acceso vascular y medicamentos en rcp

8/7/2019 Acceso Vascular y Medicamentos en Rcp

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Vascular Access and Drug Therapy

in Pediatric Resuscitation

Allan R. de Caen, MDa,*, Amelia Reis, MDb,Adnan Bhutta, MBBSc

aDivision of Pediatric Critical Care, University of Alberta, 3A3.06 Walter C. MacKenzie

Health Sciences Centre, 8440 112 Street, Edmonton, AB T6G 2B7, CanadabDepartamento de Pediatria, Faculdade de Medicina da Universidade de Sao Paulo,

Sao Paulo, BrazilcDivisions of Pediatric Cardiology and Critical Care Medicine, University of Arkansas

for Medical Sciences, Little Rock, AR, USA

In up to 50% of pediatric cardiopulmonary arrests, return of spontane-

ous circulation (ROSC) can be established with chest compressions and ven-

tilation alone [1]. However, timely delivery of resuscitation drugs may still

be necessary to restore a perfusing rhythm in some patients. For resuscita-

tion drug therapy to be successful, it must be superimposed on effective

basic life support (chest compressions and ventilation). In this article, the

common drugs used in pediatric resuscitation and the evidence supporting

their use are presented.

Intraosseous and tracheal access/drug delivery during resuscitation

Drug administration typically requires venous access, but establishing ve-

nous access in the critically ill child can be difficult and time consuming. Alter-

native approaches for emergent venous access, such as central line placement

or venous cutdown, have a poor success rate or take a significant amount of

time, especially in younger children [2,3]. A prospective study of dehydrated

children presented to the Indian Emergency Department randomized children

to either intraosseous (IO) or peripheral intravenous placement for venous ac-

cess [4]. IO placement was faster and more likely to be successful.

IO needle placement is increasingly documented for emergent venousaccess in patient ages ranging from premature infants to adults [58].

* Corresponding author.

E-mail address: [email protected] (A.R. de Caen).

0031-3955/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.pcl.2008.04.009 pediatric.theclinics.com

Pediatr Clin N Am 55 (2008) 909927
mailto:[email protected]://www.pediatric.theclinics.com/http://www.pediatric.theclinics.com/mailto:[email protected]


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Although umbilical venous access may be preferable for the newborn infant,

not all small (often ex-premature) infants can have venous access established

via this route. Some bench studies suggested that IO placement may be evenfaster than umbilical catheterization, at least in the hands of less experienced

neonatal care providers [9].

New IO devices are now available for use in adolescents and adults.

Traditionally, it was difficult to access the marrow space across the thick

bony cortex. Case series of adults describe the use of spring-loaded IO nee-

dles (the BIG or Bone Injection Gun (Fig. 1), Waismed, Yokneam, Israel

[5]); battery-powered hand-held drills (the EZ-IO (Fig. 2), VidaCare Corpo-

ration, San Antonio, Texas [6]); or sternal screw devices (the FAST-1, Pyng

Medical Corporation, Vancouver, Canada [7]).The FAST-1 is used specifi-cally for sternal vascular access and is marketed only for use in adults. The

BIG is marketed for placement in the proximal tibia or proximal humerus.

The EZ-IO can be used in all of the same sites as the traditional IO needle.

Complications of the new devices are similar to the traditional IO needle.

They include needle displacement, compartment syndrome, and infection.

Advantages of one type of IO needle over another are still subjective and

based on user preference. Bench studies failed to demonstrate a clinically

significant advantage for a specific device, such as time to placement or

rate of successful placement. There is still no convincing objective data sup-porting the superiority of any of these newer IO devices over the traditional

IO needle [5]. A major limitation to the use of the newer IO devices may be

cost, as they are expensive. The BIG is a single deployment device and can-

not be re-sited or repositioned after initial placement.

Endotracheal drug therapy has long been considered a useful route for

drug delivery to the critically ill child when conventional venous access is

not available [10]. There are concerns from recent studies that the efficacy

of lidocaine, epinephrine, atropine, and naloxone (LEAN drugs) when given

Fig. 1. The Bone Injection Gun. (Courtesy ofWaisMed Ltd., Hertzelia, Israel; with permission.)

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endotracheally may be suboptimal, and that the potential for side effects

may be increased with tracheal dosing.The absorption of endotracheal drugs is erratic and inconsistent [11,12]. To

reach therapeutic plasma concentrations of epinephrine, tracheal dosages on

the order of 10 times that of intravenous dosages must be given [13]. The lack

of clinical efficacy seen in human studies of tracheal epinephrine may stem

from using dosages insufficient to reach therapeutic plasma concentrations

[12,14]. Larger tracheal dosages of other LEAN drugs are also necessary.

Atropine requires 1.5 times (0.03 mg/kg) the usual intravenous dosage [15],

while lidocaine requires at least twice the standard intravenous dosage [16].

The use of small dosages of tracheal epinephrine can paradoxically bedetrimental. Animal studies showed that systemic absorption of tracheal

epinephrine dosages of less than 0.05 mg/kg can lead to predominantly

b-adrenergic effects. This action produces systemic vasodilation and reduced

diastolic pressures, and consequently a potential for reduced coronary per-

fusion pressures [17]. As coronary perfusion pressure is known to be a surro-

gate for likelihood of resuscitation from cardiac arrest, the use of a drug

dose that might reduce coronary perfusion pressure is counterintuitive. In

light of the unpredictable nature of tracheal drug absorption, this raises con-

cerns regarding the suitability of using this route of drug delivery while otherroutes of venous access, including IO, might be available.

Endotracheal naloxone was judged efficacious based on a single animal

study and one published human case report [18,19]. The necessary dose

was extrapolated from current IV dosing guidelines. If timely and reliable

delivery of this drug is necessary, dosing by an alternative venous access

routes (ie, IO) may be preferable.

Fig. 2. The EZ-IO. (Courtesy of VidaCare Corporation, San Antonio, TX; with permission.)

911DRUG THERAPY IN PEDIATRIC RESUSCITATION


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Intrapulmonary depot effects have been described when some resuscita-

tion drugs are given intratracheally. Tracheal epinephrines prolonged phys-

iologic half-life can cause sustained tachycardia and hypertension. This hasthe potential to cause a more sustained increase in afterload and metabolic

demands on an already compromised heart when ROSC is achieved. Tra-

cheal atropine can also cause prolonged tachycardia [13,20].

Epinephrine

Epinephrine is an endogenous catecholamine and a potent sympathomi-

metic agent, which is a nonselective adrenergic agonist stimulating the a- and

b-adrenergic receptors, although the degree of stimulation of these receptorsdepends on its circulating concentration [21]. At low doses, epinephrine has

predominantly b-adrenoreceptor agonist activity resulting in increased heart

rate (b1), widening pulse pressure (arteriolar vasodilatation from b2 activity),

and increased plasma glucose, lactate, glycerol and b-hydroxybutyrate con-

centrations with an initial decrease in plasma insulin concentration. How-

ever, the a-adrenergic effects predominate when higher doses are used [22,23].

In cardiac arrest, the a-adrenergic activity is used to increase the aortic

diastolic pressure. Animal models suggest that increased diastolic pressure

is a predictor of improved survival after cardiac arrest [24,25]. Improved di-astolic pressure is caused by the prevention of arterial collapse and intense

vasoconstriction in the peripheral vascular beds with preservation of blood

supply to essential vascular beds, including the coronary and cerebral vessels

[26]. The increased perfusion pressure from epinephrine increases cerebral

and coronary blood flow, resulting in improved cardiac function and elec-

troencephalographic activity leading to ROSC [26]. As the duration of car-

diac arrest increases, the use of epinephrine becomes increasingly important

for establishing ROSC [27]. In a global ischemia ventricular fibrillation (VF)

model, epinephrine improved the passive properties of conduction and ar-rhythmia organization, reduced arrhythmia rate, and increased its spontane-

ous termination [28]. However, with increased duration of cardiac arrest, the

myocardial dysfunction associated with epinephrine also increased [29]. The

increase in myocardial dysfunction is thought to result from its b1-receptor

action and subsequent imbalance between myocardial oxygen supply and

demand [29,30].

The 2005 American Heart Association Guidelines for Cardiopulmonary

Resuscitation and Emergency Cardiovascular Care (2005 AHA guidelines)

guidelines for cardiopulmonary resuscitation and emergency cardiovascularcare recommend using 10 mg/kg of epinephrine for children in pulseless car-

diac arrestdpulseless VF, pulseless ventricular tachycardia, pulseless electri-

cal activity (PEA), or asystoledfor the first and subsequent intravascular or

IO doses [31]. Epinephrine is also useful as a continuous infusion in symp-

tomatic bradycardia with hypotension. When intravascular or IO access

is not available, and in the presence of an endotracheal tube, a dose of

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100 mg/kg should be administered via the tracheal route for the reasons de-

tailed previously [31]. Epinephrine is available in two different concentra-

tions: 0.1 mg/mL [1:10,000] (10 mL) and 1 mg/mL [1:1000] (1 mL).Some animal studies suggested that intravenous epinephrine in the range

of 100 mg/kg resulted in higher cerebral and coronary blood flow compared

with standard doses of 10 mg/kg, leading to improved outcomes [3236].

However, other animal studies showed a detrimental effect of high-dose epi-

nephrine on hemodynamics and neurologic outcomes [3740].

The use of high-dose epinephrine was reported in some pediatric and adult

case reports and case series, which showed increased rate of ROSC, survival to

admission, and survival to discharge [4143]. This beneficial effect of high-

dose epinephrine was not duplicated in case-control studies in children andadults [4446]. Several large randomized, controlled trials in adults also

showed no benefit of using higher dose epinephrine compared with standard

dose [4751]. The only benefit noted in some randomized controlled trials

was an increase in ROSC and rate of hospital admission but there was no dif-

ference in the rate of hospital discharge or neurologic outcomes [43,52,53].

A meta-analysis of five prospective randomized, double-blinded clinical

trials that enrolled adults with out-of-hospital cardiac arrest was conducted

by Vandycke and Martens [54]. They reported an overall Odds Ratio (OR)

in favor of high-dose epinephrine of 1.14 (1.021.27) for ROSC. Of note,although the OR for hospital admission slightly favored high-dose epineph-

rine (1.03; 95% confidence interval 0.861.24) the OR for hospital discharge

was 0.74 (0.531.03), almost reaching statistical significance for an adverse

effect of high-dose epinephrine.

A pediatric prospective, randomized, blinded trial conducted by Perondi

and colleagues [55] compared high-dose epinephrine (100 mg/kg) with stan-

dard-dose epinephrine (10 mg/kg) as a rescue therapy for in-hospital pediat-

ric cardiac arrests after failure of the initial standard epinephrine dose.

Thirty-four children were recruited in each arm of the study. In the high-dose group, 1 of the 34 patients survived 24 hours while 7 of the 34 patients

survived to 24 hours in the standard-dose group (unadjusted OR 8.56 with

95%CI, 1.0397.0; P .05). The two treatment groups did not differ in the

rate of ROSC (20/34 versus 21/34). Survival to hospital discharge was 0/34

in high-dose group and 4/34 in standard-dose group.

Another multicenter randomized clinical trial in out-of-hospital pediatric

arrest conducted by Patterson and colleagues [56] did not reveal any benefit

of using high-dose epinephrine compared with standard-dose epinephrine.

There were no differences in ROSC, 24-hour survival, or neurologic out-comes. However, this study was not able to recruit the number of patients

needed to achieve statistical significance based on their power analysis.

Based on the available evidence in children, the routine use of high-dose

epinephrine via the intravascular route is not recommended and may be

harmful, particularly in cardiac arrest secondary to asphyxia. However,

high-dose epinephrine may be used in certain clinical situations characterized



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by poor response to catecholamines, such as calcium channel blocker or

b-blocker toxicity [57].

Calcium

Ionized calcium is essential for myocardial electromechanical coupling,

myocardial contractility, impulse formation and conduction, and the main-

tenance of vascular tone. Increasingly severe ionized hypocalcemia is seen

with prolonged cardiopulmonary arrest, its cause being unclear [58]. Studies

have been unable to draw a direct association between ionized calcium con-

centration and patient outcome in cardiopulmonary arrest [59].

Correction of a low ionized calcium concentration may increase systemicvascular resistance, blood pressure, and cardiac output; however, these im-

provements may be transient. The literature is inconsistent in documenting

an inotrope-sparing effect when hypocalcemia is corrected. Calcium over-

load, conversely, may blunt the effects of adrenergic drugs. Animal studies

from the 1980s showed that intracellular calcium accumulation is a final

mediator of cell injury/death associated with post-ischemic tissue reperfu-

sion. Studies also suggested that the use of calcium channel blockers would

reduce myocardial or cerebral injury after reperfusion, although none of

these animal studies was ever reproducible in human studies.Although calciums use in cardiopulmonary resuscitation (CPR) was first

described in the early 1900s, it was a small pediatric case series by Kay and

Blalock [60] that formally established its role in cardiac life support. Almost

all studies of calcium in CPR performed since that time have excluded children.

The study of calcium chlorides role in treating VF cardiac arrest is

limited; a single small retrospective study of prehospital adult VF failed

to demonstrate any benefit from the use of calcium chloride [61].

In a study investigating the treatment of PEA in a canine model of

asphyxial cardiac arrest, the use of calcium chloride failed to demonstrateany benefit over saline placebo in ROSC [62]. Two retrospective studies of

prehospital adult cardiac arrest from the 1980s examined the use of intrave-

nous or intracardiac calcium chloride in the treatment of PEA, but failed to

demonstrate any survival benefit [61,63]. A small prospective randomized

and blinded trial compared calcium chloride to saline placebo for adult pre-

hospital PEA cardiac arrest that was refractory to epinephrine and NaHC03therapy (n 90) [64]. There was no difference between groups in the rate of

survival to hospital admission, although post hoc analysis of presenting

rhythms suggested that those patients with QRS-complex durations greaterthan 0.12 might benefit from treatment with calcium chloride (increased

likelihood of ROSC). Unfortunately, only 1 out of the 90 patients in the

study survived to hospital discharge. Follow-up studies investigating bene-

fits to such subgroups have never been undertaken.

These small but disappointing prospective studies of calcium chloride use

in asystolic and PEA cardiac arrest led to limiting the role of calcium

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therapy in cardiopulmonary arrest to those patients with documented hypo-

calcemia, calcium channel blocker overdose, hypermagnesemia, and hyper-

kalemia. Despite these recommendations in the Guidelines 2000 forCardiopulmonary Resuscitation and Emergency Cardiovascular Care [65], a r e -

cent study [66] of the National Registry of Cardiopulmonary Resuscitation

(NRCPR) database showed that the use of calcium chloride in pediatric car-

diac arrest resuscitation continues to be common (45% of events), especially

in pediatric tertiary care institutions (Vinay Nadkarni, MD, personal commu-

nication, December 2007). Despite this, its use is associated with decreased

survival to hospital discharge, and is not associated with favorable neurologic

outcome; even with adjustment for confounding factors.

Magnesium

The magnesium ion is intimately involved with myocardial function and

has electrophysiologic effects that led to its use in the treatment of cardiac

arrhythmias, particularly those resulting from hypomagnesemia or in

Torsades de Pointes tachycardia. Possible benefits to magnesium therapy

during cardiac arrest include vasodilation; coronary vasodilation may im-

prove myocardial perfusion. However, systemic vasodilation following mag-

nesium administration potentially decreases aortic diastolic pressure, andthus coronary perfusion pressure, and may decrease ROSC in the clinical

setting [67].

Serum magnesium levels may change during resuscitation, and may be

associated with resuscitation outcomes. In a canine model of VF, a decrease

in serum magnesium was observed after defibrillation, although it was not

significantly different from controls [68]. Prospective and retrospective adult

cardiac arrest studies report that a normal serum magnesium level is associ-

ated with a higher rate of successful resuscitation. Canon and colleagues [69]

found abnormal serum magnesium levels during resuscitation of 59% oftheir patients; none of these patients survived, while 44% of the patients

with normomagnesemia were successfully resuscitated. Buylaert and col-

leagues [70] observed an abnormal magnesium level in 41% of patients

with out-of-hospital cardiac arrest. The percentage of survivors that were

conscious by day 14 postresuscitation was 52%, 33% and 23% in patients

with normal, hypo- and hyper- magnesium levels respectively. There is no

related pediatric data.

Two animal studies investigated the effect of magnesium administration

before cardiac arrest on outcome. Siemkowicz [71] observed that MgSO4given before or early during hypoxia-induced cardiac arrest improved car-

diac resuscitation from 15% to 100%. Proposed mechanisms included mag-

nesiums antiarrhythmic action during reperfusion, the promotion of

ventricular bradycardia, and the prevention of VF and asystole. Hollmann

and colleagues [72] investigated whether magnesium, calcium, or their com-

bination could protect against hyperkalemic cardiac arrest. There were no



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differences in survival times between experimental groups and control

(saline).

Case reports suggested an association between the administration ofmagnesium during cardiac arrest and improved survival in adults with re-

fractory or prolonged cardiac arrest. Studies investigated whether magne-

sium sulfate administered during resuscitation for adult cardiac arrest

improves outcome [7375]. None demonstrated an increased likelihood of

ROSC, hospital discharge rate and neurologic outcome, but there was

a trend toward increased rates of hypotension after ROSC, and a reduction

in aortic pressure during resuscitation.

A randomized control trial studied whether magnesium sulfate or diaze-

pan, given immediately following resuscitation of out-of-hospital adultcardiac arrest affected patient outcome [76]. No improvement was noted

in the percentage of patients awakening postresuscitation.

The available data fails to show a significant difference in any survival

endpoint in patients receiving MgSO4 before, during or after cardiopulmo-

nary resuscitation. Limitations of the data cited include the administration

of varied doses of MgSO4, and its use in a variety of cardiac arrest rhythms.

Moreover, as with other therapies in cardiac arrest, it is often difficult to

demonstrate any statistically significant treatment benefit in a study popula-

tion with such a poor prognosis.

Atropine

Atropine is a naturally occurring anticholinergic agent that counteracts

the reduction in heart rate mediated by the parasympathetic nervous system

[77]. Its principal use in resuscitation is in the treatment of vagally mediated

bradyarrhythmias, such as seen during attempted intubation [78,79]. Brady-

cardia remains one of the most common rhythm disturbances during inpa-

tient cardiac arrest [80].The 2005 AHA guidelines [57] recommend the use of transcutaneous pac-

ing for bradycardia associated with poor perfusion, but atropine may be

used while awaiting the commencement of pacing. The recommendation

to use atropine to temporarily increase the heart rate is based on adult stud-

ies that showed improvement in heart rate in patients with symptomatic bra-

dycardia [79,81,82]. Atropine may also be considered in asystole or slow

PEA. However, for patients with type II second degree or third degree

AV block, transcutaneous pacing remains the mainstay of resuscitation

[57]. The intravascular dose of atropine is 0.02 mg/kg with a minimumdose of 0.1 mg and a maximum dose of 0.5 to 1 mg in children, adolescent,

and adults. Atropine can also be administered via an endotracheal tube but

with a higher dose of 0.03 mg/kg [57]. The doses may be repeated to a total

dose of 3 mg [57,78,83]. Higher doses of atropine may be required in special

resuscitation situations, like organophosphate poisoning (0.05 mg/kg, up to

a maximum single dose of 2 mg).

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Sodium bicarbonate

The use of sodium bicarbonate during pediatric cardiopulmonary resus-

citation has been discouraged since 1986 because of a lack of evidence of

benefit, and concerns regarding possible harm. There is little data that sup-

ports the use of sodium bicarbonate during adult cardiac arrest, and no sub-

stantive data to support its use in the resuscitation of children in cardiac

arrest. Pediatric recommendations were extrapolated from animal and lim-

ited adult data.

Many animal models of cardiac arrest demonstrated benefit with the use

of bicarbonate or other buffers on early ROSC, post resuscitation myocar-

dial function and neurologic outcome [8486]. These results were difficult to

replicate potentially because of differences in the models used and study

designs [87,88].

A retrospective study examining the use of bicarbonate during adult car-

diac arrest observed a better prognosis when bicarbonate was used earlier

and improved rates of ROSC, hospital discharge and long-term neurologic

outcome [89]. Other retrospective uncontrolled trials studying similar end-

points were unable to replicate these results [90]. The lack of benefit from

NaHCO3 in some studies could be because its use is a surrogate for pro-

longed cardiac arrest and resuscitation attempts, and therefore is associated

with a worse outcome.

Adverse effects have been associated with bicarbonate administration in

some adult and experimental studies. Bicarbonate may decrease systemic

vascular resistance and lead to reduced coronary perfusion pressure [91].

This was not observed when epinephrine was administered before bicarbon-

ate dosing or when the dose of bicarbonate was w1 mEq/kg [84,92,93].

Excessive sodium bicarbonate doses may impair tissue oxygen delivery in

states of normal perfusion [94], although this has not been documented in

cardiac arrest models [84]. Hyperosmolality and hypernatremia may be

induced depending on the amount of bicarbonate given; however, retrospec-

tive studies have not reported significant increases in serum sodium concen-

tration when recommended doses of NaHCO3 are given [90,95]. In an

experimental study that used massive bicarbonate doses, increased intracel-

lular acidosis resulted [96]. This observation has not been duplicated in

other cardiac arrest models [87,97,98].

Routine sodium bicarbonate administration does not consistently im-

prove cardiac arrest outcome [85]. Respiratory failure is the leading cause

of cardiac arrest in children; sodium bicarbonate use in this setting may

worsen existing respiratory acidosis. Current AHA pediatric resuscitation

guidelines recommend that sodium bicarbonate during cardiac arrest should

be considered only for those children with prolonged cardiopulmonary

arrest, and only after good basic life support (ventilation, oxygenation,

and effective chest compressions) and vasopressor therapy have been pro-

vided [57]. Other potential indications for sodium bicarbonate use in



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pediatric resuscitation are severe metabolic acidosis with effective ventila-

tory support; and to treat hyperkalemia, hypermagnesemia, tricyclic antide-

pressant, and sodium channel blocker poisoning [99,100].

Glucose

The role of glucose in altering the outcome of cardiac arrest is controver-

sial, and there is limited human data, especially in children. Current pediat-

ric recommendations are extrapolated from animal and human adult

studies.

When studied in animal models, the impact of hyperglycemia precardiac

arrest suggests an association with worsened neurologic and survival out-comes [101103]. In some of these animal studies, however, the plasma glu-

cose concentrations were extremely elevated compared with those seen more

commonly surrounding human pediatric cardiac arrests, making it difficult

to compare results. At least two experimental studies, however, found no

differences in resuscitation times when comparing hyperglycemic and nor-

moglycemic animals [101,102]. This suggests that hyperglycemia precardiac

arrest alone may not delay or impede the ROSC. As it is difficult to predict

the exact timing of a human cardiac arrest, the design of prospective human

studies to evaluate the impact of hyperglycemia precardiac arrest on out-come is impractical. The available animal data suggests that hyperglycemia

before cardiac arrest in critically ill children could adversely affect outcome.

The data from studies investigating the effects on patient outcome of

intraresuscitation blood glucose levels is contradictory. A retrospective

study in adults evaluated blood glucose levels during out-of-hospital CPR

[104]. It demonstrated a positive association between glucose levels and

duration of resuscitation. Nonsurvivors had a steeper rise in glucose concen-

tration during resuscitation, and glucose levels that were significantly higher

than in patients who survived to hospital admission (P!.001). This studysuggests that hyperglycemia could merely be an indirect measure of duration

of resuscitation.

Retrospective studies of adults with out-of-hospital cardiac arrest

[105109], which addressed hyperglycemia postresuscitation, demonstrated

an association of elevated blood glucose at hospital admission (postresusci-

tation) with poor neurologic and survival outcomes. Conversely, one pro-

spective study [104] could not rule out the effect of confounding factors,

such as duration of resuscitation. Also, one case series [110] observed that

blood glucose increases with duration of resuscitation, but the concentrationwas not correlated with neurologic outcome following cardiac arrest. Some

clinical studies suggested after multivariate analysis that the poor neurologic

outcome in victims of cardiac arrest is associated with hyperglycemia itself,

not just an epiphenomenon [105,108]. Another recently published adult

study analyzed the blood glucose levels at 12 hours after ROSC and found

a nonlinear association between hyperglycemia and neurologic recovery

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over 6 months, even after adjustment for other variables [111]. Prospective

studies are needed to determine the potential benefits of specifically avoiding

or treating hyperglycemia following cardiac arrest, and to distinguish theassociation versus causality of serum glucose concentration on outcome.

Studies have examined the association on patient outcome of the dextrose

content of fluid given during resuscitation. Results of animal studies are

conflicting, concluding that the use of dextrose-containing solutions during

cardiac resuscitation may [101] or may not [112] result in neurologic injury.

A randomized human trial compared the neurologic outcome from out-of-

hospital cardiac arrest in adults who received either 5% dextrose solution

(D5W) or half normal saline during and after resuscitation [113]. No signif-

icant survival or neurologic outcome differences were noted between thegroups. According to this trial there is insufficient evidence to suggest that

the administration of D5W following cardiac arrest worsens neurologic out-

come in humans.

As the literature is controversial in adults and nonexistent in children, it is

advised that caution should be taken in using glucose after resuscitation

from cardiac arrest. Documented postarrest hypoglycemia should be cor-

rected. It is probably important to reduce high blood glucose levels after car-

diac arrest, but this glucose control does not have to be strict [111]. It is

unclear from available human data whether postresuscitation hyperglycemiashould even be treated, let alone whether this treatment should be done by

limiting sugar intake or by the use of insulin therapy. Prospective studies are

needed to determine the potential benefits of avoiding or treating hypergly-

cemia following pediatric cardiac arrest.

Vasopressin

Vasopressin is an exogenous, parental form of the antidiuretic hormone(ADH) [114]. It exerts its action via action on the V1a, V1b, and V2 recep-

tors. The main cardiovascular effect of vasopressin is vasoconstriction in

multiple vascular beds, including the coronary circulation, mediated by its

action on the V1a receptor. Interest in vasopressin during CPR stems from

a 1992 study by Lindner and colleagues [115], which showed that survivors

of resuscitation had higher levels of stress hormones during CPR compared

with nonsurvivors. The hormones measured during CPR included adreno-

corticotropin, cortisol, renin, and vasopressin.

A series of animal studies followed, which are well summarized byBiondi-Zoccai and colleagues [116] in a meta-analysis. This meta-analysis

showed that in animal models of cardiac arrest, vasopressin was superior

to placebo (93% versus 19%, P!.001) and epinephrine (84% versus

59%, P!.001) in establishing ROSC. Subgroup analysis showed that the

animals with cardiac arrest caused by VF who received vasopressin had a sig-

nificantly higher ROSC compared with those who received epinephrine



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(87% versus 53%, P!.001), but vasopressin was not significantly superior

for non-VF cardiac arrest (75% versus 49%, P .16).

Multiple adult human trials have been performed. Stiell and colleagues[117] conducted a randomized trial of 200 hospitalized adults who were

given a vasopressin or epinephrine injection followed by subsequent doses

of epinephrine. No differences were noted in ROSC, survival to hospital dis-

charge, or neurologic function between the epinephrine and vasopressin

study groups. In another clinical trial reported by Lindner and colleagues

[118], vasopressin was compared with epinephrine in 40 patients with out-

of-hospital shock-refractory VF. This double-blinded study found a trend

toward survival (35% versus 70%, P .06) in vasopressin treated patients.

Survival at 24 hours was superior in the vasopressin treated patients (60%versus 20%, P .02), but was not significantly different at hospital dis-

charge (15% versus 40%, P .16). No significant differences were noted

in neurologic outcomes.

In 2004, Wenzel and colleagues [119] reported results of a large, multicen-

ter randomized clinical trial in adults that compared two injections of 40 units

of vasopressin (n 589) or of 1 mg of epinephrine (n 597) in adults with

out-of-hospital cardiac arrest. The primary endpoint was survival to hospital

admission, and the secondary endpoint was survival to hospital discharge.

There were no significant differences in the rates of hospital admissionbetween the vasopressin group and the epinephrine group either among

patients with VF (46.2 percent versus 43.0 percent, P .48) or among those

with PEA (33.7 percent versus 30.5 percent, P .65). Among patients with

asystole, however, vasopressin use was associated with significantly higher

rates of hospital admission (29.0 percent, versus 20.3 percent in the epineph-

rine group; P .02) and hospital discharge (4.7 percent versus 1.5 percent,

P .04). The investigators also noted that in a subgroup of 732 patients

who did not have ROSC with the first dose of study drug and received a sub-

sequent dose of epinephrine based on the study protocol, a significantlyhigher number of patients who initially received vasopressin had a higher

ROSC and rate of hospital admission and discharge, but there was no differ-

ence in the neurologic outcomes of the survivors between the two groups.

A subsequent randomized, placebo-controlled study by Callaway and col-

leagues [120], however, showed that vasopressin and epinephrine adminis-

tered together did not increase the rate of spontaneous circulation.

Three meta-analyses have analyzed the results of these studies and

all three conclude that there is no clear benefit of using vasopressin over

epinephrine [121123].The only published pediatric experience with vasopressin in cardiac arrest

consists of two small case series. The first reported ROSC in four out of six

CPR events in which vasopressin (0.4 IU/kg) was administered after initia-

tion of conventional CPR and administration of at least two doses of epi-

nephrine. Two patients survived to 24 hours and one patient survived to

discharge [124]. The other case series used terlipressin, a long-acting analog

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of vasopressin, in seven children with asystole. ROSC was achieved in five

children and survival to discharge was reported in four of these children

[125].The 2005 AHA guidelines for cardiopulmonary resuscitation and emer-

gency cardiovascular care do not recommend for or against the use of vaso-

pressin in pulseless pediatric cardiac arrest [31]. It is part of the advanced

cardiac life support pulseless cardiac arrest algorithm in which 40 IU given

IV/IO can replace the first or second dose of epinephrine [57].

Summary

There is insufficient high-quality literature to generate strong evidence-based guidelines for the use of many drugs in pediatric cardiopulmonary

resuscitation. Interpretation of the available data is further complicated

by limitations in study design (eg, poorly defined study groups, absence of

appropriate control groups, underpowered single-center studies). Many

treatment recommendations were historically extrapolated from nonpediat-

ric models (animal, mannequin, or adult), or across injury models (eg, is the

best treatment of fibrillatory cardiopulmonary arrest the most appropriate

intervention for asphyxial cardiopulmonary arrest?). Inconsistency in study

endpoints further obscures interpretation of the available data (eg, does anincreased likelihood of ROSC matter if there is no difference in survival to

hospital discharge?). Many of these challenges are slowly being corrected

with the use of clearer definitions (ie, Utstein-based), multicenter trials,

and large national and international CPR registries (eg, NRCPR).

Our ability to generate evidence-based guidelines is further limited by the

absence of placebo-controlled trials to show that any of these drugs actually

demonstrate benefit over good basic life support alone. In addition, many of

the landmark trials that we base our treatment recommendations on were

performed at a time when the importance of what we now recognize asgood basic life support interventions (appropriate chest-compression rate

and depth, minimal interruptions, and avoidance of hyperventilation)

were not consistently monitored or applied. Instead, greater emphasis was

placed on what drug or dose of drug was delivered to a specific patient.

This has prompted many in the resuscitation science community to wonder

whether these landmark resuscitation drug trials (regardless of whether they

had positive or negative treatment outcomes) need to be repeated while

incorporating good 2005 AHA guidelines basic life support as the founda-

tion for study and control groups.The take-home message is that although we use the current treatment rec-

ommendations as the best guide to the use of drugs in the resuscitation of

children, more and better science is needed (and is coming) to support

more robust treatment recommendations. The hope is that many of the

unknowns will be further clarified by the time the next treatment guidelines

are disseminated in 2010.



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