Chapter 17 / Drug Delivery During CPR

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Principles of Drug Delivery

During CPR
Edgar R. Gonzalez, PharmD, FASHP,
Joseph A. Grillo, PharmD,
Lih-Jen Wang, MS, PharmD, BCPS,
and Jeffrey Rosenblatt, PharmD
CONTENTS
INTRODUCTION
PHARMACOKINETIC CONSIDERATIONS IN CARDIAC ARREST
BIOAVAILABILITY AND BINDING TO THE SITE OF ACTION
ALTERATIONS IN BIOTRANSFORMATION DURING CPR
PHYSIOLOGICAL APPROACH TO OPTIMAL DRUG DELIVERY DURING CPR
SUMMARY
REFERENCES

INTRODUCTION
The time from onset of cardiopulmonary arrest until restoration of an effective, spontaneous circulation is the single most important determinant of long-term, neurologically
intact survival from cardiopulmonary arrest. Prompt defibrillation of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT), when either rhythm is present, is
more likely to alter patient outcome than is immediate pharmacological management (1).
However, treatment with pharmacological agents is frequently required in patients with
VF or VT that is refractory to electrical countershocks, and in patients with asystole or
pulseless electrical activity (PEA).
Because patients who require drug therapy during cardiopulmonary rsuscitation (CPR)
often have a poor clinical outcome, there is some skepticism regarding the value of drug
therapy during CPR (2,3). The limited success observed following drug therapy during
CPR may result from interventions that are administered too late or that are administered
under suboptimal conditions (4). The use of pharmacological agents during resuscitation
must frequently proceed without adequate knowledge of the patients history, preexisting
conditions, or current medications. The interval prior to initiation of resuscitative efforts
may be highly variable or may not be known with precision. Problems with vascular
From: Contemporary Cardiology: Cardiopulmonary Resuscitation
Edited by: J. P. Ornato and M. A. Peberdy Humana Press Inc., Totowa, NJ

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access may delay initial drug administration, and the delivery of drugs to their target
end organs may be compromised by the poor blood flow generated during closed-chest
compression.
The biological actions of drugs given during resuscitation may be altered by acidosis,
hypoxemia, down-regulation of receptors, target end-organ damage, impaired metabolism and excretion, and drug interactions. We know that the pharmacokinetic properties
and the pharmacodynamic response of drugs may be altered by the presence of
hypoperfusion, hypoxia, and acidosis during cardiac arrest (CA). Although we lack
concrete information describing the pharmacokinetic and pharmacodynamic profile of
drugs in this setting, information obtained from animal models and clinical studies in the
area of CPR has increased our understanding of the delivery and absorption of medications during CPR. Today, the theory that corpora non agunt nisi fixata (substances only
act when they are linked to their site of action) is essential in understanding why drugs
may fail to produce their desired effect during CPR and advanced cardiac life support
(ACLS). This chapter discusses the link between the administration of a drug and its
subsequent pharmacokinetics and pharmacodynamics during CPR.

PHARMACOKINETIC CONSIDERATIONS IN CARDIAC ARREST

After the administration of a drug, its efficacy and safety are maintained by selective
interaction with the pharmacological site of action coupled with the bodys normal detoxification and excretion processes to eliminate unwanted drug and its metabolites. These
dose-related events define the drugs therapeutic index and recommended dosage regimen. Apart from coupling of the drug to its endogenous pharmacological receptor, the
absorption, distribution, and elimination of the drug usually occur through passive diffusion. These processes are partly dependent of the molecular species of the drug, cardiac
output, hepatic enzymatic activity, and glomerular filtration and secretion; and may be
described by mathematical construct (i.e., pharmacokinetics) that define the agents
concentrationresponse curves.
The relationship between a drug and the body is described by its pharmacodynamic
response (i.e., the drugs effects on the body) and its pharmacokinetic properties (i.e., the
relationship between the amount of drug administered and its resultant plasma concentration over time [5]). Pharmacokinetics uses mathematical models and equations to
describe the rate processing of drugs (rate of absorption, rate of distribution from the
plasma compartment to tissues, rate of metabolism, and rate of excretion) by the body.
In clinical practice, the pharmacokinetic parameters of ACLS drugs can be described by
first-order (i.e., linear), two-compartment, pharmacokinetic models (5). Drugs enter the
bloodstream directly after intravenous administration, and distribute between the central
compartment (i.e., blood and highly perfused tissue) and the peripheral compartment
(e.g., fat and other tissue). As plasma drug concentrations increase, the rate of drug
elimination increases. Therefore, mathematical models and equations can be used to
calculate pharmacokinetic parameters, which represent the average values for the rates
of absorption, distribution, metabolism, and elimination of a drug in a given sample
population (i.e., normal volunteers). These estimates are used by the clinician to predict
the serum drug concentration after a given dose.
However, pharmacokinetics parameters derived from healthy volunteers may not
accurately predict the disposition of drugs during CPR (6).The absence of spontaneous
circulation and subsequently a dramatic fall in myocardial and cerebral blood flow

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occurs during sudden cardiac death. Studies in swines show that during closed-chest
CPR, myocardial blood flow is less than 5 mL per minute per 100 g (normal value = 40
100 mL per minute per 100 g [7,8]). Circulatory collapse causes redistribution of blood
to highly perfused organs (brain and myocardium), and alters the volume of distribution
(9). Because of the reduced blood flow and increased circulation time, the method of
drug administration also affects pharmacokinetic and pharmacodynamic profiles during
CPR (6,10).

BIOAVAILABILITY AND BINDING TO THE SITE OF ACTION

Bioavailability defines the fraction of the administered dose that reaches the systemic
circulation. During CPR, drugs must have rapid and complete bioavailability to promptly
reach their sites of action. The route of drug administration greatly influences a drugs
bioavailability. In theory, an intravenously administered drug should have 100%
bioavailability, whereas other routes of administration (e.g., oral, intramuscular, or endotracheal) may alter absorption of drugs and produce incomplete bioavailability. Therefore, during CPR, drugs should be given by intravenous bolus injection, to ensure the
highest concentration of drug in the bloodstream. Once drugs reach the bloodstream,
numerous issues affect the amount and rate of binding to the sites of action.

Lipid Solubility and Volume of Distribution

First, the lipid solubility, volume of distribution, and the size of the drugs molecular
structure affect the ability of drug to diffuse passively across cell membranes to reach the
intracellular site of action. Although cell membranes have a semi-permeable, phospholipid layer, drugs with high lipid solubility have an increased likelihood of penetrating
into the site of action. However, drugs with increased lipid solubility and low plasma
protein bindings may not reach the site of action in sufficient quantities because of a large
volume of distribution throughout the body. Volume of distribution is a pharmacokinetic
parameter that describes the proportionality of the amount of drug found in the plasma
to the total amount of drug that enters the systemic circulation. If the volume of distribution of a given drug is 500 L, then a dose 500 mg will produce in a concentration of 1 mg
per liter of blood. The 500 L exceeds the total volume of body water (i.e., 42 L); therefore,
the drug distributes extensively into tissue as well as body fluids. Drugs with large
volumes of distribution (e.g., digoxin, amiodarone) usually distribute into many tissue
compartments.
The tissue compartment of the target organ greatly impacts the dosing regimen of a
given agent. For example, lidocaine follows a two-compartment pharmacokinetic model
with the heart (i.e., the site of action) located in the initial compartment (1113). Population estimates for lidocaines distribution half-life (i.e., 810 minutes) suggest that in
a normal patient, half the concentration of drug in the initial body compartment will
redistribute to other tissues within 8 to 10 minutes after a given dose of lidocaine (11).
When lidocaine is administered during CPR, a second dose should be given no later than
8 minutes after the first dose to account for redistribution of drug away from the target
organ to other areas.
Theoretically, if a drug is to redistribute to other tissues the rate and extent of this
phenomena will depend on organ perfusion. Although organ perfusion is primarily dependent on arterial pressure, theoretically, left ventricular dysfunction or vasodilatation would
limit organ perfusion and reduce the effective volume of distribution of a given drug.

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Chandra et al. documented that within 1 minute after the onset of CA, perfusion to vital
organs is reduced to approx 25 to 50% of pre-arrest values (12). Severe hypoperfusion
explains the decrease in the volume of distribution of lidocaine into the initial compartment (0.69 0.38 L/kg vs 0.06 0.07 L/kg) and the tissue compartment (1.67 0.49
L/kg vs 0.14 0.06 L/kg) during CPR in dogs (12).
McDonald measured serum lidocaine concentrations in the peripheral blood following an intravenous dose of 1.9 mg/kg in patients undergoing CPR. The results showed
that serum lidocaine concentrations within the range of 1.64.0 mg/L (mean value = 2.3
mg/L) could be achieved approx 23 minutes after administration (14). McDonald concluded that the clearance of lidocaine from the initial compartment was reduced during
CPR in humans. McDonald suggested that a second dose of lidocaine would likely not
be necessary during CPR unless spontaneous circulation was re-established (14).
Epinephrine is the classic example of a small polar molecule that rapidly equilibrates
in the bloodstream where it binds to albumin (i.e., small volume of distribution) until it
readily attaches to adrenergic receptors inside cell membranes. Epinephrines small
volume of distribution and wide therapeutic index, explain why weight dependent dosage
adjustments are not needed during CPR. In contrast, amiodarone is a large nonpolar
molecule that slowly equilibrates in the bloodstream. It is minimally protein bound and
distributes widely throughout the body (large volume of distribution) until it reaches the
site of action, and then redistributes away from it site of action back into peripheral organs
(e.g., liver, eyes, lungs, thyroid, skin [15]).During CA, it is important to dose amiodarone
on a weight-dependent basis (i.e., 5 mg/kg/dose) to sustain adequate concentrations in the
myocardium during CPR. Furthermore, amiodarones lipid solubility explains its redistribution properties and the need to administer a constant infusion to sustain adequate serum
drug concentrations at the site of action.
Changes in plasma protein binding can also alter volume of distribution. Although
drugs bind to blood cells and plasma proteins within the circulation, only the unbound
drug can cross cell membranes to exert its pharmacodynamic effects or undergo biotransformation. Reduced plasma protein binding via displacement or alterations in binding
proteins increase the free fraction of drug and enlarge the drugs volume of distribution.
Although the effect of altered plasma protein binding on the volume of distribution of
lidocaine during CA has not yet been studied, patients with acute coronary syndromes
have increased binding of lidocaine to plasma proteins and a subsequent reduction in
volume of distribution (16,17). These changes are caused by a rise in _-1-acid glycoprotein, the primary binding protein for lidocaine. Theoretically, the total plasma lidocaine
concentration may be disproportionately elevate during CA, but the concentration of free
(active) lidocaine may be disproportionally low due enhanced _-1-acid glycoprotein
binding. Therefore, CA patients may require plasma lidocaine concentrations in the
upper range of normal to achieve a therapeutic effect.

Central vs Peripheral Intravenous Drug Administration

A second factor that affects the ability of drugs to reach sites of action during CPR is
administration via central venous access or peripheral venous access. Kuhn and coworkers studied circulation time during closed-chest cardiac compression using indocyanine
green injected in either the right antecubital vein or right subclavian vein during CPR
in six patients (18). Blood samples were obtained via right femoral artery catheters at
30-second intervals for 5 minutes following injection. Arterial blood indocyanine green

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concentrations after central venous injection revealed a high concentration of the dye at
30 seconds and an emerging second peak at 5 minutes (18). After peripheral injection,
peak dye concentrations were not achieved during the 5-minute sampling period. The
authors concluded that recovery of indocyanine green from femoral arterial blood was
significantly greater after it is administered centrally vs peripherally (18).
Talit and colleagues compared the pharmacokinetics of radioisotopes administered
via peripheral vs central venous access during resuscitation in nine mongrel dogs (19).
Bolus injection of two different radioisotopes were given simultaneously through a peripheral vein and a central vein. Isotope activity was sampled through a catheter in the femoral
artery at 5-second intervals for the first 90 seconds and at 30-second intervals for the
remaining 210 seconds. The most prominent difference between central venous and
peripheral venous injection was the difference in peak concentration of radioactive tracer.
Central venous injection produced a 270% higher peak concentration (p < 0.001) and a
significantly shorter time to peak concentration (13 + 5 vs 27 + 12 seconds, p < 0.01 [19]).
Because of the additional venous blood admixture for peripheral drug injection, this
route of administration prolonged the time to peak concentration and significantly
enlarged (p < 0.01) the central compartment volume of distribution of the radioisotope
(19). Venous admixing also explains differences in peak concentrations produced by
the two methods of intravenous administration. Although the method of intravenous
administration does not alter the absolute bioavailability, there were no significant differences in area under the concentration time curve, steady state volume of distribution,
and total body clearance. These data show that route of administration would influence
peak concentrations and time to peak concentration, but not the amount of drug ultimately
available at the site of action during CPR.
Talit and colleagues (19) work was confirmed by Keats (20) and Barsan(21) who used
animal models of CA to demonstrate that time to peak drug concentrations, peak drug
concentrations, and time to onset of biological effects for epinephrine and lidocaine were
greater after central venous administration compared to peripheral venous administration. Although survival rates drop 10% for every minute that elapses between the onset
of CPR and successful defibrillation, the benefits of central venous drug administration
during CPR are obvious because central venous drug administration shortens the lag time
to peak drug concentrations.
Reductions in total blood flow and prolonged circulatory time decrease venous return
and slow the distribution of medications from the peripheral circulation into the central
circulation. During CPR, central venous administration produces rapid delivery of drug
to the site of action when compared with peripheral drug administration (10,1924).

Dilution of Bolus Injection

The volume of fluid used to dilute and administer the intravenous bolus dose is a third
factor affecting the rate and amount of drug delivered to the central compartment during
CPR. Emerman and colleagues studied the effect of a 20-mL saline bolus flush on peak
indocyanine green dye peak concentration and circulation time in a canine CA model
(25). Circulation time and peak dye concentration were significantly improved by the
administration of a 20-mL flush following peripheral injection in this animal model. In
summary, when drugs are administered from a peripheral intravenous site during CPR,
the extremity should be elevated and a 20-mL bolus of normal saline should be given to
facilitate access of the agent to the central circulation (25).

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Endotracheal Drug Administration

Atropine, epinephrine, lidocaine, naloxone, and vasopressin may be administered
via endotracheal route when intravenous access has not been established. However, the
rate and extent of absorption of drugs following endotracheal administration offers
another example of unresolved pharmacokinetic variability during CPR. Although,
lidocaine, epinephrine, and atropine are agents that are administered routinely via the
endotracheal route, only a few clinical studies have described the pharmacokinetic
profile of drugs administered in this manner during CPR (2631). Endotracheal administration produces a lower and slightly delayed peak plasma concentration, and the
onset of action may be delayed, but the magnitude of response is similar (2831).
Differences in bioavailability between intravenous drug administration and endotracheal drug administration are explained by: (a) incomplete absorption of aerosolized
drug, (b) metabolism of drug by lung parenchymal cells (i.e., epinephrine), and (c) poor
pulmonary blood flow (32).
Administration technique and dilution volume are important to assure good
bioavailability following endotracheal drug administration (3336). Ralston and coworkers
observed that the use of a catheter to deliver drug via an endotracheal airway enhanced the
response to epinephrine (33). When epinephrine (0.2 mg/kg) was administered via an
endotracheal airway without a catheter, the drug did not increase blood pressure during
CPR. When epinephrine (0.1 mg/kg) was administered via an endotracheal airway, with
the aid of a catheter wedged deep into the bronchial tree, there was a significant increase
in blood pressure (33).
Mace confirmed the value of endotracheal drug delivery and documented the importance of doubling the dose of drug and the need to use a 1020 mL volume of dilution for
achieving the highest serum drug concentrations following endotracheal drug administration during CPR (33,34). Drug dilution is important in the delivery of drugs via an
endotracheal airway, but the question of whether sterile water (SW) or normal saline (NS)
should be the preferred remains unanswered. Greenberg and coworkers compared the
effects of endotracheally administered SW vs NS on arterial blood gases in dogs (35).
Endotracheal administration of SW significantly (p < 0.05) depressed arterial pH and
PaO2 when compared with NS. Greenberg concluded that endotracheal administration
of NS produces fewer detrimental effects on arterial blood gases when compared with
endotracheal administration of SW (35). However, these results were questioned by the
evidence produced by Hahnel, who compared the effects of SW vs NS in 12 patients who
received lidocaine via the endotracheal route (36). Serum lidocaine concentrations at 5
and 10 minutes postdose were significantly higher (p < 0.05) in the SW group (2.35 and
2.67 mg/L) when compared with the NS group (1.59 and 1.88 mg/L). The PaO2 dropped
by 60 mmHg in the NS group and by 40 mmHg in the SW group (p < 0.05). Hahnel
concluded that SW produced better absorption of lidocaine and less impairment of oxygenation than NS (36).
In summary, the dose of drug to be administered via an endotracheal tube should be
2.5 times the recommended intravenous dose. The exception is vasopressin. This drug
should be given as a 40-unit endotracheal dose (i.e., the same as the intravenous dose
[37]). The endotracheal dose should be diluted in 10-mL to 20-mL of NS or SW and
injected via a catheter that extends beyond the level of the carina. Cardiac compressions
should be halted temporarily and the dose of drug should be followed by five rapid
insufflations to disperse the drug throughout the pulmonary mucosa.

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ALTERATIONS IN BIOTRANSFORMATION DURING CPR

Biotransformation of drugs used during CPR occurs via the liver for all drugs except
epinephrine. Epinephrine is metabolized by the catechol-o-methyltransferase and
monoamine oxidase enzymes present in the circulation and the mucosa of the lungs and
the gut. Hepatic biotransformation depends the drugs intrinsic clearance rate, the fraction of unbound drug in the blood, and the rate of blood flow to the liver (38). For
lidocaine, the rate-limiting step in biotransformation is the rate of blood flow to the liver
(5). Therefore, circulatory collapse, reduces the biotransformation of lidocaine. Studies
show that during CA, hepatic blood flow markedly reduced (39). Chow and colleagues
demonstrated that the clearance of lidocaine is reduced 10-fold during closed-chest CPR
in dogs (40). A series of case reports in humans show that the elimination half-life of
lidocaine increased threefold to 6 hours during CA (40). This observations does not affect
the bolus dose of lidocaine (i.e., 1.53.0 mg/kg) because drug clearance does affect
loading dose, but it does suggest that the maintenance dose of lidocaine should be decreased
by 5075% because of circulatory shock (4144). Furthermore, if lidocaine is used in the
postresuscitation period, serum drug concentrations should be monitored to reduce the
risk of lidocaine toxicity, especially in patients over 70 years of age (41,4445). In
patients with renal failure, there is no need to adjust the dose of lidocaine because its
clearance and volume of distribution are unchanged. However, renal failure leads to the
accumulation of MEGX and GX, lidocaines metabolites, which have little pharmacologic activity but can produce significant neurotoxicity (42).

PHYSIOLOGICAL APPROACH TO OPTIMAL

DRUG DELIVERY DURING CPR
As stated earlier, compartmental pharmacokinetic analysis is commonly used to
describe how drugs are distributed in and eliminated from the body. This approach does
not provide any information about the relationship of these kinetic compartments and
rate constants to anatomic structures or physiological function; it assumes instantaneous distribution in each compartment. Compartmental analysis, typically, uses firstorder differential equations or polyexponential equations containing distribution and
elimination rate constants to describe the pharmacokinetic behavior of a drug. CA is
a complex physiological state resulting from a hemodynamic collapse further complicated by augmentation of blood flow via chest compression and vasoactive pharmacotherapy. The assumption of instantaneous compartmental distribution may not be valid
in this setting. This limits the usefulness of compartmental pharmacokinetic modeling
in the CA setting.
Recently, physiologically based pharmacokinetic modeling (PBPK) has been studied
as alternative approach to compartmental pharmacokinetic modeling in the CA patient
(46). This approach uses sets of nonlinear differential equations to provide a description
of the time course of drug concentrations in any organ tissue and describes drug movement in the body based on organ blood flows and organ penetration (4750). Changes in
hemodynamics or bloodtissue partitioning will thus affect the disposition kinetics of the
drug under study (4752). Physiological parameters used in the model can be obtained
from invasive animal studies and scaled to humans (4752).
Grillo et al. designed a flow-dependent PBPK model representing nine body tissues
for lidocaine (see Fig. 1 [46]).Physiological organ flow rates, tissue volumes, and plasma
tissue partition parameters for lidocaine in humans were taken from the literature. Data

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Fig. 1. PBPK model. SET, slowly equilibrating tissue (long bone, skull, spine, skin, and chest
wall); Q, organ blood flow. (Used with permission from ref. 46.)

from published animal studies were used to estimate loss of organ blood flow during CA
and lidocaine tissue partition coefficients. The model assumed a 70-kg CA patient. The
following five lidocaine dosing regimens were simulated: (a) 4 mg/kg IV push (IVP) (b)
1.5 mg/kg IVP then 1.5 mg/kg IVP in 4 minutes, (c) 3 mg/kg IVP, (d) 2 mg/kg IVP, and
(e) 1.5 mg/kg IVP.
This PBPK model of lidocaine in CA predicted that lidocaine distribution is dramatically prolonged during resuscitation. Shunting of blood during CA results in reduced
flow to muscle, adipose, and other slowly equilibrating tissues. If this model prediction
is correct, relatively higher than expected lidocaine concentrations will be present in
relatively well-perfused tissues (e.g., brain, heart, lungs, and so on).
A simulation of regimen 2, which at the time of the study was the current American
Heart Association (AHA) recommendation, suggested that the concentration of lidocaine
was suboptimal at the decision point (35 minutes) to administer another dose. Regimen
4 offered a slightly more rapid optimization of cardiac concentrations and more acceptable brain concentrations compared to regimens 1 through 3. The authors concluded that
simulations from this PBPK model suggest that the then AHA lidocaine-dosing regimen
for CA may not result in optimal lidocaine concentrations in the heart and brain. Simulations suggested that 2 mg/kg IVP may be the most acceptable lidocaine dosing regimen
during CA.
Potential shortcomings of this method may involve the assumptions made and the
estimates of the physiological parameters that were derived from animal studies. This is
an area for future research.

SUMMARY
The ideal route of drug administration during CPR is one that combines rapid access
with quick delivery of drug to the central circulation. Hemodynamic changes during
CPR make central venous access the ideal route for drug delivery. The expediency

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required in drug administration cause peripheral venous access to be used most frequently, especially in the prehospital setting. When drugs are administered via peripheral venous access, the site of drug administration should be elevated above the level of
the heart and a 20-mL bolus of NS should be administered to expedite the delivery of
drug to the central compartment. If venous access cannot be readily obtained, atropine,
epinephrine, lidocaine, and vasopressin may be administered via an established endotracheal airway. Except for vasopressin, which is administered at the conventional intravenous dose, the dose of drug should be increased by 2.5 times the recommended
intravenous dose. The drug should be diluted to 10 to 20 mL with SW or NS, and injected
via catheter that extends beyond the tip of the endotracheal tube. Cardiac compressions
should be held temporarily as the drug is administered and five insufflations are delivered to aerosolize drug throughout the pulmonary mucosa. Once intravenous access is
achieved, the dose should be repeated via the intravenous route.

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