failure Loss End-Stage (RIFLE) classification of acute
kidney injury 88]. A prospective study in Kenyan children 60] showed that an elevated creatinine (80 mmols/L) complicated 96/469 (20%) cases at
admission and was associated with a case fatality of 26%. In the same study, four
factors were independently associated with fatal outcome (deep ‘acidotic’ breathing,
hypoxia (SaO₂??90%), hypoglycaemia (2.5 mmol/L) and creatinine 80 mmol/L (the odds ratio for
mortality with elevated creatinine was 5.76 (95% CI 2.3 to 14.3) P?=?0.0002). In the AQUAMAT trial 1,009/4,148 (24%) had a BUN 20 mg/dL 30] and this parameter was established as one of the three independent clinical features
predicting fatal outcome, together with acidosis and impaired consciousness/convulsions
31]. The mortality in children with all three predictors was 43% (Figure 2). In the FEAST trial BUN 20 mg/dL was present on admission in 444/2,118 (21%), with
prevalence varying across the sites, being more frequent in hyperendemic areas of
Eastern Uganda 265/1,037 (25.6%) and less frequent in Kilifi, Kenya where malaria
is mesoendemic (25/189 (13.2%) 89] (KM, unpublished data).

The aetiology of renal injury in the paediatric kidney is unknown and may reflect
multiple insults including hypovolaemia or dehydration (pre-renal failure) and direct
tubular or glomerular injury. Pathological studies in adults with severe malaria have
shown sequestration of parasitised red cells in glomerular and tubulo-interstitial
vessels and acute tubular damage due to accumulation of monocytes in glomerular capillaries.
The level of sequestration in the kidney was greater in those who developed renal
failure than in fatal cases without renal failure 90]. No equivalent autopsy data are available for African children. WHO malaria treatment
guidelines consider acute kidney injury as a serum creatinine level 250 mmol/L in
adults 91] but does not indicate any criteria for children. Guidelines for the diagnosis and
treatment of renal involvement are needed, as is rational integrated fluid management
and other supportive treatment in paediatric malaria 87], which do not currently exist.

Haemoglobinuria

Haemoglobinuria, or blackwater fever (BWF), a syndrome comprising acute intravascular
haemolysis, fever and the passage of dark- or red-coloured urine, in patients with
current or recent malaria infection, is recognised as a potential complication of
malaria. Classically, it was noted to be a consequence of long term use of quinine
in non-immune expatriates 92]-94]. In African children BWF is considered as a rare complication of malaria 27],28],91],95], which is now supported by data from the AQUAMAT trial 30]. BWF was reported in only 237/5,426 (4.4%) with a case fatality rate similar to the
rest of the trial participants (22 deaths: 9.3%) 31]. The development of haemoglobinuria in children after admission, irrespective of
treatment arm, was also rare, 1%. A prospective study of severe malaria in children
in Papua New Guinea, reported the presence of BWF, attributable to the passage of
haemoglobin and/or myoglobin (suggesting muscle breakdown) in the urine, but found
no association with glucose-6-phosphate dehydrogenase (G6PD) deficiency 96]. In Vietnam, in a case series of semi-immune adults with BWF, in which only 32% had
concurrent P. falciparum malaria infection, aetiological factors included quinine treatment (56%) and G6PD
deficiency (54%) 97]. In Africa, recent publications describing case-series of BWF tend to be from regions
where children are exposed to intense P. falciparum malaria transmission (Nigeria, Democratic Republic of Congo (DRC), and Uganda) 98]-100]. In a case-control study conducted in the DRC, the majority (88.4%) of BWF cases
occurred in the rainy season when BWF was apparently more likely to be related to
quinine pre-treatment. In this series, seven children (16.2%) developed acute renal
failure 98]. In Nigerian children, a study of severe malaria reported that haemoglobinuria (defined
by dip-stick testing of urine) occurred in 48/251 (19.1%), was commonly associated
with clinical jaundice (28/48, 58.3%) and that 6% developed renal failure 100]. Unlike the G6PD variants in southeast Asia the African variant (A-) is a mild variant,
with most males retaining 20% of normal G6PD activity, sufficient to protect carriers
from side-effects of oxidizing drugs or food products. G6PD deficiency is, therefore,
unlikely to be a major cause of BWF; if it were, then one would expect that BWF would
be more widely reported as a common complication of malaria owing to the high population
frequencies in sSA, where it is present in 18% to 20% in males and 5% in females 101].

There is, however, renewed interest in this topic since there have been a number of
case series reported from Europe of delayed haemolytic anaemia following treatment
of severe malaria with injectable artesunate 102],103]. All cases were successfully treated with transfusions. The syndrome, now labeled
as Post-Artesunate Non-infectious Delayed Haemolysis and Anaemia (PANDHA) or PADH
for short, is reported to occur in up to 25% of artesunate-treated non-immune adults,
typically two weeks after the treatment course. An expert group review panel reviewed
world literature and found that PADH was not specific to a particular preparation
or manufacturer 104]. Further insights into its pathogenesis have now been established as the delayed
clearance (through haemolysis) of once-infected red cells. These ‘pitted’ erythrocytes
had been previously spared by artesunate (with quinine treatment they would be removed
from the circulation), since the artemisinins induce splenic removal of parasites
leaving the red cell intact (a process known as pitting) 105]. Why some patients are susceptible to PADH remains unknown. Data from malaria endemic
areas on the occurrence of this condition are lacking.

Increased risk of bacterial co-infection

Bacteraemia is an important complication of severe malaria in African children but
is often under recognised, largely a result of limited and poorly maintained microbiology
services across sSA. Nevertheless, data have slowly emerged, mainly from hospitals
linked to research programmes, indicating that there may be a biological link between
malaria and susceptibility to invasive bacterial infection (IBI). A study in Teule,
Tanzania, reported that up to a third of paediatric severe malaria deaths were attributed
to bacteraemia 106]. Another large epidemiological study conducted in Kilifi, Kenya, showed that more
than 50% of all cases of bacteraemia occurred in the presence of malaria 107]. A systematic review compiling data from epidemiological studies and clinical studies
of paediatric hospital admissions of P. falciparum malaria (describing IBI) across sSA examined the evidence supporting a biological
or epidemiological relationship 108]. In the meta- analysis of ten studies which included data from 15 centers in 11 sSA
countries involving 7,208 children with severe malaria, reported over the period 1992
to 2010, found a mean prevalence of IBI co-infection of 6.4% (95% CI 5.81 to 6.98%).
Bacterial co-infection resulted in higher case fatalities compared to children with
severe malaria alone 81/336 (24.1%) versus 585/5,760 (10.2%). The major pathogens
associated with IBI were non-typhoidal salmonellae (NTS), Escherichia coli and other enteric gram-negative organisms. There was also some evidence indicating
greater risk of NTS IBI in children with malarial anemia 108].

In order to reduce IBI-associated malaria mortality, whilst minimising the risks of
excess antibiotic prescribing, further research is needed to establish children at
greatest risk of bacteraemia, to inform a policy for targeted antibiotic therapy.
For example, Nadjm and colleagues proposed simple clinical criteria 106] which identified 85% of malarial cases with culture-proven bacteraemia. The criteria
included an axillary temperature 38°C or 36°C with parasitological evidence of current
or recent P. falciparum malaria infection plus one or more of: prostration, respiratory distress (chest indrawing
or deep breathing), severe anaemia (Hb 5 g/dL), or HIV infection. A pathogen was
isolated from aerobic blood cultures in approximately 20% of children (1-week to 12-years
old) meeting these criteria. The ‘Teule criteria’ are yet to be tested in prospective
intervention trials, which could help with future policy of directed (where microbiological
services are not available) or short-course empiric therapy with early termination
guided by culture results to prevent development of resistance, which is commonly
practiced in high-income countries 109].

Treatment of severe malaria

Quinine has been the mainstay of treatment for African children with severe malaria
for decades; it remains effective and little drug resistance has been reported from
the continent. The arrival of the artemesinin compounds led to a series of small clinical
trials to test their safety and efficacy. The first comparative clinical trials investigated
artemether (derivative of dihydroartemisinin, the active antimalarial agent), which
because of its poor water solubility can only be injected by the intramuscular route.
In clinical trials it proved to be safe but when the data on efficacy were collated
in a meta-analysis (including 1,919 randomised patients) it did not lead to an improved
overall survival, specifically in African children. This was followed by trials investigating
another artemisinin formulation, artesunate, which in contrast to parenteral artemether,
is water-soluble and can be given intravenously and is instantly bioavailable 110]. Even intramuscular artesunate is absorbed reliably and rapidly, with peak concentrations
occurring within one hour 111]. The SEAQUAMAT trial, conducted in South East Asia (including 202 children) was stopped
early after enrolment of 1,461 patients owing to a substantial benefit for patients
receiving artesunate 33]. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of
731) in quinine recipients; a relative reduction of 34.7% (95% CI 18.5 to 47.6%; P?=?0.0002).

A further trial in African children was justified since expert review at that time
considered that the issue of parasite drug resistance to quinine was not an issue
(as it was in South East Asia), that quinine remained the optimal antimalarial and
owing to the rapid tempo of severe disease in African children with severe malaria
compared with adults in South East Asia there were questions about the generalisabilty
of the SEAQUAMAT trial. In severe malaria in children most deaths occur within the
first 24 hours whereas survival benefit for many patients in the SEAQUAMAT trial occurred
after this time point. These issues highlight the importance of equipoise as a strong
scientific justification and a prerequisite to conduct further clinical trials with
meaningful clinically relevant endpoints (that is, disability-free survival). The
AQUAMAT trial enrolled children at the point of hospital admission. The criteria for
enrolment were broad and pragmatic with a view to future generalisability of the trial
results, principally if the clinician considered the child required parenteral antimalarial
medication they were eligible for inclusion in the trial. Diagnosis was reinforced
by quality controlled laboratory evidence of P. falciparum malaria infection. The primary endpoint was in-hospital mortality. By intention to
treat, 297 children (10.9%) receiving quinine treatment died compared to 230 (8.5%)
children who received artesunate. Overall, this translated to a relative reduction
in mortality of 22.5% (95% CI 8.1 to 36.9) in children in the artesunate arm (P?=?0.002) 30], with no difference in outcome whether the drugs were administered intravenously
or intramuscularly. In the analysis of secondary endpoints there were no differences
in outcome across any of the major clinical spectra defining severe malaria. The development
of coma and/or convulsions was more common during hospital admission in the quinine
arm (P?=?0.02); but there were no other differences between the arms in number of other
complications, additional treatments prescribed, time to recovery or numbers with
neurological sequelae – which included 61 persistent mild, moderate or severe such
sequelae among survivors 30]. The trial led to a major guideline change for anti-malarial treatment of paediatric
severe malaria, which now recommends a preference for parenteral artesunate over quinine
21].

Adjunctive therapies in severe malaria

The outcome of severe malaria is largely determined by the complications and number
of vital organ dysfunction and quality of care available. For most African children
this will not include an admission to an intensive care or high-dependency care unit,
instead management will be more usually on a busy paediatric ward. It is important
to emphasize that the most important factor for management is the implementation of
specific antimalarial drug treatment and that this is given as early as possible to
reduce the risk of adverse outcome. As is the case in management of severe sepsis,
supportive therapies aimed at correcting deranged physiology are also fundamental
to improving outcome; however, of the adjunctive agents tested in clinical trials
in both adults and children all have failed to show benefit, with the exception of
renal replacement therapy in adults 112]. With respect to the high risk group of cerebral malaria, of the 33 clinical trials
summarised in Table 2 investigating a range of specific or supportive therapies, 15 have been targeted
to the sub-group with cerebral malaria and most have shown harm in those receiving
the interventional therapy. These will be reviewed, initially in chronological order,
but are largely clustered within a treatment-specific paradigm.

Table 2. Randomised clinical trials of adjunctive therapies in severe malaria in adults and
children

In general, many of these trials were single-centre phase I or II studies with low
sample sizes, often constrained by funding and slow or truncated trial recruitment.
A number of trials were terminated early due to political instability, meeting pre-defined
safety stopping rule or due to evidence of adverse outcome in the interventional arm.
Many trials had primary endpoints targeting clinical surrogates for prognosis (for
example, correction of acidosis or cytokine or parasite clearance) and so, as is usual
in Phase II trials were not powered to inform meaningful endpoints such as mortality,
but are important steps in the justification for further testing in larger trials.
Methodological issues were noted in some trials, for example, in some the primary
endpoint was not pre-specified, methods of randomisation were not reported and some
trials appeared to recruit patient populations with substantially lower overall lower
mortality than would be expected, thus reducing the external validity of the results.
How we interpret these trials is possibly helped by one overarching emerging theme:
that most did not result in a positive outcome for any of the patient-centred endpoints
in the interventional arms (that is, those that are clinically relevant). Ordinarily,
the early stopping of trials, especially when interim analysis suggests large treatment
effects, has been criticised as, more often than not, interim results on small numbers
tend to overestimate treatment effects 113] which are often not replicated in larger multi-centre studies. Some therapies may
have been disregarded for the same reason in severe malaria; however, it would be
difficult to warrant further exploration of a therapeutic intervention in which a
trial had been stopped by an external committee reviewing safety for excess harm rather
than for futility.

Steriods: dexamethasone

In order to reduce or prevent cerebral oedema, two separate trials investigated whether
the addition of dexamethasone improved the outcome of cerebral malaria in adults and
children 114],115]. The trial in Thai adults showed that dexamethasone-treated patients had a more prolonged
period of coma (mean 63.2 hours versus 47.4 hours in the placebo arm). Disturbingly,
its use led to an increased risk of pneumonia and/or gastrointestinal bleeding in
26/50 compared to 11/50 in the placebo arm 114]. The second trial, conducted in Indonesian children and adults with cerebral malaria,
also showed that dexamethasone led to an increased risk of gastrointestinal bleeding
with no apparent benefit 115]. A Cochrane review that pooled the data from these two trials (N?=?143 participants)
found no difference in mortality (relative risk 0.89; 95% CI 0.48 to 1.68; 143 participants,
increased risk of GI bleeding in both trials 7/71 (10%) in the intervention-arm compared
to 0/72 (0%) in control, a relative risk of 8.17 (1.05, 63.57). The review found no
overall increased risk in invasive bacterial infection 116] but highlighted that a major limitation was that neither had trial follow up beyond
discharge from hospital, so that the effects of corticosteroids on residual neurological
deficits, therefore, could not be assessed. The review concluded there was no evidence
to support the use of dexamethasone in cerebral malaria, although numbers involved
were small and the assessment of complications in both trials was incomplete.

Pentoxifyllin

The pathogenesis of severe malaria involves several different processes, including
enhanced production of the cytokines including tumour necrosis factor (TNF), sequestration
of parasite red cells to the endothelium and decreased erythrocyte deformability.
Since pentoxfylline (Pt) has beneficial effects on many of these processes, in particular
increasing red cell deformability (and thus improving local tissue perfusion), it
was postulated that it might improve outcome in severe malaria. The next phase of
trials investigated the addition of Pt to standard antimalarial therapies, primarily
aimed at suppression of TNF? production. In total, five trials investigated its use
in cerebral malaria, or all-cause severe malaria 117]-121]. Two were conducted in African children (Burundi 117] and Kenya 121]). Three trials were stopped early: one due to civil conflict 117] and two due to safety concerns 119],121]. The Burundi trial had enrolled 56 of a projected 100 children with cerebral malaria
when it was stopped. There were no deaths in the Pt arm (n?=?26) compared to 5 of
30 (17%) in the control arm; 8% of both groups developed neurological sequelae 117]. Owing to the small sample size the results were inconclusive. The second paediatric
study, a dose escalation study, conducted in Kenyan children with cerebral malaria
was stopped due to safety concerns. A significantly higher mortality occurred in the
Pt arm 4/10 (40%) versus 1/5 (20%) in controls 121]. A trial conducted in Thai adults (n?=?45) showed no significant differences in any
of the arms (which investigated low dose Pt, high dose Pt versus control) for any
of the outcome measures 118]. Another trial conducted in Indian adults involving 22 in the Pt arm and 30 controls
showed reductions in TNF? (baseline to day 3) in the Pt arm compared to increases
in the control arm. Mortality was 25% in the control arm and 10% in the Pt arm 120]. However, there were methodological limitations in this trial since the method for
allocation of study arms was not stipulated nor were the study endpoints pre-specified.
Owing to lack of overall clinical benefit, and those that were favorable largely related
to secondary endpoints, and a suggestion of increased adverse outcome, further exploration
of anti-TNF therapies have not been pursued.

Monoclonal antibodies, immunoglobulins and anti-sequestration therapies

A controlled factorial trial of monoclonal antibodies (Mab) against TNF-? in Gambian
children (N?=?610) which also compared artemether and quinine, showed faster fever
clearance but no survival benefit in children treated with Mab (19.9%) compared to
controls (20.8%), after adjustment for antimalarial strategy 122]. The trial also demonstrated a significantly increased risk of long-term (six months)
neurological sequelae in survivors 15/221 (6.8%) in Mab recipients compared with 5/225
(2.2%) in controls. The authors suggested that whilst there was evidence that antibody
acts to retain and prolong TNF within the circulation (leading to fever reduction)
this may inadvertently increase its harmful effects on the vascular endothelium and,
in turn, aggravate neurologic complications. A trial investigating pooled intravenous
immunoglobulin (IVIG) from blood bank adult donors and, thus, presumptively immune
to malaria in Malawian children with cerebral malaria was stopped early after enrolling
31 children for futility (in accordance to a pre-planned stopping rule) 123]. For those receiving IVIG 10/16 (62.5%) died or developed neurological sequelae compared
to 3/15 (20%) in the placebo arm. A further placebo controlled trial conducted in
28 Thai adults 14 years old (enrolled using WHO severe malaria criteria) investigated
polyclonal anti-TNF-? antibodies in addition to artesunate. Included in the study
were seven participants with cerebral malaria, 46% had hyperparasitemia (13 of 28)
and 39% had circulatory shock (11 of 28) 124]. Compared to controls antibody treatment reduced IFN-g concentrations in a dose-related
manner and unbound TNF-? was undetectable after Fab treatment, irrespective of dose.
The composite clinical endpoint, including duration of coma in cerebral malaria and
the development of other severe manifestations or complications, was hampered since
it was only possible to record coma recovery in five patients; hence, the results
were largely inconclusive.

A controlled Phase II trial investigating the use of the oral anthelmintic drug levamisole
hydrochloride (previously shown to inhibit cytoadherence in vitro and reduce sequestration of late-stage parasites in uncomplicated P. falciparum malaria 125]) included 56 Bangladeshi adults with criteria for all-cause severe malaria 126]. Linked pharmokinetic studies indicated absorption of levamisole was reliable with
a mean plasma level of 97% of expected levels in healthy adults. However, there was
little marked effect upon parasite sequestration, lactate clearance (a putative marker
of tissue oxygenation and microcirculatory perfusion) or mortality. The authors suggested
that despite previous observations in uncomplicated malaria treated with quinine,
rapid parasite clearance with intravenous artesunate may have obscured any marginal
benefit of levamisole on parasite sequestration.

Seizure prophylaxis

Since convulsions are common in severe malaria, in particular the sub-group with cerebral
malaria, and associated with adverse outcomes including death and neurological sequelae
(in children), routine administration of anti-epileptics to prevent the seizures was
suggested. In a double-blind controlled trial in Thailand involving both children
and adults with cerebral malaria, randomised to receive either a single dose of phenobarbitone
(Pb) or placebo, there was a lower seizure rate in the Pb group at 12.5% (3/24) compared
to 54% (13/24) in the placebo arm (P?=?0.006) 127]. There was no effect on mortality, eight (33%) versus five (21%), respectively. Based
on this small study the authors recommended that guidelines should advocate that all
patients with cerebral malaria should receive a single intramuscular loading dose
of Pb. A large single centre paediatric placebo-controlled trial (N?=?340) conducted
in Kenyan children with cerebral malaria, designed to provide the evidence for this
new recommendation, examined a single intramuscular dose of Pb (20 mg/kg) versus placebo.
As expected Pb recipients had a lower rate of seizures (defined as three or more seizures
of any duration) than the placebo recipients (18 (11%) versus 46 (27%) odds ratio
0.32 (95% CI 0.18 to 0.58)) but the case fatality rate was more than double in the
Pb arm (30 (18%) compared to placebo 14 (8%) deaths, relative risk 2.39 (95% CI 1.28
to 4.64)) 128]. The chief mode of death in those receiving Pb was respiratory arrest. Following
this trial the guidelines changed and no longer recommend Pb prophylaxis in cerebral
malaria. A further placebo controlled trial, conducted at the same centre in Kenya,
in non-traumatic encephalopathy (including a cerebral malaria subgroup (N?=?110))
investigated the use of fosphenytoin (a drug often used for seizure prophylaxis in
neuro-trauma that has minimal cardiorespiratory side effects). It was terminated due
to slow recruitment/futility. At least one seizure (monitored clinically and by electroencephalogram)
occurred in 33/83 (40%) in children receiving fosphenytoin versus 32/88 (36%) receiving
placebo (P?=?0.733) 129]. In the cerebral malaria subgroup the prevalence of seizures in the fosphenytoin
arm was 20, 37% which was identical to the placebo arm 21, 38%. Overall, 18 children
treated with fosphenytoin (21%) died compared with 15 in the placebo arm (17%) (P?=?0.489). In survivors rates of neurologic sequelae at three months were the same
(10%) in both arms 129]. A study from India, reporting results from a clinical trial in adults as a correspondence
piece, gave only limited details of the clinical trial methodology. The successful
use of prophylactic Pb reported in this trial is questionable since it was not reported
in full 130].

Osmotherapy: mannitol for treatment or prevention of cerebral oedema

Leading up to these trials were two observational studies, one case series and one
uncontrolled trial, investigating mannitol and other osmotic diuretics as adjuncts
for treating brain swelling (cerebral oedema) in African children with cerebral malaria
39],131]. These early studies suggested that mannitol may improve outcomes 39], and case series of children receiving urea with dexamethasone was reported to have
a dramatic improvement 131]. A subsequent placebo-controlled trial, conducted in 156 Ugandan children with cerebral
malaria, investigated a single dose of 5 ml/kg of 20% (1 g/kg) of intravenous mannitol
infused over 20 minutes in addition to intravenous quinine. No important differences
were found in the main outcomes, including time to regain consciousness or death 132]. Six children had postmortems of whom five had signs of anoxia and cerebral oedema;
the sixth child had signs of acute tubular necrosis at autopsy. A controlled trial
examining the use of 1.5 g/kg mannitol followed by 0.5 g/kg every eight hours in Indian
adults with death as the primary endpoint found an increased mortality in those receiving
mannitol, 9/30 (30%), compared to 4/31 (13%) in the control (no mannitol) arm 133]. Mannitol also prolonged coma resolution. Whilst there is good evidence that brain
swelling complicates both adult and paediatric cerebral malaria, trials to date have
shown no benefit of osmotherapy or steroids (see earlier).

Iron chelation

The use of iron chelating agents was considered for adjunctive therapy in severe malaria.
The positive hypothesis suggested that by chelating free iron these drugs would thus
withhold iron which is required by malaria parasites to mature and multiply and, thus,
limit or inhibit parasite reproduction rate. A Cochrane review of the data on the
uses of iron chelation was conducted in 2007 134]. Whilst seven trials involving 570 participants met the inclusion criteria, four
of these were excluded as they included non-severe or asymptomatic malaria or had
methodological issues. In children with severe malaria two controlled trials examined
desferrioxamine (DFO) 135],136] with cerebral malaria and one studied deferiprone 137] in Indian adults (13 to 84 years) with severe malaria.

The first study conducted in a Zambian hospital involving 83 children with cerebral
malaria indicated a lower mortality in DFO recipients, 7/42 (16.7%), compared to placebo,
9/41 (22%). Moreover, time to coma recovery was faster in the DFO arm 135]. A second, larger paediatric trial conducted at two centres in Zambia was stopped
early on the recommendations of the data monitoring committee for safety, as there
were more deaths in the DFO arm, 18.3% (32/175) compared to 10.7% (19/177) in the
placebo group 136]. Overall, the pooled estimate for both trials (435 participants) indicated a non-significant
increased risk of death in the DFO group. The risk of experiencing persistent seizures
was lower with DFO compared with placebo (RR 0.80, 95% CI 0.67 to 0.95; 334 participants,
one trial), but adverse effects (including phlebitis and recurrent hypoglycaemia)
were more common with DFO (risk ratio for hypoglycaemia 1.48 (95% CI 0.97 to 2.26))
134]. The adult trial comparing deferiprone with placebo found that the deferiprone group
had significantly faster coma recovery and parasite clearance 137]. No adverse effects were reported for this trial. No evidence of benefit or harm
overall was concluded by Cochrane review 134].

Acidosis correction

N-acetylcysteine (NAC) has been proposed to lead to correction of metabolic acidosis
by its antioxidant effect acting through direct scavenging of free radicals and replenishment
of glutathione and cysteine. NAC has also been shown to have anti-parasitic effects
138]. Three trials have examined effects of different doses as adjunctive treatments to
quinine or artesunate. The first, a small placebo controlled trial of NAC in Thai
adults (N?=?15 in each arm) had lactate clearance as the primary endpoint. Lactic
acidosis resolution was better at 24 hours in the NAC group (10/15) than in the placebo
group (3/15) (P?=?0.011), as was median coma resolution although with wide variation and, thus, was
non-significant. Need for renal replacement therapy (two in each arm) or death (arm
in each arm) were similar 139]. A placebo controlled trial of three different NAC dosage regimens given in addition
to artesunate had some methodological issues since the key endpoints were not pre-specified;
methods of randomisation were not indicated and the study required patients to remain
in hospital for 28 days. Few differences were found in fever, parasitaemia clearance
and adverse medical events, although the reporting of these was incomplete. There
were only two deaths in the trial indicating that the patients probably did not have
severe malaria 140]. A multisite double-blind placebo controlled trial on the use of high dose intravenous
NAC as adjunctive treatment to artesunate in 108 adults in South East Asia found that
NAC had no significant effect on mortality, lactate clearance times (P?=?0.74) or coma recovery times (P?=?0.46). Parasite clearance time was increased but largely attributable to differences
in baseline parasitaemia,nor did NAC have any effect on red cell deformability properties
141]. In summary, despite some methodological concerns and the small size of the trials,
the limited data available from these do not provide justification for further investigation
of NAC as an adjunctive treatment. Similarly, a lack of efficacy was found in another
small study of L-arginine; however, the results were not conclusive since the trial
was halted early due to political instability 142].

Fluid resuscitation, inotrope and and vasopressors: shock and acidosis

Both dopamine and adrenaline (epinephrine) are used in the management of infection-induced
haemodynamic shock as second line treatments when shock is refractory to fluid boluses
or when hypotension prevails 109]. Dopamine has been used to improve mean arterial pressure (MAP) and cardiac output,
primarily by increasing stroke volume and heart rate and low dose therapy has been
used in the past to treat pre-renal acute kidney injury. Dopamine however carries
an increased risk of supraventricular and ventricular arrhythmias. Adrenaline increases
the MAP since it is a powerful vasopressor agent, but increases the risk of aerobic
lactate production 109]. In Vietnamese adults with severe sepsis (n?=?10) and severe malaria (n?=?13), a
crossover trial examining increasing intravenous adrenaline infusion compared to increasing
dopamine doses found adrenaline and dopamine infusions led to significant mean increases
in cardiac index (which was greater with adrenaline than dopamine), increased MAP
and a reduction in systemic vascular resistance. However, inotropic doses of adrenaline
resulted in the development of lactic acidosis and falling pH and thus curtailed the
adrenaline dose-profile at some stage in 16 patients (84%). No significant differences
were found between sepsis and malaria subgroups with respect to disease effects or
responses to treatments 143]. Further investigation of adrenaline was, therefore, not warranted.

Justification for investigating fluid resuscitation as an adjunctive treatment in
children with severe malaria originated from the high mortality noted in association
with metabolic acidosis 27],67],144]. It was postulated that in children with severe malaria complicated by metabolic
acidosis in accordance with other causes of paedaitric severe life threatening illness
this is commonly due to some degree of hypovolaemia 145], although this view was controversial in severe malaria 146]. Prospective studies had identified markers of impaired perfusion (delayed capillary
refilling time, weak pulse, subnormal systolic blood pressure and increased creatinine)
in children with metabolic acidosis as key correlates with poor outcome 60]. Initial dose-finding studies in this subgroup established that boluses of 20 to
40 ml/kg normalised low central venous pressure, reduced tachycardia and tachypnoea
without adverse consequences 147] and further studies established appropriate effects of fluid therapy on myocardial
performance 148]. In total, five Phase II trials were conducted in Kenyan children with severe malaria
comparing different fluid types on physiological endpoints, including correction of
metabolic acidosis (base excess) and haemodynamic parameters as well as mortality
and neurological sequelae in survivors. The results of these trials are individually
summarised in Table 260],149]-152] but have been formally collated (four of five) in a meta-analysis examining types
of fluid resuscitation therapy published in 2010 153]. This review compiled data from all published paediatric clinical trials of fluid
resuscitation. In the subgroup with malaria these were the only four trials (none
of which had a control arm), and all had similar designs, all showing comparable reductions
in acidosis (the primary endpoint) as well as features of shock in children receiving
either 0.45% human albumin solution, 0.9% saline or Gelofusine (a gelatin based colloid)
153]. When the mortality data from all four trials were combined in the meta-analysis
this indicated that albumin significantly reduced mortality (secondary endpoint) compared
to either of the other fluids (saline or Gelofusine), risk ratio 0.31 (95% CI 0.14
to 0.68) (P?=?0.004). There was a non-significant increase in neurological sequelae in survivors
in those treated with albumin 9/97 (9%) compared to other resuscitation fluids, 6/54
(6%) in saline and 1/37 (3%) in gelofusine 153]. A further trial comparing Dextran 70 (D70) (n?=?39) and 6% hydroxyethyl starch (HES)
(n?=?40) found no difference in the primary outcome (shock resolution at eight hours)
(D70: 23/37 (62%) versus HES: 25/39 (64%)), although resolution of acidosis was better
in the HES arm. Overall, case fatality (four in each arm, 5%) was similar 152].

The Fluid Resuscitation as A Supportive Therapy trial (FEAST) was conducted to provide
evidence on the best fluid management for children with shock and severe febrile illness
for doctors practicing in hospitals in resource-limited settings 89]. FEAST was a multicenter three-arm controlled trial comparing albumin bolus, and
saline bolus to no bolus control. FEAST was conducted at six centres in three East
African countries and involved 3,121 children enrolled at the point of hospital admission.
Shock was defined pragmatically (incorporating parameters from all the published paediatric
shock definitions including modest hypotension) and the controlled part of the trial
(FEAST A) only excluded children without severe hypotension. Two major subgroups included
in the trial were those with severe sepsis (n?=?1,330) and severe P. falciparum malaria (n?=?1,793). The data monitoring committee stopped the trial early after
enrollment of 3,141 of a projected 3,600 due to safety concerns. The primary endpoint,
48-hour mortality, was significantly worse in the two fluid bolus arms, 111/1,050
(10.6%) in the albumin-bolus and 110/1,047 (10.5%) in the saline-bolus, compared to
the control (no bolus) 76/1,044 (7.3%); relative risk (95% CI) any bolus versus control
1.45 (1.13 to 1.86, P?=?0.003). Secondary endpoints including 28-day mortality were worse in the bolus
arms, 12% versus 8.7% in the control arm. There was no difference between the treatment
arms in the number of adverse events (suspected pulmonary oedema, brain swelling or
allergic events). In the subgroup with severe malaria, 48-hour mortality was 110/1,202
(9.2%) in the bolus arms compared to 34/591 (5.7%) in the control (no bolus) arm,
a relative risk of death of 1.59 (1.10 to 2.31). In all pre-specified sub-groups analysis,
there was no evidence of a benefit of fluid boluses 89]. In a subsequent publication, early shock reversal at one hour (responders), the
central principle of the surviving sepsis guidelines, was superior in the bolus arms
compared to no bolus control (43% versus 32%, P 0.001). Despite this, excess mortality with boluses was still evident in both ‘responders’
(relative risk 1.98 (0.94 to 4.17), P?=?0.06), as well as ‘non-responders’ at one hour (relative risk 1.67 (1.23 to 2.28),
P?=?0.001), with no evidence of heterogeneity (P?=?0.68) 154]. Examining the terminal modes of death, the major difference between bolus and control
arms was the higher proportion of cardiogenic shock in the bolus arms (n?=?123; 4.6%
versus 2.6% in controls, P?=?0.008), rather than respiratory events or neurological terminal clinical events
154]. A major issue raised following the publication of FEAST was whether the criteria
used to define shock in the trial were applicable to other guidelines, including the
WHO definition of shock. A further publication provided data to address this issue
showing that of the relatively limited number of children fulfilling the WHO shock
definition 48-hour mortality was 24/50 (48%) in those receiving boluses compared to
3/15 (20%) in the no-bolus control, an increased absolute risk of 28% and a relative
increase of 240% (P?=?0.07 by two-sided Fisher’s exact test). Moderate hypotension, consistent with many
definitions in paediatric shock, was also associated with increased 48-hour mortality
on boluses (an absolute risk of 9.4% (?2.6 to 21.4%)) 155].

A systematic review conducted after the FEAST trial concluded that the majority of
evidence from randomised trials to date came from the FEAST trial and that boluses
significantly increased mortality of children in shock, compared to those who did
not receive boluses. The evidence was considered to be of high quality and sufficiently
precise 156]. Prior to FEAST the evidence supporting fluid resuscitation was reviewed in the 2008
Surviving Sepsis Campaign Guidelines which was informed by a modified Delphi process,
graded the current paediatric recommendation (20 ml/kg boluses over five to ten minutes
up to 60 ml/kg) as 2C, indicating a weak recommendation with low quality of evidence
109],157]. The systematic review concluded that withholding of bolus fluids should be considered
for populations similar to those enrolled in FEAST and that there remained important
questions about the extent to which these results are applicable to other populations
156].

Transfusion

A Cochrane review including the only two African randomised controlled trials (RCTs)
158],159] conducted before 2000 (involving 114 and 116 children randomised to blood transfusion
or oral haematinics) concluded that there was insufficient information on whether
routinely giving blood to clinically stable children with severe anaemia either reduces
death or results in a higher haematocrit measured at one month, and indicated the
need for a definitive trial 64]. Since then a recent trial has evaluated the safety and efficacy of a higher volume
of whole blood (30 ml/kg, n?=?78) against the standard volume (20 ml/kg, n?=?82) in
Ugandan children which was found to be safe and resulted in an accelerated hematological
recovery in children with severe anaemia 160]. A clinical trial is underway that is evaluating whether a liberal rather than conservative
transfusion strategy in terms of a larger initial volume of transfused blood and incorporating
a higher threshold of haemoglobin of 6 g/dl for transfusion will decrease both short
and long term mortality (TRACT trial: ISRCTN84086586).