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Intensive Care Med (2006) 32:958961DOI 10.1007/s00134-006-0189-3 E D I T O R I A L

Joseph A. CarcilloRobert C. Tasker

Fluid Resuscitation of Hypovolemic Shock:

Acute Medicines Great Triumph for Children

Received: 12 April 2006Accepted: 12 April 2006Published 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 ()Childrens Hospital of Pittsburgh, Department of Critical CareMedicine,Pittsburgh Pennsylvania, USAe-mail: carcilloja@ccm.upmc.edu

R. C. TaskerAddenbrookes 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 causesof death of infants and children worldwide. Becausefluid resuscitation reduces mortality tenfold in each ofthese conditions, a worldwide initiative now exists onthe importance of improving access to this type of acutetherapy. Two global priorities for realizable and costefficient improvement in child survival are therefore:(1) improved access to facilities capable of time-sensitiveintravenous fluid resuscitation, and (2) clinical studies thatdetermine which fluid composition(s) best attain earlyresuscitation goals in various forms of hypovolemic shock.However, consensus has not been fully reached on thetype of isotonic fluids to be used in each form or conditionassociated with hypovolemic shock [1, 2, 3, 4, 5]. In thisissue of Intensive Care Medicine, colleagues from theNetherlands share their national guidelines for use of fluidresuscitation and provide support for their contention thatin their population of children, initial resuscitation withisotonic crystalloid is indicated [6].

How have we arrived at this position, and what have

we really learnt over the past 150 years? Hypovolemicshock has been recognized as a leading reversible causeof death in the medical literature for many years [7]. In1831, William OShaughnessy observed that blood fromcholera victims had lost a large portion of its water, andhe later suggested treatment aimed at returning the bloodto its natural specific gravity by replacing its deficientsaline. A year later Thomas Latta reported the firstknown attempt at intravenous fluid resuscitation. Althoughdramatic improvements were noted, the standard practicewas not altered for many decades. At the beginning ofthe 20th century Walter Cannon was unable to resolvethe inconsistencies of the then popular toxic theory of

shock. Alfred Blalock, however, developed experimentalproof that injury precipitated fluid losses, the effects ofwhich could be ameliorated by vigorous restoration ofplasma volume. Then, in 1927, Blalock experimented withincremental hemorrhage to induce shock in dogs. He usedblood pressure, cardiac output, and blood oxygen contentfrom the right and left ventricles to evaluate the effects ofthree types of therapies: transfusion, drugs (i.e., digitalis,strychnine, ether, caffeine, epinephrine, ephedrine), orsaline. Shock first appeared at 2030 ml/kg of blood lossand was fatal after 40 ml/kg hemorrhage. Tachycardiaalways preceded a fall in blood pressure. Blood pres-sure remained remarkably stable during bleeding, andcardiac output always fell and proceeded reduction inblood pressure. Only fluid resuscitation restored cardiacoutput. Blalock interpreted these findings as follows: Theessential circulatory effects of a diminished volume ofblood are: 1) decreased minute cardiac output and 2)diminished caliber of peripheral arteries. It is believedthat the other circulatory effects are secondary. Theblood pressure is an inadequate guide to the state of thecirculation in incipient shock. Based on this new insight,treatment of hemorrhagic, traumatic, and burn shockchanged in World War II, with intravenous resuscitation

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performed in patients who had tachycardia and narrowpulse pressure [8, 9]. Towards the end of the 20th centuryCarroll and colleagues, among others, reported that animalmodels of septic shock survived the experimental periodand attained an increased or normal cardiac output onlywhen 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 thatdeaths from three major causes of hypovolemic shock (diarrheal dis-ease, enteritis and other intestinal infections; hernia and intestinalobstruction; and septicemia) have decreased greater than tenfold

Fig.2 Single-center best mortality rates (%) from septic shockhave decreased with the implementation of aggressive fluid resusci-tation in the emergency department: 1963, University of Minnesota mortality from gram-negative bacteria sepsis in infants and chil-dren before modern intensive care medicine became standard [16];1985, National Childrens Medical Center mortality from all-causeinfant and pediatric septic shock before aggressive fluid adminis-tration became standard [17]; 1997, St Marys Hospital mortalityfrom meningococcus with early albumin resuscitation in communityhospital emergency departments [18]; 2004, Kenya mortality frommalarial shock with early albumin resuscitation in the emergencyroom [19]; 2005, Vietnam mortality from dengue shock with earlyadministration of isotonic crystalloid or colloid [2022]

isotonic crystalloid or colloid fluid was rapidly infusedwithin the first hour of sepsis [10, 11, 12, 13].

The above adult clinical and experimental approachto fluid resuscitation was applied to the treatment ofshocked children in 1991 [14]. Fluid resuscitation of 60 ml/kg fluid resuscitation in septic shock reduced

mortality when administered within an hour of presenta-tion in the emergency room in patients already receivingketamine, steroid, and inotropic support. These childrendemonstrated resolution of hypovolemia without anincrease in the incidence of pulmonary edema or cerebraledema. Although some patients needed only 20 ml/kg,others needed up to 200 ml/kg of fluid resuscitation inthe first hour. These patients received two-thirds of theirinitial fluid boluses as saline followed by an additionalthird as colloid. Based on these findings, standard ofcare in fluid resuscitation changed for children. TheAmerican Heart Association and Pediatric Advanced LifeSupport Group now recommends rapid 20 ml/kg saline

or albumin fluid boluses up to 60 ml/kg and greater untilperfusion improves or signs of fluid overload occur, suchas respiratory rales or a newly palpable liver edge. Theimpact of this approach in regard to overall child health isreflected in US vital statistics for childhood disease, 1960to 2001. These data show the significance of emergencyfluid management. The mortality from diseases associatedwith hypovolemic shock (i.e., diarrheal disease, enteritis,hernia and obstruction, and septicemia) decreased morethan tenfold (from 121.2 to 8.8 deaths per 100,000 infants)with the development of plastic intravenous catheters,commercially prepared intravenous fluids, and intensivecare 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, anddiarrhea/enteritis, respectively (Fig. 1) [15]. Expandingupon the approach suggested in a previous clinical report,we have now added more recent data to illustrate thispoint [16, 17, 18, 19, 20, 21, 22]. For example, inves-tigators at St. Marys Hospital, London, implementeda protocol for emergency room fluid resuscitation usingalbumin as well as peripheral inotropic support in thecommunity hospital setting before transfer to the tertiarycenter. They observed a remarkable, almost tenfold re-duction in mortality from 22.5% to 2.5% in children withmeningococcemia (Fig. 2) [18, 23]. The effects of fluidresuscitation appeared to be time-sensitive and thereforegreatest when administered in the community hospitalsetting. In this regard, Han and colleagues also reportedthat each hour of delay in restoration of normal bloodpressure and a capillary refill to < 2 s is associated witha increase in the mortality odds rate [24]. Similar resultshave been observed in adults. Rivers and colleagues foundthat time-sensitive emergency department resuscitationto blood pressure and a superior vena cava oxygensaturation > 70% decreased mortality by nearly 50%compared with resuscitation to blood pressure alone. The

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significant difference in survival was attributable to morefluid resuscitation as well as inotropic support [25]. Last,investigators from the Kritikus foundation have similarlyreported that implementation of a shock resuscitationprogram starting in the community hospital decreasedtime to fluid resuscitation and concomitantly improved

outcomes in adults with hypovolemic shock [26].For much of the 20th century the WHO concentratedon the practicalities of oral rehydration therapy in savinglives from diarrhea and dehydration, the then num-ber 1 cause of death of children in the developing world.These efforts have been successful, since pneumonia, notdiarrhea, is now the top killer. However, at the turn ofthe century, the WHO turned to saving lives from hypo-volemic 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 beenperformed in Southeast Asia using various colloid andcrystalloid solutions to resuscitate children with dengue

shock in the first hour after presentation to the emergencydepartment [20, 21, 22, 23]. Using the principles firstoutlined by OShaughnessy, Latta, and Blalock, the vastmajority of these patients were recognized as being inshock and treated while they had tachycardia and narrowpulse pressure, rather than after the onset of hypotension.Fluid resuscitation directed at establishing normal heartrate, 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 thedeveloping world that do not have universal access tomechanical ventilators has also been investigated in

a variety of etiologies. In two studies from two differenthospitals in India, mixed populations of children withbacterial septic shock or dengue shock associated withhypotension were examined. In one study children had30% mortality with crystalloid or colloid resuscitationand inotropic support [29]. The other study demonstratedthat implementation of a fluid removal regimen using di-uretics and, in some cases, continuous peritoneal dialysismarkedly reduced this mortality in children by reversingfluid overload [30]. (Of note, we similarly used diureticsand, occasionally, peritoneal dialysis in fluid-overloadedpatients in our clinical report of aggressive fluid resusci-tation [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 noticedthat children who died of severe malaria, similar tothe findings of Blalock, first developed tachycardia andacidosis before hypotension [32, 33]. They noted that thechildren who were resuscitated with fluid had better out-comes than historical controls. In a follow-up, randomized

controlled trial these investigators also found that albuminresuscitation reduced mortality to 4%, compared with 18%in those resuscitated with saline [19]. Now, at some levelof severe anemia, children resuscitated with fluids otherthan blood will be expected to do poorly. For example,fluid-induced dilution of hemoglobin concentration mayreduce oxygen delivery more than the fluid-inducedincrease in stroke volume increases oxygen delivery[oxygen delivery = cardiac output (heart rate strokevolume)Oxygen content (1.36Hgb g/dl% oxygensaturation + paO2 0.003)]. The efficacy of albuminresuscitation in some studies (see above) suggests thatpatients are not dying from severe anemia, but rather from

hypovolemic shock. Albumin may have been beneficialdue to low oncotic pressure in these children. It is alsopossible that albumin may be preferred in septic shock inadults as well. In the SAFE trial, crystalloid was associatedwith improved survival from traumatic shock, but in thealbumin-treated group there was a trend to better outcomein septic shock (p = 0.05) [34].

In summary, the historical clinical studies and recentpediatric experience indicate that fluid resuscitation shouldbe given in a time-sensitive manner and directed towardthe goal of improved stroke volume as evidenced by thefollowing clinical signs: return to normal heart rate, capil-lary refill < 2 s, peripheral pulses, and blood pressure, as

well as correction of hemoglobin concentration, and supe-rior vena cava saturation > 70%. Patients who do not re-spond to fluid resuscitation alone commonly benefit fromaddition of inotropic therapy to overcome cardiac dysfunc-tion; sometimes, they will also require hydrocortisone foradrenal insufficiency [15]. If fluid overload occurs (as evi-dencedby the clinical signs of respiratory rales, wet cough,or hepatomegaly), then diuretics should be used. In caseswhere fluid overload is resistant to this therapy, dialysis orhemofiltration techniques will be required. The guidelinereported by Boluyt and colleagues [6] in this issue ofIn-tensive Care Medicine provides us with additional, system-atic recommendations on the initial choice of resuscitationwith crystalloid.

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