17 Principles of Drug DeliveryDuring CPR

275

From: Contemporary Cardiology: Cardiopulmonary Resuscitation Edited by: J. P. Ornato and M. A. Peberdy © Humana Press Inc., Totowa, NJ

17 Principles of Drug Delivery During CPR

Edgar R. Gonzalez, ^P harm ^D , ^FASHP , Joseph A. Grillo, ^P harm ^D ,

Lih-Jen Wang, ^MS , ^P harm ^D , ^BCPS , and Jeffrey Rosenblatt, ^P harm ^D

C

I

P

C

C

A

B

B

S

A

A

B

D

CPR

P

A

O

D

D

D

CPR S

R

INTRODUCTION

The time from onset of cardiopulmonary arrest until restoration of an effective, spon- taneous circulation is the single most important determinant of long-term, neurologically intact survival from cardiopulmonary arrest. Prompt defibrillation of ventricular fibril- lation (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 patient’s 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

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 metabo- lism 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 medica- tions 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 body’s normal detoxi- fication and excretion processes to eliminate unwanted drug and its metabolites. These dose-related events define the drug’s therapeutic index and recommended dosage regi- men. Apart from coupling of the drug to its endogenous pharmacological receptor, the absorption, distribution, and elimination of the drug usually occur through passive dif- fusion. 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 agent’s concentration–response curves.

The relationship between a drug and the body is described by its pharmacodynamic response (i.e., the drug’s effects on the body) and its pharmacokinetic properties (i.e., the relationship between the amount of drug administered and its resultant plasma concen- tration 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

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 drug’s bioavailability. In theory, an intravenously administered drug should have 100%

bioavailability, whereas other routes of administration (e.g., oral, intramuscular, or en- dotracheal) may alter absorption of drugs and produce incomplete bioavailability. There- fore, 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 drug’s 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, phospho- lipid 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 distribu- tion 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 (11–13). Popu- lation estimates for lidocaine’s distribution half-life (i.e., 8–10 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 depen-

dent on arterial pressure, theoretically, left ventricular dysfunction or vasodilatation would

limit organ perfusion and reduce the effective volume of distribution of a given drug.

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 compart- ment (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 follow- ing an intravenous dose of 1.9 mg/kg in patients undergoing CPR. The results showed that serum lidocaine concentrations within the range of 1.6–4.0 mg/L (mean value = 2.3 mg/L) could be achieved approx 23 minutes after administration (14). McDonald con- cluded 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. Epinephrine’s 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, amiodarone’s lipid solubility explains its redis- tribution 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 it’s pharmacodynamic effects or undergo biotrans- formation. Reduced plasma protein binding via displacement or alterations in binding proteins increase the free fraction of drug and enlarge the drug’s 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 glycopro- tein, 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 cowork-

ers 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

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 periph- eral 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 dif- ferences 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 administra- tion. 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 (10,19–24).

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).

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 (26–31). Endotracheal admin- istration produces a lower and slightly delayed peak plasma concentration, and the onset of action may be delayed, but the magnitude of response is similar (28–31).

Differences in bioavailability between intravenous drug administration and endotra- cheal 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 (33–36). 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 impor- tance of doubling the dose of drug and the need to use a 10–20 mL volume of dilution for achieving the highest serum drug concentrations following endotracheal drug adminis- tration 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 PaO

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 oxy- genation 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.

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 drug’s intrinsic clearance rate, the frac- tion 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., 1.5–3.0 mg/kg) because drug clearance does affect loading dose, but it does suggest that the maintenance dose of lidocaine should be decreased by 50–75% because of circulatory shock (41–44). 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 (41,44–45). 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, lidocaine’s metabolites, which have little pharmaco- logic 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 instanta- neous distribution in each compartment. Compartmental analysis, typically, uses first- order 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 compli- cated by augmentation of blood flow via chest compression and vasoactive pharmaco- therapy. 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 move- ment in the body based on organ blood flows and organ penetration (47–50). Changes in hemodynamics or blood–tissue partitioning will thus affect the disposition kinetics of the drug under study (47–52). Physiological parameters used in the model can be obtained from invasive animal studies and scaled to humans (47–52).

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

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 dramati- cally 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 (3–5 minutes) to administer another dose. Regimen 4 offered a slightly more rapid optimization of cardiac concentrations and more accept- able 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. Simu- lations 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

required in drug administration cause peripheral venous access to be used most fre- quently, especially in the prehospital setting. When drugs are administered via periph- eral 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 endot- racheal airway. Except for vasopressin, which is administered at the conventional intra- venous 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 deliv- ered to aerosolize drug throughout the pulmonary mucosa. Once intravenous access is achieved, the dose should be repeated via the intravenous route.

REFERENCES

1. Kaye W, Mancini ME, Rallis SF, et al. Can better basic and advanced cardiac life support improve outcome from cardiac arrest. Crit Care Med 1985; 13:916–920.

2. Gonzalez ER: Pharmacologic controversies in CPR. Ann Emerg Med 1993; 22:317–323.

3. Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiac Care. JAMA 1992; 268:

2171–2302.

4. Ornato JP, Gonzalez ER, Jaffe AS. The use of cardiovascular drugs during cardiopulmonary resus- citation. In: Cardiovascular Drug Therapy. Messerli FH, ed. Philadelphia, PA: W. B. Saunders Co., 1990, pp. 121–138.

2. Comstock TJ. Pharmacotherapeutics in the emergency department. In: Drug Therapy in Emergency Medicine. Ornato JP, Gonzalez ER, eds. New York: Churchill Livingstone, 1990, pp. 23–48.

6. Pentel P, Benowitz N. Pharmacokinetic and pharmacodynamic considerations in drug therapy of cardiac emergencies. Drugs 1984; 9:273–308.

7. Brown CG, Werman HA, Davis EA, et al. Comparative effect of graded doses of epinephrine on regional brain blood flow during CPR in a swine model. Ann Emerg Med 1986; 15:1138–1144.

8. Pharmacology I. In: Textbook of Advanced Cardiac Life Support. Jaffe AS, ed. Dallas: American Heart Association, 1987; 97–114.

9. Voorhees, WD, Babbs CF, Tacker WA. Regional blood flow during cardiopulmonary resuscitation in dogs. Crit Care Med 1980; 8:134–136.

10. Doan LA: Peripheral versus central venous delivery of medications during CPR. Ann Emerg Med 1984;

13:784–786.

11. Pieper JA, Rodman JH. Lidocaine. In: Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 2nd edition. Evans WE, Schentag J, Jusko WJ eds. Spokane: Applied Therapeutics Inc., 1986, pp. 639–681.

12. Chandra NC, Beyar R, Halperin HR, et al. Vital organ perfusion during assisted circulation by manipu- lation of intrathoracic pressure. Circulation 1991; 28:279–286.

13. Chow MSS, Ronfeld RA, Hamilton RA, et al. Effect of external cardiopulmonary resuscitation on lidocaine pharmacokinetics in dogs. J Pharmacol Exp Ther 1983; 224:531–537.

14. McDonald JL. Serum lidocaine levels during cardiopulmonary resuscitation after intravenous and en- dotracheal administration. Critical Care Med 1985; 13:914–915.

15. Gonzalez ER, Kannewurf BS, Ornato JP. Intravenous amiodarone for ventricular arrhythmias: overview and clinical use. Resuscitation 1998; 39:34–42.

16. Routledge PA, Shand DG, Barchowsky A, et al. Relationship between alpha 1-acid glycoprotein and lidocaine disposition in myocardial infarction. Clin Pharmacol Ther 1981;30:154–157.

17. Johansson BG, Kindmark CO, Trell EY, et al. Sequential changes of plasma proteins after myocardial infarction. Scand J Clin Lab Invest 1972;29:117–129.

18. Kuhn GJ, White BC, Swetman RE, et al. Peripheral versus central circulation time during CPR. A pilot study. Ann Emerg Med 1981;10:417–419.

19. Talit U, Braun S, Halkin H, et al. Pharmacokinetic differences between peripheral and central drug administration during cardiopulmonary resuscitation. J Am Coll Cardiol 1985;6:1073–1077.

20. Keats S, Jackson RE, Kosnik JW, et al. Effect of peripheral versus central injection of epinephrine on changes in aortic diastolic blood pressure during closed-chest massage in dogs. Ann Emerg Med 1985;

14:495 (Abstract).

21. Barsan WG, Levy RC, Weir H. Lidocaine levels during CPR. Ann Emerg Med 1981; 10:73–78.

22. Kuhn GJ, White BC, Swetman RE, et al. Peripheral versus central circulation time during CPR. A pilot study. Ann Emerg Med 1981; 10:417–419.

23. Hedges JR, Barsan WG, Doan LA, et al. Central versus peripheral intravenous routes in cardiopulmo- nary resuscitation. Am J Emerg Med 1984; 2:385–390.

24. Redding JS, Pearson JW. Effective routes of drug administration during cardiac arrest. Anesth Analg 1967; 46:253–258.

25. Emerman CL, Pinchak AC, Hancock D, Hagen JF. The effect of bolus injection on circulation times during cardiac arrest. Am J Emerg Med 1990; 8:190–193.

26. Hasegawa EA. The endotracheal administration of drugs. Heart Lung 1986; 15:60–63.

27. Redding JS, Asuncion JS, Pearson JW. Effective routes of drug administration during cardiac arrest.

Anesth Analg 1967; 46:253–258.

28. Roberts JR, Greenberg MI, Knaub M, Baskin SI. Comparison of the pharmacological effects of epineph- rine administered by intravenous and endotracheal routes. JACEP 1978; 7:260–264.

29. Roberts JR, Greenberg MI, Knaub MA, Kendrick ZV, Baskin SI. Blood levels following intravenous and endotracheal epinephrine administration. JACEP 1979; 8:53–56.

30. Scott B, Martin FG, Matchett J, Whites S. Canine cardiovascular responses to endotracheally and intravenously administered atropine, isoproterenol and propranolol. Ann Emerg Med 1987; 16:1–10.

31. Rubertsson S, Wiklund L. Hemodynamic effects of epinephrine in combination with different buffers during experimental, open chest, cardiopulmonary resuscitation. Crit Care Med 1983; 21:

1051–1057.

32. Ralston SH, Tacker WA, Showen L, et al. Endotracheal versus intravenous epinephrine during elec- tromechanical dissociation with CPR in dogs. Ann Emerg Med. 1985; 14:1044–1048.

33. Mace SE. Effect of technique of administration on plasma lidocaine levels. Ann Emerg Med 1986;

15:552–556.

34. Mace SE. The effect of dilution on plasma lidocaine levels with endotracheal admininstration. Ann Emerg Med 1987; 16:522–526.

35. Greenberg MI, Baskin SI, Kaplan AM, et al. Effects of endotracheally administered distilled water or normal saline on the arterial blood gases in dogs. Ann Emerg Med 1982; 11:600–604.

36. Hahnel JH, Linder KH, Schurmann C, et al. Plasma lidocaine levels and PaO2 with endotracheal administration. Dilution with normal saline or distilled water. Ann Emerg Med 1990; 19:1314–1317.

37. Linder KH, Prengel AW, Brinkman A, et al. Vasopressin administration in refractory cardiac arrest. Ann Intern Med 1996; 124:1061–1064.

38. Wilkinson GR. Influence of Hepatic disease on pharmacokinetics. In: Applied Pharmacokinetics: Prin- ciples of Therapeutic Drug Monitoring, 2nd edition. Evans WE, Schentag JJ, Jusko WJ, eds. Applied Therapeutics Inc, Spokane, 1986, pp. 116–138.

39. Tabrizchi R, Lim SL, Pang CY. Possible equilibration of portal venous and central venous pressures during circulatory arrest. Am J Physiol 1993; 264:H259–H261.

40. Chow MSS, Ronfeld RA, Ruffett D, et al. Lidocaine pharmacokinetics during cardiac arrest and external cardiopulmonary resuscitation. Am Heart J 1981; 102:799–801.

41. Benowitz NL. Clinical applications of the pharmacokinetics of lidocaine. In: Cardiovascular Drug Therapy. Melmon KL, ed. Philadelphia, PA: FA Davis Co., 1976, pp. 77–101.

42. Thomson PD, Melmon KL, Richardson JA, et al. Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann Intern Med 1973; 78:499–508.

43. Thomson PD, Rowland M, Melmon KL. The influence of heart failure, liver disease and renal failure on the disposition of lidocaine in man. Am Heart J 1971; 82:417–421.

44. Davison R, Parker M, Atkinson AJ. Excessive serum lidocaine levels during maintenance infusions:

Mechanisms and prevention. Am Heart J 1982; 104:203–208.

45. Pfeifer HJ, Greenblat, DJ, Koch-Weser J. Clinical use and toxicity of intravenous lidocaine: a report from the Boston Collaborative Drug Surveillance Program. Am Heart J 1976; 92:168–173.

46. Grillo JA, Venitz J, Ornato JP. Prediction of lidocaine tissue concentrations following different dosing regimens during cardiac arrest using a physiologically based pharmacokinetic model. Resuscitation 2001; 50:331–340.

47. Leung HW. Development and utilization of physiologically based pharmacokinetic models for toxico- logical applications. J Toxicol Environ Health 1991; 32:247–267.

48. Gerlowski LE, Jain RK. Physiologically based pharmacokinetic modeling: principles and applications.

J Pharm Sci 1983; 72:1103–27.

49. Ings RMJ. Interspecies scaling and comparisons in drug development and toxicokinetics. Xenobiotica 1990; 20:1201–1231.

50. Gibaldi M, Perrier D. Physiologic pharmacokinetic models. In: Pharmacokinetics, 2nd edition. Gibaldi M, Perrier D, eds. Drugs and the Pharmaceutical Sciences, volume 15. New York: Marcel Dekker, 1982, pp. 355–384.

51. Colburn WA. Physiologic pharmacokinetic modeling. J Clin Pharmacol 1988; 28:673–677.

52. Benowitz N, Forsyth RP, Melman KL, et al. Lidocaine Disposition in monkey and man: Prediction by a perfusion model. Clin Pharm Ther 1974; 16:87–98.