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Blackwell Science, Ltd

Oxford, UK

BCPBritish Journal of Clinical Pharmacology

0306-5251Blackwell Publishing 2003

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Original Article

Management of severe malariaK. Marsh

Correspondence:

Professor K. Marsh, Welcome Trust/KEMRI, Centre for Geo-graphic Medicine Research/Coast, Po Box 230, Kilifi, Kenya. Email:kmarsh@kilifi.mimcom.net

Received 18 December 2002, accepted 27 January 2003.

Management of severe malaria: implications for research

Kevin Marsh

Welcome Trust/KEMRI, Centre for Geographic Medicine Research/Coast, Po Box 230, Kilifi, Kenya.

This paper deals with two aspects of severe malaria:firstly, the process and requirements for clinical research,and secondly, a consideration of those areas whereresearch could make a difference.

What’s happening now?

Research on severe malaria is research on failure-failureto prevent malaria and failure to treat it quickly andappropriately when it occurs, well before a hospital isrequired. That being the case I am in no doubt that thefundamental research priority lies in these areas. Whythen do we continue to do research on severe malaria atall? The answer is that even if the most optimistic targetsof us all are met, it is still the fact that a very large partof the clinical load facing health-care professionalsthroughout Africa for the next 20 years (at least) willcontinue to be severe malaria. It is very sobering toreflect on how little clinical research has had any realeffect on practice in the ordinary hospitals all over Africa,which deal with severe malaria on a day-to-day basis.

Have there really been any major improvements in thepast 10, or even 20 years? I wonder how many of us evenknow what is really going on in these hospitals; what isthe case fatality of severe malaria in ordinary, nonresearchhospitals across Africa? Yet, unless we know what is goingon, and probably more importantly what is not happen-ing, we start from a pretty unrealistic position if we wantresearch to have a real impact. I do not simply meanwhat is happening in technical terms: ‘can blood sugarbe measured?’ ‘what is the fluid policy?’, etc., but whatis happening in terms of staffing, morale, training and allthe other factors that have an impact on the care ofseverely ill children? Of course one of the reasons whywe often do not have a clear picture is that this kind ofresearch, whether one calls it audit or operationalresearch or applied health systems research, is very diffi-cult. Unfortunately it is also seriously unattractive; thereare not many papers in

Nature

or the

New England Journalof Medicine

to be written on these topics. This mustchange, or otherwise we have no basis on which todevelop strategies for clinical research that stand a chanceof affecting practice.

Research requirements

Once one knows what is happening, the second require-ment is to have a good research infrastructure to generateideas and act as a test bed to establish which ones arepromising. The issue of sustainable funding for researchcentres in Africa is critical and an absolute requirement.Related, and as important, is the issue of developingcritical mass. This is important for both capacity-buildingand for raising intellectual temperature and rigour; noarea of science can afford to be happy with just tickingover, but given the scale of the problem we deal with,we cannot afford to be carrying out poorly thought-outstudies or rediscovering wheels. Further, it is very diffi-cult to see how much progress can be made by isolatedresearchers in small groups with precarious funding.

A further requirement is that research at this stage isclosely tied in with the national ministry of health andthe national control programmes. There needs to be adegree of involvement or ownership. If this is not estab-lished it will be an uphill task to promote policy changesfurther down the line. I do not advocate a prescriptiveattitude; to my mind the tension between so-called‘directed’ research and ‘imaginative’ or curiosity-drivenresearch is meaningless. What is important is to haveshort-, medium- and long-term strategies, and to be ableto distinguish them. Short-term strategies will necessarilybe more concerned with immediate realities and long-term strategies may involve a large degree of speculation,the applicability of which may not be immediately appar-ent, but we have to be clear which is which. For exam-ple, we should not pretend that finding out which genesare transcribed in a particular clinical syndrome is goingto have much clinical impact over the next few years inlocal hospitals.

Testing the fruits of research

Having generated good ideas, for example a promisingancillary treatment for cerebral malaria or a new regimenfor quinine, the next requirement is to know quickly anddefinitively whether or not it works and what it costs.We cannot afford to continue to perform studies that arejust not quite large enough to be certain of the results,nor powerful enough to convince policy-makers. Ofcourse, this is in no way a problem restricted to Africaand the answer is in one sense simple: numbers, numbers,

Management of severe malaria

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numbers. There has been a remarkable movement overthe last 15 years or so to conduct larger studies in clinicalresearch in general but there are some particular problemsthat we face in Africa. For a start there are not enoughcentres that can participate in such studies, given thatthey require a minimum in terms of infrastructure andpersonnel. The development of a research network forsevere malaria through a MIM (Multilateral Initiative forMalaria) initiative is a very promising development butwe should not be complacent. Firstly, we have to recog-nize that whatever the altruistic motives of researchers,we cannot escape from the fact that there is a tensionbetween the need for individuals and research groups tomaximize their research outputs, and the desire to poolresources. In a nutshell, which would you rather have, afirst-author paper in the Lancet describing a promisingreduction in coma resolution time in cerebral malaria orbe listed in the acknowledgements, with 48 others, in adefinitive study of 2000 children that shows that theintervention is useless? If we can solve this problem, andI think we can only if funders really take it on board,there remains the concern that by their very nature thefew sophisticated research units in Africa are really veryuntypical of the average under-resourced district hospital.What we really need is an approach that can mount large,simple, outcome trials in a network of such district hos-pitals, and this presents a formidable challenge.

Translation and sustainability

Finally having established that ‘wonderquin’ at only 5 ¢a dose can reduce case fatality by 20%, we come to thereal crunch issue: the translation of the research findingsinto practice. As researchers we tend to have a poor graspon what is required. The first mistake we tend to makeis the idea that there is a person in the Ministry of Healthto whom it is only necessary to explain our most recentfindings in order to change practice throughout the land.When this does not happen, we complain that no oneseems very interested in our findings. Of course the truthis that there is no such person. The whole process ofpolicy formation and implementation is enormouslymore complex, involving many individuals and groupingsat different levels within different departments and withmany different priorities, all of which are very pressing.Worse, many of the key parts of the chain are not in theministry of health but in other sectors such as financewhere decisions are taken on budgets for procurement.

Does this mean that all researchers have to engage inlearning the arcane rules of the civil service and spendcountless hours sitting outside the door of the permanentsecretary? Clearly it would be a waste of time to do sobut it is important that the research community and allother stakeholders in health policy find ways of working

together from an early stage if we are to avoid years offrustrating delay.

The second mistake we tend to make is to carry overour concept of ourselves as only malaria researchers. Inthe real world children do not turn up at health facilitiesneatly labelled as malaria but as sick children in whommalaria may or may not be a major factor. It is importantto realize that translation of research about malaria intouseful practice often involves a broadening of theapproach; this is why the Integrated Management ofChildhood Illness (IMCI) is such an important and cen-tral concept. The Division of Curative Services maysometimes be a more important target for networkingthan the national malaria control programme.

There are many reasons why perfectly good researchdoes not end up being translated into practice, fromfailure to convey the information to the right people toproblems at the other end of the line where hard-pressed demoralized staff treat sick children. This bringsus back to where we started, with the need for bothhealth-systems research and operational research. Thisperspective is shown in Figure 1, with a continuousinteraction between what is happening, what could intheory be done, demonstrating that it works and isaffordable, and then translating it into practice and see-ing its effect.

Room for improvement?

So much then for the broader perspective; but all thisdoes presuppose that there are things that clinical researchcan generate that will improve the outlook for childrenwith severe malaria.

Table 1 is taken from the World Health Organizationguidelines on severe malaria. It is a list of interventionsthat have been suggested but for which there is noevidence to support their efficacy. That does not meanthat they are all useless (some may yet turn out to beimportant), but as yet, despite the fact that most have

Figure 1

Practice in the real world

Hypothesis generationand preliminary testing

Does it work?What does it cost?

K. Marsh

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been talked about for many years, there is no evidenceto support their use. One can look at this in differentways: a pessimist might say that there is not much chanceof the next on the list doing much better, an optimistwould say we must find one that works soon.

One thing that one notices from the list is that manyof these drugs are not ones that would be found closeto hand in an average hospital. This raises the issue ofwhether the drugs we do have available are being usedin an optimum way. One might hope that this is the casebecause, after all, there are only very few interventionsavailable to us which can truly be described as potentiallylifesaving and it ought to be possible to use them prop-erly; these are shown in Table 2.

With the addition of oxygen this would constitute thekey list of therapies that could make a critical differenceto any very sick child in a district hospital, whatever thediagnosis.

Antimalarials

This is dealt with more fully in Peter Winstanley’s paper[1]. Quinine is the standard treatment; it is widely avail-able and resistance is not yet a problem. Resistance willappear, however, and quinine is not an innocuous drug.

Further, it is far from clear that we have formulated themost appropriate treatment regimens. One problem is thespeed with which children die from malaria, and yetquinine is rather a slowly acting drug. This makes theqinghasou/artemisinin group potentially very attractive asalternatives to quinine. Quinine and artemether areequally effective, which is important and represents goodnews. There is a strong argument that we may havesomewhat loaded the dice against artemether by doingtrials in patients with cerebral malaria. On the face of it,it makes sense to test the most exciting new drugs in themost dramatic cases but there is a strong argument thatwe should also be looking at the use of these drugs inless severe forms of the disease. Many people feel thatartesunate may have quite major advantages over arte-mether, and if trials to substantiate this are to be carriedout it will be necessary to develop the sort of multicentrefacility discussed above.

Antibiotics

Why discuss antibiotics for the treatment of malaria?Recent experience in Kilifi shows that a significant pro-portion of children with severe malaria also have con-current bacteraemias and that this syndrome is associatedwith very high mortality. This is potentially a very impor-tant management issue that also presents interesting eth-ical issues: should we do randomized trials of broad-spectrum antibiotics if observational studies reveal theirefficacy? In Kilifi local data have convinced us that allchildren under 3 years who have severe malaria shouldbe treated with broad-spectrum antibiotics. Clearly, thisissue requires further examination but it raises the ques-tion as to what is the optimum management.

Sugar

One of the cheapest and most widely available lifesavinginterventions for malaria is sugar. Hypoglycaemia isstrongly associated with death and it is also a major riskfactor for neurological sequelae and for cognitive deficit,even in children with no obvious sequelae.

In most series of children with severe malaria, around15% have hypoglycaemia on admission but somethingless well appreciated is that other children who are nor-moglycaemic on admission often develop hypoglycaemiadespite routine 5% dextrose as part of management fluids.More worrying is that children already known to havebeen hypoglycaemic and who have received 50% dex-trose and then maintenance with 10% dextrose still com-monly develop recurrent hypoglycaemia. These data arefrom a setting where it is possible to monitor glucoseregularly and act if the patient shows any deterioration.Most hospitals are not able to provide regular and quick

Table 1

Cerebral malaria: ancilliary treatments not recommended.

1 Corticosteroids2 Other anti-inflammatory agents3 Other anticerebral oedema agents4 Low molecular weight dextran5 Adrenaline6 Heparin7 Prostacyclin8 Oxypentifylline9 Hyperbaric oxygen

10 Cyclosporin A11 Hyperimmune serum12 Iron chelators13 Dichloroacetate14 Anti-TNF antibodies

Table 2

Treatments available in most hospitals and potentially of major importance in severe malaria.

1 Antimalarials2 Antibiotics3 Sugar4 Fluids5 Blood6 Anticonvulsants7 Antipyretics8 Common sense

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measurements. Glucose dipsticks are the obvious answerbut are prohibitively expensive. Thus it seems certain thatone of the most important complications of severemalaria is often not recognized or managed.

There is no simple answer to this problem. Some havesuggested using sugar solutions administered throughnasogastric tubes as a potential approach. This initiallymay sound like good practical sense but the problem ofrecurrent hypoglycaemia during receipt of intravenousdextrose, suggests that it is unlikely that one could keepup with demand by this route. Testing nasogastric regi-mens presents important ethical problems as hypoglycae-mia is considered by most people to be an emergency,given its potential for brain damage. Any research centrethat can measure levels quickly enough in a kinetic mon-itoring of nasogastric glucose will certainly be well setup to give definitive intravenous treatment. Can it bejustified to delay this? If not, then how can one everbe sure of the safety or efficacy for recommendations tobe used in less optimum conditions? Hypoglycaemia isone of the most important problems we face and thereare no easy answers.

Blood

The overlap of anaemia and respiratory distress is a com-mon situation associated with a high mortality, for whicha relatively cheap and widely available treatment, blood,is available. However, there is a dilemma. If one talks toclinicians across Africa, there remains almost unanimityon the idea that transfusions in these pale breathlesschildren should be given very slowly, minimizing volumeby the use of packed cells and further by the use ofdiuretics. The reasoning, hallowed by generations of rep-etition, is that these children are in congestive cardiacfailure.

However we now know that the usual reason for thesechildren being breathless is that they are severely acidotic.The pathophysiology of acidosis in these children is com-plex but it can be summarized in two major factors,hypovolaemia as well as anaemia. Hypovolaemic acidosisis not unique to malaria: it is a common end-stagepresentation of many lifethreatening conditions all overthe world. The management of such children presentingat casualty or in intensive care units in Europe, Americaor Africa involves an absolutely key component: rapidresuscitation, often with large volumes of fluid. You willnote that this is the exact opposite of the practice

described above in malaria, because hitherto the causehas been presumed to be different.

So, here is a situation with diametrically opposite pos-sibilities for the delivery of a lifesaving intervention. Ifthose who worry about congestive cardiac failure arecorrect, rapid resuscitation with blood will put the childat high risk of dying through volume overload. If thescenario for the development of severe acidosis is correct,the traditional approach will fail to provide a lifesavingtreatment to the highest risk group and fluid is needed.This would seem to be a very important researchquestion.

Conclusions

The key issue is to prevent events progressing to severemalaria. We expect severe malaria to remain a massiveclinical problem in African hospitals for many years tocome. Therefore we need a strategic approach involvingshort-, medium- and long-term approaches to reducingcase fatality. The paper concentrates on what could becalled short-term research because I have argued thatthere is a great urgency for this. It also argues that wehave not been active enough in making what is actuallyhappening now, in real hospitals across Africa, the centrepoint from which we set our research objectives. I makethe argument that there is a need for a much greatercapacity to take promising interventions through to adefinitive answer in short-term and subsequently thatmuch greater attention to the process of translation ofresearch findings into policy is required. On the subjectof what specific research can be expected to make adifference I have concentrated on the limited set of keyoptions that may be lifesaving in district hospitals. I alsoargue that in many, indeed I would say all, cases thereare major unresolved research issues that, if not actuallyignored, have certainly not received the attention theydeserve. I hope that this paper conveys a sense that farfrom there being little that can be done there is in factan enormously important challenge for all of us here,whether we are researchers, policy makers orimplementers.

Reference

1. Winstanley P. The contribution of clinical pharmacology to antimalarial drug discovery and development.

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