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Intensive Care Med (2006) 32:958961

DOI 10.1007/s00134-006-0189-3

Joseph A. Carcillo
Robert C. Tasker

EDITORIAL

Fluid Resuscitation of Hypovolemic Shock:


Acute Medicines Great Triumph for Children

Received: 12 April 2006


Accepted: 12 April 2006
Published online: 24 May 2006
Springer-Verlag 2006
This editorial refers to the article available at: http://dx.doi.org/
10.1007/s00134-006-0188-4
J. A. Carcillo (u)
Childrens Hospital of Pittsburgh, Department of Critical Care
Medicine,
Pittsburgh Pennsylvania, USA
e-mail: carcilloja@ccm.upmc.edu
R. C. Tasker
Addenbrookes Hospital, Department of Paediatrics, Cambridge
University Clinical School,
Cambridge, UK

The World Health Organization (WHO) lists diarrhea,


malaria, and bacterial sepsis as three of the leading causes
of death of infants and children worldwide. Because
fluid resuscitation reduces mortality tenfold in each of
these conditions, a worldwide initiative now exists on
the importance of improving access to this type of acute
therapy. Two global priorities for realizable and cost
efficient improvement in child survival are therefore:
(1) improved access to facilities capable of time-sensitive
intravenous fluid resuscitation, and (2) clinical studies that
determine which fluid composition(s) best attain early
resuscitation goals in various forms of hypovolemic shock.
However, consensus has not been fully reached on the
type of isotonic fluids to be used in each form or condition
associated with hypovolemic shock [1, 2, 3, 4, 5]. In this
issue of Intensive Care Medicine, colleagues from the
Netherlands share their national guidelines for use of fluid
resuscitation and provide support for their contention that
in their population of children, initial resuscitation with
isotonic crystalloid is indicated [6].

How have we arrived at this position, and what have


we really learnt over the past 150 years? Hypovolemic
shock has been recognized as a leading reversible cause
of death in the medical literature for many years [7]. In
1831, William OShaughnessy observed that blood from
cholera victims had lost a large portion of its water, and
he later suggested treatment aimed at returning the blood
to its natural specific gravity by replacing its deficient
saline. A year later Thomas Latta reported the first
known attempt at intravenous fluid resuscitation. Although
dramatic improvements were noted, the standard practice
was not altered for many decades. At the beginning of
the 20th century Walter Cannon was unable to resolve
the inconsistencies of the then popular toxic theory of
shock. Alfred Blalock, however, developed experimental
proof that injury precipitated fluid losses, the effects of
which could be ameliorated by vigorous restoration of
plasma volume. Then, in 1927, Blalock experimented with
incremental hemorrhage to induce shock in dogs. He used
blood pressure, cardiac output, and blood oxygen content
from the right and left ventricles to evaluate the effects of
three types of therapies: transfusion, drugs (i.e., digitalis,
strychnine, ether, caffeine, epinephrine, ephedrine), or
saline. Shock first appeared at 2030 ml/kg of blood loss
and was fatal after 40 ml/kg hemorrhage. Tachycardia
always preceded a fall in blood pressure. Blood pressure remained remarkably stable during bleeding, and
cardiac output always fell and proceeded reduction in
blood pressure. Only fluid resuscitation restored cardiac
output. Blalock interpreted these findings as follows: The
essential circulatory effects of a diminished volume of
blood are: 1) decreased minute cardiac output and 2)
diminished caliber of peripheral arteries. It is believed
that the other circulatory effects are secondary. The
blood pressure is an inadequate guide to the state of the
circulation in incipient shock. Based on this new insight,
treatment of hemorrhagic, traumatic, and burn shock
changed in World War II, with intravenous resuscitation

959

performed in patients who had tachycardia and narrow


pulse pressure [8, 9]. Towards the end of the 20th century
Carroll and colleagues, among others, reported that animal
models of septic shock survived the experimental period
and attained an increased or normal cardiac output only
when two conditions were met: (1) ketamine was used
as the induction/anesthesia agent, and (2), 60 ml/kg of

Fig. 1 United States vital statistics (modified from [15]) show that
deaths from three major causes of hypovolemic shock (diarrheal disease, enteritis and other intestinal infections; hernia and intestinal
obstruction; and septicemia) have decreased greater than tenfold

Fig. 2 Single-center best mortality rates (%) from septic shock


have decreased with the implementation of aggressive fluid resuscitation in the emergency department: 1963, University of Minnesota
mortality from gram-negative bacteria sepsis in infants and children before modern intensive care medicine became standard [16];
1985, National Childrens Medical Center mortality from all-cause
infant and pediatric septic shock before aggressive fluid administration became standard [17]; 1997, St Marys Hospital mortality
from meningococcus with early albumin resuscitation in community
hospital emergency departments [18]; 2004, Kenya mortality from
malarial shock with early albumin resuscitation in the emergency
room [19]; 2005, Vietnam mortality from dengue shock with early
administration of isotonic crystalloid or colloid [2022]

isotonic crystalloid or colloid fluid was rapidly infused


within the first hour of sepsis [10, 11, 12, 13].
The above adult clinical and experimental approach
to fluid resuscitation was applied to the treatment of
shocked children in 1991 [14]. Fluid resuscitation of
60 ml/kg fluid resuscitation in septic shock reduced
mortality when administered within an hour of presentation in the emergency room in patients already receiving
ketamine, steroid, and inotropic support. These children
demonstrated resolution of hypovolemia without an
increase in the incidence of pulmonary edema or cerebral
edema. Although some patients needed only 20 ml/kg,
others needed up to 200 ml/kg of fluid resuscitation in
the first hour. These patients received two-thirds of their
initial fluid boluses as saline followed by an additional
third as colloid. Based on these findings, standard of
care in fluid resuscitation changed for children. The
American Heart Association and Pediatric Advanced Life
Support Group now recommends rapid 20 ml/kg saline
or albumin fluid boluses up to 60 ml/kg and greater until
perfusion improves or signs of fluid overload occur, such
as respiratory rales or a newly palpable liver edge. The
impact of this approach in regard to overall child health is
reflected in US vital statistics for childhood disease, 1960
to 2001. These data show the significance of emergency
fluid management. The mortality from diseases associated
with hypovolemic shock (i.e., diarrheal disease, enteritis,
hernia and obstruction, and septicemia) decreased more
than tenfold (from 121.2 to 8.8 deaths per 100,000 infants)
with the development of plastic intravenous catheters,
commercially prepared intravenous fluids, and intensive
care medicine. Death rates per 100,000 infants decreased
from 31.6 to 7.7, from 22.4 to 1.1, and from 67.2 to
< 0.1 for septicemia, hernia/intestinal obstruction, and
diarrhea/enteritis, respectively (Fig. 1) [15]. Expanding
upon the approach suggested in a previous clinical report,
we have now added more recent data to illustrate this
point [16, 17, 18, 19, 20, 21, 22]. For example, investigators at St. Marys Hospital, London, implemented
a protocol for emergency room fluid resuscitation using
albumin as well as peripheral inotropic support in the
community hospital setting before transfer to the tertiary
center. They observed a remarkable, almost tenfold reduction in mortality from 22.5% to 2.5% in children with
meningococcemia (Fig. 2) [18, 23]. The effects of fluid
resuscitation appeared to be time-sensitive and therefore
greatest when administered in the community hospital
setting. In this regard, Han and colleagues also reported
that each hour of delay in restoration of normal blood
pressure and a capillary refill to < 2 s is associated with
a increase in the mortality odds rate [24]. Similar results
have been observed in adults. Rivers and colleagues found
that time-sensitive emergency department resuscitation
to blood pressure and a superior vena cava oxygen
saturation > 70% decreased mortality by nearly 50%
compared with resuscitation to blood pressure alone. The

960

significant difference in survival was attributable to more


fluid resuscitation as well as inotropic support [25]. Last,
investigators from the Kritikus foundation have similarly
reported that implementation of a shock resuscitation
program starting in the community hospital decreased
time to fluid resuscitation and concomitantly improved
outcomes in adults with hypovolemic shock [26].
For much of the 20th century the WHO concentrated
on the practicalities of oral rehydration therapy in saving
lives from diarrhea and dehydration, the then number 1 cause of death of children in the developing world.
These efforts have been successful, since pneumonia, not
diarrhea, is now the top killer. However, at the turn of
the century, the WHO turned to saving lives from hypovolemic shock using intravenous therapies. As it turns out,
this is a highly cost effective and achievable endeavor [27,
28]. Three randomized controlled trials have now been
performed in Southeast Asia using various colloid and
crystalloid solutions to resuscitate children with dengue
shock in the first hour after presentation to the emergency
department [20, 21, 22, 23]. Using the principles first
outlined by OShaughnessy, Latta, and Blalock, the vast
majority of these patients were recognized as being in
shock and treated while they had tachycardia and narrow
pulse pressure, rather than after the onset of hypotension.
Fluid resuscitation directed at establishing normal heart
rate, normal blood pressure, and normal hematocrit (i.e.,
resolution of hemoconcentration) achieved near 100%
survival, regardless of the fluid used.
The role of fluid resuscitation in hospitals in the
developing world that do not have universal access to
mechanical ventilators has also been investigated in
a variety of etiologies. In two studies from two different
hospitals in India, mixed populations of children with
bacterial septic shock or dengue shock associated with
hypotension were examined. In one study children had
30% mortality with crystalloid or colloid resuscitation
and inotropic support [29]. The other study demonstrated
that implementation of a fluid removal regimen using diuretics and, in some cases, continuous peritoneal dialysis
markedly reduced this mortality in children by reversing
fluid overload [30]. (Of note, we similarly used diuretics
and, occasionally, peritoneal dialysis in fluid-overloaded
patients in our clinical report of aggressive fluid resuscitation [14].) In hypovolemic shock due to severe malaria,
fluid resuscitation has also been shown to be effective [31].

In a series of studies, investigators in Kenya first noticed


that children who died of severe malaria, similar to
the findings of Blalock, first developed tachycardia and
acidosis before hypotension [32, 33]. They noted that the
children who were resuscitated with fluid had better outcomes than historical controls. In a follow-up, randomized
controlled trial these investigators also found that albumin
resuscitation reduced mortality to 4%, compared with 18%
in those resuscitated with saline [19]. Now, at some level
of severe anemia, children resuscitated with fluids other
than blood will be expected to do poorly. For example,
fluid-induced dilution of hemoglobin concentration may
reduce oxygen delivery more than the fluid-induced
increase in stroke volume increases oxygen delivery
[oxygen delivery = cardiac output (heart rate stroke
volume) Oxygen content (1.36 Hgb g/dl % oxygen
saturation + paO2 0.003)]. The efficacy of albumin
resuscitation in some studies (see above) suggests that
patients are not dying from severe anemia, but rather from
hypovolemic shock. Albumin may have been beneficial
due to low oncotic pressure in these children. It is also
possible that albumin may be preferred in septic shock in
adults as well. In the SAFE trial, crystalloid was associated
with improved survival from traumatic shock, but in the
albumin-treated group there was a trend to better outcome
in septic shock (p = 0.05) [34].
In summary, the historical clinical studies and recent
pediatric experience indicate that fluid resuscitation should
be given in a time-sensitive manner and directed toward
the goal of improved stroke volume as evidenced by the
following clinical signs: return to normal heart rate, capillary refill < 2 s, peripheral pulses, and blood pressure, as
well as correction of hemoglobin concentration, and superior vena cava saturation > 70%. Patients who do not respond to fluid resuscitation alone commonly benefit from
addition of inotropic therapy to overcome cardiac dysfunction; sometimes, they will also require hydrocortisone for
adrenal insufficiency [15]. If fluid overload occurs (as evidenced by the clinical signs of respiratory rales, wet cough,
or hepatomegaly), then diuretics should be used. In cases
where fluid overload is resistant to this therapy, dialysis or
hemofiltration techniques will be required. The guideline
reported by Boluyt and colleagues [6] in this issue of Intensive Care Medicine provides us with additional, systematic recommendations on the initial choice of resuscitation
with crystalloid.

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