Chapter 17 / Drug Delivery During CPR

17

275

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

275

These processes are partly dependent of the molecular species of the drug. the drug’s effects on the body) and its pharmacokinetic properties (i. distribution. This chapter discusses the link between the administration of a drug and its subsequent pharmacokinetics and pharmacodynamics during CPR. hypoxemia. These estimates are used by the clinician to predict the serum drug concentration after a given dose. Today. pharmacokinetic models (5). 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 .e. and may be described by mathematical construct (i. Apart from coupling of the drug to its endogenous pharmacological receptor. mathematical models and equations can be used to calculate “pharmacokinetic parameters.e.e.” which represent the average values for the rates of absorption.. down-regulation of receptors. These dose-related events define the drug’s therapeutic index and recommended dosage regimen. and the delivery of drugs to their target end organs may be compromised by the poor blood flow generated during closed-chest compression. distribution.e. 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. pharmacokinetics) that define the agent’s concentration–response curves. We know that the pharmacokinetic properties and the pharmacodynamic response of drugs may be altered by the presence of hypoperfusion.e.e. the rate of drug elimination increases. As plasma drug concentrations increase. rate of metabolism. and elimination of a drug in a given sample population (i. blood and highly perfused tissue) and the peripheral compartment (e.. Drugs enter the bloodstream directly after intravenous administration.. PHARMACOKINETIC CONSIDERATIONS IN CARDIAC ARREST After the administration of a drug. the relationship between the amount of drug administered and its resultant plasma concentration over time [5]). However.. and glomerular filtration and secretion. Therefore. hepatic enzymatic activity. and elimination of the drug usually occur through passive diffusion. 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. metabolism. target end-organ damage. The relationship between a drug and the body is described by its pharmacodynamic response (i. linear). the absorption. cardiac output.. The biological actions of drugs given during resuscitation may be altered by acidosis. the pharmacokinetic parameters of ACLS drugs can be described by first-order (i. and drug interactions. Although we lack concrete information describing the pharmacokinetic and pharmacodynamic profile of drugs in this setting. normal volunteers).276 Cardiopulmonary Resuscitation access may delay initial drug administration. fat and other tissue). and rate of excretion) by the body. impaired metabolism and excretion. hypoxia. 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). and acidosis during cardiac arrest (CA). two-compartment. and distribute between the central compartment (i. In clinical practice.g. its efficacy and safety are maintained by selective interaction with the pharmacological site of action coupled with the body’s normal detoxification and excretion processes to eliminate unwanted drug and its metabolites..

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. Population estimates for lidocaine’s distribution half-life (i. drugs should be given by intravenous bolus injection. Because of the reduced blood flow and increased circulation time. The tissue compartment of the target organ greatly impacts the dosing regimen of a given agent.10). oral. then a dose 500 mg will produce in a concentration of 1 mg per liter of blood. Although cell membranes have a semi-permeable. When lidocaine is administered during CPR. Although organ perfusion is primarily dependent on arterial pressure. BIOAVAILABILITY AND BINDING TO THE SITE OF ACTION Bioavailability defines the fraction of the administered dose that reaches the systemic circulation.e. amiodarone) usually distribute into many tissue compartments. Studies in swines show that during closed-chest CPR. whereas other routes of administration (e. intramuscular.e. digoxin. The route of drug administration greatly influences a drug’s bioavailability. volume of distribution.8]). Theoretically. In theory. lidocaine follows a two-compartment pharmacokinetic model with the heart (i. . 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). to ensure the highest concentration of drug in the bloodstream. 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 a drug is to redistribute to other tissues the rate and extent of this phenomena will depend on organ perfusion. Once drugs reach the bloodstream. drugs must have rapid and complete bioavailability to promptly reach their sites of action. the drug distributes extensively into tissue as well as body fluids.e. myocardial blood flow is less than 5 mL per minute per 100 g (normal value = 40– 100 mL per minute per 100 g [7. 8–10 minutes) suggest that in a normal patient. and alters the volume of distribution (9). the site of action) located in the initial compartment (11–13). Circulatory collapse causes redistribution of blood to highly perfused organs (brain and myocardium). the lipid solubility. an intravenously administered drug should have 100% bioavailability.. the method of drug administration also affects pharmacokinetic and pharmacodynamic profiles during CPR (6. If the volume of distribution of a given drug is 500 L.. phospholipid layer. 42 L). 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. left ventricular dysfunction or vasodilatation would limit organ perfusion and reduce the effective volume of distribution of a given drug. Lipid Solubility and Volume of Distribution First. For example. therefore.g. during CPR. 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. numerous issues affect the amount and rate of binding to the sites of action. However. The 500 L exceeds the total volume of body water (i. drugs with high lipid solubility have an increased likelihood of penetrating into the site of action.. During CPR. Drugs with large volumes of distribution (e..g. Therefore.Chapter 17 / Drug Delivery During CPR 277 occurs during sudden cardiac death. or endotracheal) may alter absorption of drugs and produce incomplete bioavailability.

documented that within 1 minute after the onset of CA. McDonald measured serum lidocaine concentrations in the peripheral blood following an intravenous dose of 1. small volume of distribution) until it readily attaches to adrenergic receptors inside cell membranes.3 mg/L) could be achieved approx 23 minutes after administration (14).49 L/kg vs 0. Changes in plasma protein binding can also alter volume of distribution. In contrast.0 mg/L (mean value = 2. lungs. thyroid. 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)..17). Severe hypoperfusion explains the decrease in the volume of distribution of lidocaine into the initial compartment (0.278 Cardiopulmonary Resuscitation Chandra et al. the primary binding protein for lidocaine. 5 mg/kg/dose) to sustain adequate concentrations in the myocardium during CPR. Furthermore. CA patients may require plasma lidocaine concentrations in the upper range of normal to achieve a therapeutic effect.g.During CA. These changes are caused by a rise in _-1-acid glycoprotein.9 mg/kg in patients undergoing CPR. Epinephrine is the classic example of a small polar molecule that rapidly equilibrates in the bloodstream where it binds to albumin (i. Therefore. it is important to dose amiodarone on a weight-dependent basis (i.69 ± 0. skin [15]).06 L/kg) during CPR in dogs (12). 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.06 ± 0. Blood samples were obtained via right femoral artery catheters at 30-second intervals for 5 minutes following injection. only the unbound drug can cross cell membranes to exert it’s pharmacodynamic effects or undergo biotransformation.67 ± 0. Theoretically. Although the effect of altered plasma protein binding on the volume of distribution of lidocaine during CA has not yet been studied. Although drugs bind to blood cells and plasma proteins within the circulation. eyes. Epinephrine’s small volume of distribution and wide therapeutic index. Arterial blood indocyanine green . and then redistributes away from it site of action back into peripheral organs (e. patients with acute coronary syndromes have increased binding of lidocaine to plasma proteins and a subsequent reduction in volume of distribution (16. but the concentration of free (active) lidocaine may be disproportionally low due enhanced _-1-acid glycoprotein binding. the total plasma lidocaine concentration may be disproportionately elevate during CA. amiodarone is a large nonpolar molecule that slowly equilibrates in the bloodstream. liver.6–4.07 L/kg) and the tissue compartment (1.14 ± 0. McDonald concluded that the clearance of lidocaine from the initial compartment was reduced during CPR in humans..e. amiodarone’s 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. It is minimally protein bound and distributes widely throughout the body (large volume of distribution) until it reaches the site of action. explain why weight dependent dosage adjustments are not needed during CPR.. 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.38 L/kg vs 0.e. The results showed that serum lidocaine concentrations within the range of 1. McDonald suggested that a second dose of lidocaine would likely not be necessary during CPR unless spontaneous circulation was re-established (14). perfusion to vital organs is reduced to approx 25 to 50% of pre-arrest values (12).

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. During CPR. In summary. Although the method of intravenous administration does not alter the absolute bioavailability. After peripheral injection. 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). and total body clearance.Chapter 17 / Drug Delivery During CPR 279 concentrations after central venous injection revealed a high concentration of the dye at 30 seconds and an emerging second peak at 5 minutes (18). 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. but not the amount of drug ultimately available at the site of action during CPR.001) and a significantly shorter time to peak concentration (13 + 5 vs 27 + 12 seconds.01 [19]). p < 0. Circulation time and peak dye concentration were significantly improved by the administration of a 20-mL flush following peripheral injection in this animal model. . and time to onset of biological effects for epinephrine and lidocaine were greater after central venous administration compared to peripheral venous administration. The most prominent difference between central venous and peripheral venous injection was the difference in peak concentration of radioactive tracer. 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. when drugs are administered from a peripheral intravenous site during CPR. central venous administration produces rapid delivery of drug to the site of action when compared with peripheral drug administration (10. Bolus injection of two different radioisotopes were given simultaneously through a peripheral vein and a central vein. peak dye concentrations were not achieved during the 5-minute sampling period. Because of the additional venous blood admixture for peripheral drug injection. peak drug concentrations. Talit and colleagues compared the pharmacokinetics of radioisotopes administered via peripheral vs central venous access during resuscitation in nine mongrel dogs (19). the benefits of central venous drug administration during CPR are obvious because central venous drug administration shortens the lag time to peak drug concentrations. Central venous injection produced a 270% higher peak concentration (p < 0. there were no significant differences in area under the concentration time curve.19–24). Venous admixing also explains differences in peak concentrations produced by the two methods of intravenous administration. The authors concluded that recovery of indocyanine green from femoral arterial blood was significantly greater after it is administered centrally vs peripherally (18). These data show that route of administration would influence peak concentrations and time to peak concentration. Although survival rates drop 10% for every minute that elapses between the onset of CPR and successful defibrillation. this route of administration prolonged the time to peak concentration and significantly enlarged (p < 0. steady state volume of distribution. 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).01) the central compartment volume of distribution of the radioisotope (19). 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.

This drug should be given as a 40-unit endotracheal dose (i. Greenberg concluded that endotracheal administration of NS produces fewer detrimental effects on arterial blood gases when compared with endotracheal administration of SW (35). naloxone. When epinephrine (0. Differences in bioavailability between intravenous drug administration and endotracheal drug administration are explained by: (a) incomplete absorption of aerosolized drug.. epinephrine). and atropine are agents that are administered routinely via the endotracheal route. 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. the same as the intravenous dose [37]).e.34). Hahnel concluded that SW produced better absorption of lidocaine and less impairment of oxygenation than NS (36). but the magnitude of response is similar (28–31).67 mg/L) when compared with the NS group (1. lidocaine. the dose of drug to be administered via an endotracheal tube should be 2. but the question of whether sterile water (SW) or normal saline (NS) should be the preferred remains unanswered. Serum lidocaine concentrations at 5 and 10 minutes postdose were significantly higher (p < 0.05) depressed arterial pH and PaO2 when compared with NS. only a few clinical studies have described the pharmacokinetic profile of drugs administered in this manner during CPR (26–31). and (c) poor pulmonary blood flow (32). . However. Endotracheal administration of SW significantly (p < 0.35 and 2. and vasopressin may be administered via endotracheal route when intravenous access has not been established.2 mg/kg) was administered via an endotracheal airway without a catheter. However..e. with the aid of a catheter wedged deep into the bronchial tree. Although. epinephrine. the rate and extent of absorption of drugs following endotracheal administration offers another example of unresolved pharmacokinetic variability during CPR. who compared the effects of SW vs NS in 12 patients who received lidocaine via the endotracheal route (36). Mace confirmed the value of endotracheal drug delivery and documented the importance 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 administration during CPR (33.05). Ralston and coworkers observed that the use of a catheter to deliver drug via an endotracheal airway enhanced the response to epinephrine (33). lidocaine. Drug dilution is important in the delivery of drugs via an endotracheal airway. epinephrine. and the onset of action may be delayed. When epinephrine (0. (b) metabolism of drug by lung parenchymal cells (i. the drug did not increase blood pressure during CPR. Endotracheal administration produces a lower and slightly delayed peak plasma concentration.1 mg/kg) was administered via an endotracheal airway. there was a significant increase in blood pressure (33).05) in the SW group (2.5 times the recommended intravenous dose. these results were questioned by the evidence produced by Hahnel.88 mg/L). The exception is vasopressin. The PaO2 dropped by 60 mmHg in the NS group and by 40 mmHg in the SW group (p < 0. Administration technique and dilution volume are important to assure good bioavailability following endotracheal drug administration (33–36). Greenberg and coworkers compared the effects of endotracheally administered SW vs NS on arterial blood gases in dogs (35). 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. In summary.280 Cardiopulmonary Resuscitation Endotracheal Drug Administration Atropine.59 and 1.

Data .Chapter 17 / Drug Delivery During CPR 281 ALTERATIONS IN BIOTRANSFORMATION DURING CPR Biotransformation of drugs used during CPR occurs via the liver for all drugs except epinephrine. For lidocaine. This observations does not affect the bolus dose of lidocaine (i.. Therefore. which have little pharmacologic activity but can produce significant neurotoxicity (42). Changes in hemodynamics or blood–tissue partitioning will thus affect the disposition kinetics of the drug under study (47–52). physiologically based pharmacokinetic modeling (PBPK) has been studied as alternative approach to compartmental pharmacokinetic modeling in the CA patient (46). Grillo et al. This approach does not provide any information about the relationship of these kinetic compartments and rate constants to anatomic structures or physiological function. and the rate of blood flow to the liver (38). 1. the fraction of unbound drug in the blood. reduces the biotransformation of lidocaine.44–45). compartmental pharmacokinetic analysis is commonly used to describe how drugs are distributed in and eliminated from the body.0 mg/kg) because drug clearance does affect loading dose. renal failure leads to the accumulation of MEGX and GX. the rate-limiting step in biotransformation is the rate of blood flow to the liver (5). typically. but it does suggest that the maintenance dose of lidocaine should be decreased by 50–75% because of circulatory shock (41–44). CA is a complex physiological state resulting from a hemodynamic collapse further complicated by augmentation of blood flow via chest compression and vasoactive pharmacotherapy.5–3. there is no need to adjust the dose of lidocaine because its clearance and volume of distribution are unchanged. if lidocaine is used in the postresuscitation period. hepatic blood flow markedly reduced (39). especially in patients over 70 years of age (41. and plasma– tissue partition parameters for lidocaine in humans were taken from the literature. it assumes instantaneous distribution in each compartment. serum drug concentrations should be monitored to reduce the risk of lidocaine toxicity. Furthermore. uses firstorder differential equations or polyexponential equations containing distribution and elimination rate constants to describe the pharmacokinetic behavior of a drug. designed a flow-dependent PBPK model representing nine body tissues for lidocaine (see Fig. In patients with renal failure. Hepatic biotransformation depends the drug’s intrinsic clearance rate. However. 1 [46]). Studies show that during CA. Chow and colleagues demonstrated that the clearance of lidocaine is reduced 10-fold during closed-chest CPR in dogs (40). Compartmental analysis.Physiological organ flow rates. 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 (47–50). circulatory collapse.e. PHYSIOLOGICAL APPROACH TO OPTIMAL DRUG DELIVERY DURING CPR As stated earlier. Physiological parameters used in the model can be obtained from invasive animal studies and scaled to humans (47–52). This limits the usefulness of compartmental pharmacokinetic modeling in the CA setting. lidocaine’s metabolites. A series of case reports in humans show that the elimination half-life of lidocaine increased threefold to 6 hours during CA (40). 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. tissue volumes. The assumption of instantaneous compartmental distribution may not be valid in this setting. Recently.

The model assumed a 70-kg CA patient. relatively higher than expected lidocaine concentrations will be present in relatively well-perfused tissues (e. and chest wall).5 mg/kg IVP. Hemodynamic changes during CPR make central venous access the ideal route for drug delivery. spine.5 mg/kg IVP then 1. and other slowly equilibrating tissues. (Used with permission from ref. The expediency . lungs. This is an area for future research.) from published animal studies were used to estimate loss of organ blood flow during CA and lidocaine tissue partition coefficients. The following five lidocaine dosing regimens were simulated: (a) 4 mg/kg IV push (IVP) (b) 1. (d) 2 mg/kg IVP. heart. A simulation of regimen 2. suggested that the concentration of lidocaine was suboptimal at the decision point (3–5 minutes) to administer another dose. SET.g. slowly equilibrating tissue (long bone. adipose. 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.5 mg/kg IVP in 4 minutes. PBPK model.282 Cardiopulmonary Resuscitation Fig. If this model prediction is correct. skull. Shunting of blood during CA results in reduced flow to muscle. brain. Q. and so on). which at the time of the study was the current American Heart Association (AHA) recommendation. 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. 46. and (e) 1. skin. SUMMARY The ideal route of drug administration during CPR is one that combines rapid access with quick delivery of drug to the central circulation. This PBPK model of lidocaine in CA predicted that lidocaine distribution is dramatically prolonged during resuscitation. organ blood flow. 1. Regimen 4 offered a slightly more rapid optimization of cardiac concentrations and more acceptable brain concentrations compared to regimens 1 through 3. (c) 3 mg/kg IVP..

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