Intensive Care Med (2015) 41:111114

DOI 10.1007/s00134-014-3568-1

Anders Perner
Robert A. Fowler
Rinaldo Bellomo
Ian Roberts

WHATS NEW IN INTENSIVE CA RE

Ebola care and research protocols

Received: 11 November 2014

Accepted: 11 November 2014
Published online: 27 November 2014
Springer-Verlag Berlin Heidelberg and ESICM 2014
A. Perner ())
Department of Intensive Care, Rigshospitalet, University
of Copenhagen, Copenhagen, Denmark
e-mail: anders.perner@rh.regionh.dk
Tel.: ?45-35458333
R. A. Fowler
Department of Medicine, Sunnybrook Health Sciences Centre,
University of Toronto, Toronto, Canada
e-mail: Rob.fowler@sunnybrook.ca
R. A. Fowler
Department of Critical Care Medicine, Sunnybrook Health
Sciences Centre, University of Toronto, Toronto, Canada
R. Bellomo
Australian and New Zealand Intensive Care Research Centre,
Melbourne, Australia
e-mail: Rinaldo.bellomo@austin.org.au
I. Roberts
London School of Hygiene and Tropical Medicine, Keppel Street,
London, UK
e-mail: Ian.roberts@lshtm.ac.uk

Thousands of patients have died in West Africa during the

worst Ebola virus disease (EVD) epidemic recorded to
date, and many more patients will die in the coming
months [1]. The overall case fatality rate in West Africa is
6070 % but this rate is highly variable, depending
greatly upon the treatment centre. Mortality also appears

to be lower in repatriated patients and in infected

healthcare workers receiving intensive care in nonresource constrained settings. Both of these findings
suggest that effective supportive care has the potential to
increase survival.
EVD is a febrile illness with severe gastrointestinal
manifestations starting 35 days after symptom onset
[2]. Vomiting and diarrhoea cause profound water and
electrolyte depletion and ultimately hypovolaemia and
shock [38]. High blood levels of creatinine and urea,
indicating dehydration, are associated with mortality
[8]. Pro-inflammatory mediators may contribute to
vascular leakage, hypotension and multi-organ failure
[5]. However, in West Africa, EVD patients are presenting with minimal clinically appreciable capillary
leak (i.e. peripheral or pulmonary oedema) that so
commonly complicates sepsis in Western intensive
care units (ICUs). Acute hypoxaemic respiratory failure is also distinctly uncommon among patients with
EVD in West Africa [3, 8]. These differences may be
due to true pathophysiological differences, or they may
result from the administration of lower fluid volumes
during care. Clinically important bleeding is not as
common as previously suspected [3, 8].
The supportive care of EVD comprises fluid and
electrolyte repletion, symptom relief with anti-emetics
and analgesia, anti-malaria agents (if relevant) and prophylaxis against secondary bacterial infection [3, 8]. Most
patients receive oral rehydration and electrolyte substitution, whereas the use of intravenous (IV) fluids appears
to depend on the treatment centre, staffing levels and
treatment philosophy [3, 4, 6, 8]. Barriers against the
higher use of IV fluids are the time constraints on personnel due to the overwhelming number of patients and
the need for personal protective equipment which limits
time at the bedside due to heat and dehydration [4].

112

Fluid and electrolyte treatment protocol

The development of practical supportive care protocols
that take into account information on the clinical and
biochemical course of patients with EVD, evidence from
intensive care research and the available resources is
urgently needed. Several reports have pointed to the
importance of improved fluid and electrolyte management
in patients who cannot provide self-care [4, 6]. Patients
who can provide self-care have been treated with balanced oral rehydration solutions [4]. Fluid and electrolyte
therapy should substitute for the patients deficiencies and
ongoing losses. The estimated gastrointestinal losses
appear to vary from 5 to 10 l [4, 7]. Data from a hospital
in Sierra Leone show that patients initially present with
low plasma concentrations of sodium, potassium and
calcium and biochemical evidence of dehydration [8],
indicating gastrointestinal loss and some substitution
using hypotonic oral solutions (bottled water) prior to
admission. The only Ebola patient with documented fluid
loss and plasma electrolyte management over several days
maintained the levels with a daily infusion of 10 l of
balanced crystalloid (Ringers acetate) and 810 mmol/h
of potassium during the 5 days of high gastrointestinal
losses [7].
Based on the above observations we suggest a tiered
approach which takes available resources into account
(Fig. 1). The fluid and electrolyte protocol for average
adult patients with EVD may include at least 5 l of a
balanced crystalloid solution supplemented with
100 mmol of potassium per day on days with gastrointestinal losses. Hypotonic parenteral solutions should be

Treatment intensity

Haemodialysis
Invasive monitoring
Invasive venlaon
Vasopressor infusion
Oxygen and blood transfusion
Ca2+- and Mg-tesng and dosing
Test-guided uid and electrolyte dosing
Na, K, bicarbonate and Hb POC tesng
Fluid volume guided by assessment
Simple circulatory assessment
Fixed electrolyte dosing*
Fixed uid volume*

Available resources
Fig. 1 A tiered approach to critical care interventions for patients
with Ebola virus disease based on available resources. Hb
Haemoglobin, POC point-of-care. Asterisk indicates that an adult
patient on days with gastrointestinal losses should receive per day
at least 5 l of balanced crystalloid solution and 100 mmol of
potassium

avoided. In the case of more severe hypoperfusion, more

fluid may be needed.
With access to point-of-care blood testing, sodium and
potassium substitution should be guided by plasma values, since the above suggestions are based on biochemical
parameters from a limited number of cases. The measurement and substitution of bicarbonate, calcium and
magnesium are likely to be of value.
Colloid solutions and liberal blood transfusion should
be avoided based on evidence from patients with septic
shock [9, 10].

Treatment uncertainties that should be resolved

Although widespread implementation of simple care
protocols limiting hypovolaemia will likely reduce mortality, there are important treatment uncertainties which if
resolved could improve mass management of EVD
patients. We propose an iterative process of pragmatic
trials of alternative supportive care protocols, with the
aim of achieving the lowest mortality possible given the
available resources.
Parenteral access
Fast and safe parenteral access to deliver fluids and
electrolytes are likely to have an immediate impact on the
survival of patients with EVD, but there are barriers to IV
access in West Africa, as mentioned above. Early insertion of peripheral vascular catheters, assessments of the
effect and safety of modern and simple intraosseous
injection systems and, in some settings, insertion of
longer dwelling peripherally inserted central catheters
could have important implications for the management of
large numbers of patients with EVD.
Volume of parenteral fluids
The main clinical uncertainty is the volume of fluid
needed to prevent shock and, ultimately, death in EVD
patients. Varying estimates of gastrointestinal losses in
EVD make it difficult to set a fixed volume for these
patients. In addition, the usual care of patients with septic
shock in the USA and Australasia includes the administration of approximately 4 l of crystalloid over an 8-h
period [11, 12]. On the other hand, higher fluid volumes
may be detrimentalat least if given as bolusesto
febrile children in Africa [13]. The lack of therapeutic
oxygen in most parts of West Africa is an additional
reason to optimize fluid balance while avoiding pulmonary oedema. Trials of higher versus lower parenteral fluid

113

volumes (e.g. 5 vs. 10 l over 24 h) and usual care versus

clinically and biochemically guided fluid volumes using
mortality as the primary outcome measure would help to
resolve this uncertainty.

widely available interventions may be tested. There is

pathophysiological rational for testing prophylactic
parenteral antibiotics with Gram-negative cover and
hydrocortisone [14] (200 mg every 24 h), as presently
tested in septic shock in the ADRENAL trial
(NCT01448109).

Electrolyte substitution
The resuscitation fluids used in usual care are crystalloids,
including saline and balanced salt solutions. Although the
choice of fluid can have important impact on acidbase
status and electrolyte levels, the effects and side-effects of
the different crystalloid solutions remain unclear in general, and there is as yet no information on these effects/
side-effects in patients with EVD. The roles of potassium,
bicarbonate, magnesium and calcium supplementation
represent important uncertainties. A pre-mixed solution
that is most appropriate for EVD-related fluid losses is
urgently needed as it may have benefits for patients and
staff. Resolving these uncertainties is essential for the
management of large numbers of patients with EVD.
Other supportive interventions
After the establishment of protocols for parenteral
access and fluid and electrolyte management, other

Perspective
We urgently need to deploy and evaluate Ebola-specific
supportive care. The provision of effective supportive
care for EVD is not only an unmet standard of care for
individual patients, but improving clinical care also plays
a role in controlling the epidemic. If mortality in treatment centres can be lowered through widespread
application of the standard of care, there may be a greater
acceptance of presenting to treatment centres as a means
of surviving Ebola [4]. This may subsequently decrease
the risk of patients remaining in the community and
infecting others.
Conflicts of interest The ICU at Rigshospitalet, where AP is head
of research, receives research funds from Fresenius Kabi and CSL
Behring. The other authors have no conflicts of interests.

References
1. WHO Ebola Response Team (2014)
Ebola virus disease in West Africathe
first 9 months of the epidemic and
forward projections. N Engl J Med
371:14811495
2. Tattevin P, Durante E, Massaquoi M
(2014) Does this patient have Ebola
virus disease? Intensive Care Med
40:17381741
3. Bah EI, Lamah MC, Fletcher T, Jacob
ST, Brett-Major DM, Sall AA, Shindo
N, Fischer WA, Lamontagne F, Saliou
SM, Bausch DG, Moumi B, Jagatic T,
Sprecher A, Lawler JV, Mayet T,
Jacquerioz FA, Baggi MaFM, Vallenas
C, Clement C, Mardel S, Faye O, Faye
O, Soropogui B, Magassouba N,
Koivogui L, Pinto R, Fowler RA (2014)
Clinical presentation of patients with
Ebola virus disease in Conakry, Guinea.
N Engl J Med. doi:
10.1056/NEJMoa1411249
4. Chertow DS, Kleine C, Edwards JK,
Scaini R, Giuliani R, Sprecher A (2014)
Ebola virus disease in West Africa
clinical manifestations and
management. N Engl J Med. doi:
10.1056/NEJMp1413084

5. Fisher-Hoch SP, Platt GS, Neild GH,

Southee T, Baskerville A, Raymond
RT, Lloyd G, Simpson DI (1985)
Pathophysiology of shock and
hemorrhage in a fulminating viral
infection (Ebola). J Infect Dis
152:887894
6. Fowler RA, Fletcher T, Fischer WA,
Lamontagne F, Jacob S, Brett-Major D,
Lawler JV, Jacquerioz FA, Houlihan C,
ODempsey T, Ferri M, Adachi T,
Lamah MC, Bah EI, Mayet T,
Schieffelin J, McLellan SL, Senga M,
Kato Y, Clement C, Mardel S, Vallenas
Bejar De Villar RC, Shindo N, Bausch
D (2014) Caring for critically ill
patients with ebola virus disease.
Perspectives from West Africa. Am J
Respir Crit Care Med 190:733737
7. Kreuels B, Wichmann D, Emmerich P,
Schmidt-Chanasit J, de HG, Kluge S,
Sow A, Renne T, Gunther S, Lohse
AW, Addo MM, Schmiedel S (2014) A
case of severe Ebola virus infection
complicated by Gram-negative
septicemia. N Engl J Med. doi:
10.1056/NEJMoa1411677

8. Schieffelin JS, Shaffer JG, Goba A,

Gbakie M, Gire SK, Colubri A, Sealfon
RSG, Kanneh L, Moigboi A, Momoh
M, Fullah M, Moses LM, Brown BL,
Andersen KG, Winnicki S, Schaffner
SF, Park DJ, Yozwiak NL, Jiang PP,
Kargbo D, Jalloh S, Fonnie M, Sinnah
V, French I, Kovoma A, Kamara FK,
Tucker V, Konuwa E, Sellu J, Mustapha
I, Foday M, Yillah M, Kanneh F, Saffa
S, Massally JLB, Boisen ML, Branco
LM, Vandi MA, Grant DS, Happi C,
Gevao SM, Fletcher TE, Fowler RA,
Bausch DG, Sabeti PC, Khan SH, Garry
RF (2014) Clinical illness and outcomes
in patients with Ebola in Sierra Leone.
N Engl J Med. doi:
10.1056/NEJMoa1411680
9. Perner A, Junttila E, Haney M,
Hreinsson K, Kvale R, Vandvik PO,
Moller MH (2014) Scandinavian
clinical practice guideline on choice of
fluid in resuscitation of critically ill
patients with acute circulatory failure.
Acta Anaesthesiol Scand. doi:
10.1111/aas.12429

114

13. Maitland K, Kiguli S, Opoka RO,

11. Yealy DM, Kellum JA, Huang DT,
10. Holst LB, Haase N, Wetterslev J,
Engoru C, Olupot-Olupot P, Akech SO,
Barnato AE, Weissfeld LA, Pike F,
Wernerman J, Guttormsen AB,
Nyeko R, Mtove G, Reyburn H, Lang
Terndrup T, Wang HE, Hou PC,
Karlsson S, Johansson PI, Aneman A,
T, Brent B, Evans JA, Tibenderana JK,
LoVecchio F, Filbin MR, Shapiro NI,
Vang ML, Winding R, Nebrich L,
Crawley J, Russell EC, Levin M,
Angus DC (2014) A randomized trial of
Nibro HL, Rasmussen BS, Lauridsen
Babiker AG, Gibb DM (2011) Mortality
protocol-based care for early septic
JR, Nielsen JS, Oldner A, Pettila V,
after fluid bolus in African children
shock. N Engl J Med 370:16831693
Cronhjort MB, Andersen LH, Pedersen
with severe infection. N Engl J Med
UG, Reiter N, Wiis J, White JO, Russell 12. Peake SL, Delaney A, Bailey M,
364:24832495
Bellomo R, Cameron PA, Cooper DJ,
L, Thornberg KJ, Hjortrup PB, Muller
14. Fletcher T, Fowler R, Beeching N
Higgins AM, Holdgate A, Howe BD,
RG, Moller MH, Steensen M, Tjader I,
(2014) Understanding organ
Webb SA, Williams P (2014) GoalKilsand K, Odeberg-Wernerman S,
dysfunction in Ebola virus disease.
directed resuscitation for patients with
Sjobo B, Bundgaard H, Thyo MA,
Intensive Care Med 40:19361939. doi:
early septic shock. N Engl J Med
Lodahl D, Maerkedahl R, Albeck C,
10.1007/s00134-014-3515-1
371:14961506
Illum D, Kruse M, Winkel P, Perner A
(2014) Lower versus higher
hemoglobin threshold for transfusion in
septic shock. N Engl J Med
371:13811391