Optimal Fluid Management in Adult Severe Malaria
Condition: Malaria; Sepsis
MeSH terms: Malaria
Study type: Observational [Patient Registry]

Summary: 
      Optimal fluid therapy in severe falciparum malaria has not been well defined, especially in
      resource poor settings where access to mechanical ventilation is limited. Recent studies
      suggest that liberal fluid resuscitation is harmful for severe malaria patients despite they
      often being hypovolemic on admission. In order to elucidate the minimum fluid therapy
      required to prevent complications in severe malaria, we will conduct a prospective
      observational study in adults with severe malaria, and also in adults with severe sepsis as a
      comparison group. The objective of this study is to describe the association between
      hemodynamic variations in conventional fluid management and the probability of developing
      acute kidney injury (AKI) or pulmonary edema in adults with severe malaria and severe sepsis.
      Hemodynamic measurements will be obtained by using transpulmonary thermodilution and arterial
      pulse contour analysis.
    

Detailed description: 
      Background

      Fluid therapy in severe malaria and severe sepsis.

      Severe falciparum malaria causes multiple organ dysfunction including metabolic acidosis,
      coma, anemia, acute kidney injury (AKI), and pulmonary edema. The mortality rate of the
      disease is still around 15-23% despite optimal antimalarial therapy. Supportive therapy and
      intensive care are crucial elements in the treatment of the multiple complications of the
      disease. Optimal fluid therapy however, one of the fundamental elements of the supportive
      therapy, has not been well defined. A large randomized controlled trial of fluid therapy in
      shocked African children (the FEAST study) showed that fluid bolus resuscitation increased
      the mortality in severe malaria. A retrospective study in adult patients with severe malaria
      showed that fluid loading had no effect on acid-base status or renal failure. A recent study
      by our group showed that liberal fluid management guided by invasive monitoring was not
      associated with improved renal function or acid-base status, but did aggravate pulmonary
      edema in patients developing pulmonary capillary leakage during admission in the intensive
      care unit. The study found that 38% of severe malaria patients developed clinical pulmonary
      edema, 80% of which occurred after liberal fluid resuscitation. In this study, plasma lactate
      as a crude measure of tissue hypoperfusion correlated with the degree of sequestration
      (directly observed by OPS imaging), and not with the volume of fluid resuscitation. It was
      concluded that liberal fluid management is not indicated in adult severe malaria. However,
      this same study showed that all patients with severe malaria present with intravascular
      dehydration, and often have not been able to maintain proper fluid intake for a considerable
      time. Failure to give these patients enough fluid therapy could therefore be expected to
      precipitate renal failure and tissue hypoperfusion. Overall, the evidence suggests that in
      severe malaria, liberal fluid resuscitation is harmful despite patients often being
      hypovolaemic on admission. The minimum fluid therapy required to prevent complications has
      yet to be defined. Currently, the clinician has no guidance except for the very general
      adage: "keep them dry".

      Evidence for fluid therapy in sepsis and septic shock is also limited. Goal-directed
      resuscitation during the first 6 hours is recommended by the Surviving Sepsis Campaign
      Guideline (SSCG), based on two randomized controlled study. Fluid challenges are one of the
      methods used to achieve the goals, with administration of fluid boluses and initial higher
      volume of intravenous fluids. Due to its inclusion in guidelines1, early goal-directed
      therapy (EGDT) and fluid challenges have now become common clinical practice in resource-rich
      countries. On the other hand, the efficacy of large fluid bolus resuscitation is questioned
      because of low level of evidence for physiological support and lack of clinical controlled
      trials comparing fluid bolus therapy versus no fluid bolus therapy. The variable availability
      of mechanical ventilation must be considered when making recommendations for fluid
      resuscitation. Since access to mechanical ventilation is often limited in developing world
      settings, the recommendations in the SSCG are not applicable in this context without
      additional evaluation. Recently, the FEAST trial in East African children with compensated
      shock in severe malaria and sepsis revealed that fluid bolus therapy of 20 to 40 mL/kg body
      weight caused a dramatic increase in case fatality. Several studies have found positive fluid
      balance to be associated with increased mortality in sepsis or septic shock. A retrospective
      study (the VASST study) included 778 patients with septic shock showed that there is
      significant correlation between a more positive fluid balance at both time points of 12 hours
      and day 4 and increased mortality. In the SOAP study, multicenter prospective cohort study
      enrolled 1177 patients with sepsis, cumulative fluid balance within first 72 hours after the
      onset was an independent predictor of mortality. Also, a prospective observational study of
      164 patients with septic shock reported that there was no significant difference in 90-days
      mortality between patients with higher fluid volume infused (> 4.0 L) and lower volume (< 4.0
      L) on day 1. They concluded that initial fluid volume administered was not associated with
      mortality in patients with septic shock. Optimal initial fluid volume and strategy in sepsis
      and septic shock is thus unclear. Especially in resource-limited countries, fluid overload is
      more dangerous than that in resource-rich countries, because development of pulmonary edema
      and ALI/ARDS is almost always fatal in settings without access to mechanical ventilation. The
      recommendation of fluid bolus resuscitation therapy as promoted in the SSCG should therefore
      be evaluated cautiously in the resource-poor setting.

      Rationale

      As outlined above, the optimum fluid management in severe malaria and sepsis has yet to be
      established, particularly in resource poor settings where access to mechanical ventilation is
      limited. Whilst liberal fluid resuscitation appears deleterious, it is not clear what the
      minimum fluid requirements are; this study aims to address this question.

      Procedures

      The investigators will longitudinally monitor the hemodynamic parameters along with
      cumulative fluid administration and fluid balance during conventional fluid strategy, as
      practiced by the local physicians. For monitoring, we will use transpulmonary thermodilution
      and arterial pulse contour analysis (PiCCO-plus, Pulsion Medical System, Germany). The PiCCO
      system is in routine use as part of standard clinical practice to provide hemodynamic
      monitoring of severely ill patients admitted to ICU. It uses a central venous and arterial
      line to provide continuous monitoring of hemodynamic function.

      Overall, the investigators believe that by monitoring the hemodynamics using the PiCCO system
      will give valuable new insight into the relationship between fluid management and renal
      function, pulmonary edema, and acid-base status in adult patients with severe malaria.
      Patients with severe sepsis will be recruited as a comparison group, and the volume status
      will be evaluated in the same manner.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Patients with severe malaria or severe sepsis admitted to the secondary or tertiary care
        center
      
Keywords: malaria, falciparum; sepsis; fluid therapy; thermodilution; extravascular lung water; acute kidney injury