Pharmacokinetics of Tumescent Lidocaine
This was sometime a Paradox, but now the time gives it proof.
— Shakespeare, Hamlet
The efficacy and safety of the large doses of lidocaine used in tumescent local anesthesia are perceived as a paradox by many physicians. Time-honored teachings about local anesthesia are difficult to reconcile with the principles of tumescent local anesthesia. Tens of thousands of tumescent liposuction patients have received 35 to 50 mg/kg of lidocaine with no known reports of deleterious effect, which has proved the safety of tumescent local anesthesia for liposuction. An understanding of the pharmacokinetics of tumescent lidocaine eliminates the paradox from the assertion that less (concentration) is more (effective and safe).
The Science of Pharmacokinetics
Pharmacokinetics is the branch of pharmacology concerned with the movement of drugs within the body. More specifically, pharmacokinetics is a science that studies the time course of drug concentrations and disposition in the body. In practice, pharmacokinetics uses mathematical models that describe the body in terms of one or more theoretic compartments and allows one to calculate and predict the timedependent concentration of drugs in the blood. A good pharmacokinetic model permits an accurate estimation of both the maximum drug concentration (Cmax) in the blood and the time (Tmax) when the peak concentration will occur.
For lidocaine the risk of toxicity is closely correlated with the peak plasma lidocaine concentration. The ability to estimate the values of Cmax and Tmax allows one to anticipate or predict the risks of lidocaine toxicity. Important factors in determining these values are the rates of lidocaine absorption and metabolism.
To be useful, a pharmacokinetic model must be accurate and relatively simple. The accuracy of predictions depends on how accurately the model reflects the clinical reality. The simplicity of a mathematical model determines its usefulness. A pharmacokinetic model that is too complex may not be useful in many clinical situations.
This chapter is written for the “nonmathematical” physician who may be unfamiliar with pharmacokinetics. Bypassing the few sections on calculations will not impair an understanding of other concepts. This chapter provides the reader with an intuitive insight into the most important concepts involved in the pharmacokinetics of tumescent lidocaine. This presentation is heuristic rather than an elegant mathematical development. The mathematics sections at the end of this chapter provide more rigorous analyses and descriptions for interested readers.
Elimination. Drug elimination refers to the irreversible removal of drug and metabolites from the body by all routes of elimination.
Half-life. The elimination half-life (t1/2) of a drug is the length of time required for the elimination of half the total drug present in the body at any given time.
Clearance. Drug clearance (ClT), or total body clearance, refers to the process of drug elimination from the body without specifying any of the processes involved. From a conceptual perspective, clearance can be defined as the volume of plasma that is completely cleared of drug per unit time. Thus clearance has the dimensions of volume/time (e.g., ml/min or L/hr).
From a computational perspective, clearance can be defined as the rate of drug elimination divided by the plasma concentration:
ClT = [Elimination rate]/[Plasma concentration (C)]
where D is the amount of drug that has been eliminated, and dD/dt is the instantaneous rate of elimination. Thus:
dD/dt = ClT × C
Concentration. Drug concentration (C), unless otherwise specified, refers to the concentration (mg/L = μg/ml) of a drug in plasma. As noted, Cmax is the maximum or peak concentration of a drug during a specified time interval, and Tmax is the exact point in time when Cmax is achieved. Thus Tmax is the length of time that has elapsed from the beginning of the drug administration to the point where the drug concentration achieves its peak value.
Distribution. Volume of distribution (V), or the apparent volume of distribution (VD), is the theoretic volume within the body into which the drug is dissolved. In simple terms, V is defined by calculating X/C, where X represents the total amount of drug in the body and C the concentration of the drug in plasma at steady-state conditions. The volume of distribution represents a mathematical concept rather than a real anatomic space; in general, no welldefined anatomic volume of tissues within the body corresponds to V.
As a purely mathematical concept, if the value of C is relatively small, V can exceed the volume of the body. For example, because lidocaine has a high degree of lipid solubility, a large proportion of lidocaine will be distributed into fat, and C will be relatively small. For any value of X, the smaller the value of C, the greater will be the value of the mathematical term X/C = V.
Three important safety issues involve the dosages and concentrations of lidocaine when used as a local anesthetic.
First, safe doses of tumescent (very dilute) lidocaine and epinephrine are not the same for commercial (considerably more concentrated) lidocaine. Whereas the safe maximum dosage of tumescent lidocaine (with epinephrine) at concentrations of 0.05% to 0.15% is 45 to 50 mg/kg, the traditional dosage limitation for commercial lidocaine (with epinephrine) at concentrations of 0.5%, 1%, or 2% remains valid at 7 mg/kg. All physicians should recognize this vital distinction.
Second, the surgeon must provide detailed written and signed orders explicitly specifying the concentration (mg/L) and maximum allowable total dosage (mg/kg) before the anesthetic solutions are prepared for tumescent liposuction.
Third, lidocaine concentrations in tumescent anesthetic solutions must always be specified in terms of milligrams of lidocaine per liter or bag of anesthetic solution. It is potentially dangerous to give orders in terms of volume (ml) of the commercial preparations of lidocaine multiplied by the concentration of the commercial preparation.
For example, when an order specifies 1000 mg of lidocaine and 1 mg of epinephrine in 1000 ml of normal saline, there is little risk of a dosage error or miscommunication between surgeon, nurse, or anesthetist. On the other hand, it is not immediately obvious how many milligrams of lidocaine have been given after half a bag containing “100 ml of 1% lidocaine (1%) with epinephrine (1:100,000)” has been infiltrated.
Furthermore, in several cases, surgeons have ordered “100 cc of lidocaine per liter” with the intention that 1% lidocaine be used, but instead the nurse used 2% lidocaine when mixing the anesthetic solution. This type of error is more easily avoided when dosages are specified in terms of milligrams rather than milliliters of lidocaine.
Kinetic studies and models
For tumescent local anesthesia, pharmacokinetics provides a basis for predicting safe dosages and for understanding the factors that might increase the risk of lidocaine toxicity. A clinically useful prediction of the maximum plasma lidocaine concentration following a specific dose of tumescent lidocaine requires an accurate kinetic model.
The pharmacokinetics of lidocaine is based on the time course of concentrations of lidocaine measured at intervals in samples of peripheral blood. This is reasonable because of the close correlation between lidocaine concentrations in blood and in other tissues. Although lidocaine concentration in the blood is not the same as in other tissues, at steady-state conditions the concentrations differ only by a constant factor.
The essence of the tumescent technique is the direct infiltration of very dilute (0.05% to 0.15%) lidocaine with epinephrine into an area of subcutaneous fat, resulting in an unprecedented slow rate of systemic lidocaine absorption. The success of tumescent local anesthesia is based on the synergistic interplay between (1) the unprecedented slow rate of lidocaine absorption and (2) the well-known rapid rate of lidocaine metabolism by the liver and subsequent renal excretion of less toxic metabolites.
Table 19-1 lists pharmacokinetic parameters for tumescent lidocaine.1,2
Rate of Lidocaine Absorption
Before the tumescent technique, researchers assumed that lidocaine was always absorbed rapidly from the injection site and that the peak plasma lidocaine concentration (Cmax) was always achieved within 2 hours of the injection. Before 1987, most pharmacokinetic studies of lidocaine were based on treatment of cardiac dysrhythmias or on peripheral nerve blocks.
Treatment of ventricular fibrillation involved the direct intravenous infusion of lidocaine and its instantaneous absorption into the intravascular space. Peripheral nerve blocks typically involved the injection of lidocaine directly into highly vascular tissues, such as the epidural space, the spinal fluid in the subarachnoid space, the axilla, or the intercostal nerves. In the few studies that examined subcutaneous injections of lidocaine, plasma lidocaine concentrations were not measured beyond 2 hours.
Two-compartment Model. The rapid absorption of lidocaine into the blood is usually represented by a twocompartment model. First, as lidocaine is rapidly absorbed into the bloodstream and highly vascular tissues (central compartment), the plasma lidocaine concentration rapidly reaches its peak level, Cmax. As the plasma lidocaine is redistributed into other less vascular tissues (peripheral compartment), the lidocaine concentration in the plasma falls precipitously until a lidocaine concentration equilibrium is established among all the tissues.
Second, after lidocaine has been distributed throughout the body, and after the plasma lidocaine concentration is in equilibrium with the lidocaine concentration in all the other tissues, the rate of decline in plasma lidocaine concentration is slowed considerably. Once an equilibrium has been established between the plasma and all other tissues, the further decline in plasma lidocaine concentration is entirely the result of metabolism and excretion of lidocaine. Thus, when lidocaine is rapidly absorbed, it behaves as if the body were divided into two theoretic compartments.
Because of the assumption that lidocaine was always rapidly absorbed from the injection site, it became unquestioned dogma that lidocaine behaved as a two-compartment pharmacokinetic model. For example, as stated in one of the most influential works on local anesthesia, “Lidocaine, for certain, behaves in a kinetic sense as if man were a two- or even a three-compartment system.”3
Anesthesiologists who assume that lidocaine can only behave as a two-compartment model cannot reconcile their view with the relatively large doses of lidocaine used in tumescent liposuction. Under this assumption, 50 mg/kg of lidocaine is an unacceptably large and potentially dangerous dose. The dogma of anesthesiology has assumed that 7 mg/kg of lidocaine with epinephrine is the true maximum safe dose for subcutaneous lidocaine. In fact, tumescent lidocaine behaves as a one-compartment model, so 50 mg/kg of tumescent lidocaine for liposuction totally by local anesthesia is much safer than expected.
As shown later, tumescent lidocaine is unique in that it behaves as if the body were a one-compartment pharmacokinetic model, which explains the safety of large tumescent doses.
Safety Limits. Although the tumescent technique permits an increase in the maximum safe dose of lidocaine, it does not permit unlimited or titanic doses of lidocaine. The maximum recommended dose of tumescent lidocaine is finite (45 mg/kg for thin patients and 50 mg/kg for heavier patients). Ignoring the estimated safe dose of tumescent lidocaine is dangerous and not in the patient’s best interest. Caution is paramount.
The physician must always remember that, for any drug, a published estimate of a maximum safe dosage is merely an estimate. Any estimate may eventually prove to be inaccurate and may need to be adjusted.
From a traditional perspective, standard tumescent doses of lidocaine appear excessive, and concern about the risk of toxicity is legitimate. Surgeons and anesthesiologists are appropriately cautious about the “standard dose limitation of lidocaine” that has no rational scientific basis.
The standard lidocaine dose limitation of 7 mg/kg remains a reasonable limit for standard concentrations of commercial “out-of-the-bottle” lidocaine. The 7-mg/kg limit, however, is unnecessarily restrictive when very dilute (1.5 g/L = 0.15% or less) lidocaine with epinephrine is used.
Patients and physicians should be concerned about the risk of toxicity whenever an anesthetic is administered. Decisions regarding the relative safety of local versus systemic anesthesia should be based on modern scientific data, not on incomplete studies. An excessively conservative limit on the dose of tumescent lidocaine may expose the patient unnecessarily to the risks of general anesthesia.
The dosage limit of 7 mg/kg of lidocaine with epinephrine for local anesthesia is an example of a pharmacologic standard based on an unwarranted extrapolation of limited data (see Chapter 1). The only justification for 7 mg/kg is the letter to the U.S. Food and Drug Administration (FDA) stating that “the maximum safe dose of lidocaine is probably the same as for procainamide.”
In fact, 7 mg/kg is probably an accurate estimate of a maximum safe dose of lidocaine with epinephrine at lidocaine concentrations in the range of 1% or 2%, when injected into highly vascular tissue (e.g., intercostal block). Again, however, this dosage limitation is unreasonably conservative for subcutaneous infiltration of very dilute lidocaine with epinephrine into fat. As a result, patients are exposed to general anesthesia for procedures that are more safely and less painfully accomplished by local anesthesia.
Dermatology and Local Anesthesia. In recent years, dermatology has been undergoing a transformation into a surgical specialty that relies almost exclusively on local anesthesia. Dermatologists have begun to examine critically the pharmacologic basis of local anesthesia infiltrated into the skin and subcutaneous tissues. This information is now starting “to diffuse across the semipermeable membrane” that separates surgeons of different specialties.
Having overcome the prejudice against using more than 7 mg/kg of lidocaine, specialties other than dermatology are beginning to appreciate the great potential for using dilute local anesthesia for procedures that have traditionally required general anesthesia.
The following sections explain the critical significance of delayed absorption for the safety and efficacy of tumescent local anesthesia.
Tumescent Bulk Spread Through Fat
The process of tumescent infiltration involves the spread of the local anesthetic solution through the interstitial space by a process known as bulk flow. This is simply the flow of liquid through a porous substance, such as the interstitial gel. The optimal distribution and spread of the tumescent anesthetic solution throughout the targeted compartment of fat are not instantaneous. Even with an optimal infiltration technique, it requires many minutes for local anesthesia to become completely effective and for hemostasis to become optimal.
Histologically, the individual adipocytes are not swollen beyond their usual size. The tumescent anesthetic solution is embedded within the interstitial connective tissue gel that envelops adipocytes.
On incising the skin and examining the gross appearance of tumescent fat, one appreciates a marbled appearance of pale-yellow lobules of fat embedded between the gray, glistening, diaphanous sheets of collagen and within the supersaturated interstitial tissue gel. The consistency of tumescent fat is gelatinous, soft, and jellylike; this is literally the interstitial colloidal gel. Grape-sized puddles of anesthetic solution are loculated within and between connective tissue septa, similar to a Swiss cheese or honeycomb pattern. These lakes of anesthetic solution act as physical reservoirs of lidocaine. As the liquid is dispersed through the interstitial tissue, some lidocaine is absorbed locally into the lipids within fat cells (see Chapter 26).
Based on clinical observation, optimal anesthesia and hemostasis do not occur for at least 15 to 30 minutes after tumescent local anesthetic infiltration. Typically, within 15 minutes of infiltration, sufficient anesthesia and vasoconstriction have occurred to permit painless liposuction without significant blood loss.
With a greater duration of time between the completion of infiltration and initiation of liposuction surgery, tumescent local anesthesia becomes increasingly effective. Also, the greater the delay after infiltration before starting surgery, the smaller is the volume of blood-tinged infranatant anesthetic solution that is aspirated and appears at the bottom of the collection jar containing the aspirate. The extra time permits more complete spreading and bulk flow of the anesthetic solution through the interstitial gel and along fascial planes. This results in more extensive diffusion of the lidocaine into sensory nerves.
Adequate delivery of tumescent anesthesia to a compartment of fat depends on the direct, physical spreading of the anesthetic solution by bulk flow.
True chemical diffusion only becomes important once the anesthetic solution is within a few millimeters of a targeted neural axon or a capillary wall.
The tumescent lidocaine, consisting of free and tissue-bound lidocaine, is slowly absorbed into the intravascular compartment by a process of diffusion. The unbound (free) fraction of tumescent lidocaine arrives in the systemic circulation by chemical diffusion across fibrous membranes and cells of the adipose tissue, through capillary endothelium and vascular walls, and into the intravascular space for transport throughout the circulation.
The time required for diffusion of a chemical from point A to point B, as it moves through a medium, depends on several physicochemical factors. For lidocaine, rate of diffusion through the interstitial tissue gel is a function of (1) the distance between points A and B and (2) the concentration gradient of free lidocaine (unbound to tissue) between points A and B. The rate of lidocaine diffusion out of the tumescent tissue and into the capillary lumen is delayed by the following:
- Physical distance and isolation of lidocaine molecules created by the large volume of anesthetic solution within the interstitium of fat tissue
- Minuscule lidocaine concentration gradient, resulting from the prodigious degree of dilution
- Profound tumescent vasoconstriction
In reality the pharmacokinetic compartment is purely a theoretic or mathematical concept that assists in understanding the concentration of drugs in the body as a function of time. A basic pharmacokinetic assumption is that, at any point in time, the concentration of the drug is essentially uniform throughout the compartment.
Conceptually, a pharmacokinetic compartment is a group of tissues where the relative concentrations of a drug in different parts of the compartment are in constant equilibrium. In other words, any change of lidocaine concentration in one tissue results in a rapid (essentially instantaneous) and proportional change of lidocaine concentration in all other parts of that compartment.
For tumescent lidocaine, the one compartment consists of intravascular space, certain interstitial tissues, and highly vascular organs such as the lungs, liver, and pancreas. Although the lidocaine concentration varies from tissue to tissue, the lidocaine concentrations in any two distinct tissues are always in equilibrium.
One-compartment Model. The science of pharmacokinetics uses mathematical modeling to describe and predict the time-dependent course of a drug’s concentration in blood and body tissues. Typically the body is represented by a system of hypothetic compartments that do not necessarily correspond to any true anatomic or physiologic entity. Such theoretic models represent a oversimplified totality of pharmacologic activity. Despite this, the resulting information is often valuable. Simple, linear differential equations can be used to describe the rate of change in lidocaine concentration within each compartment.
Deciding which is the most appropriate model depends on the route of administration. The fate of intravenous (IV) bolus lidocaine, with instantaneous systemic absorption, is best described by a two-compartment model.
The tumescent technique for subcutaneous delivery or slow IV infusion of lidocaine is best described using a one-compartment model. In this simplest kinetic model, the body is a single, homogeneous unit. In order for a one-compartment model to be a good representation of a drug’s behavior, the following criteria must be satisfied:
- A one-compartment model assumes that any change in plasma drug concentration corresponds to an immediate and proportional change of concentration in all other body tissues.
- At any given time, the rate of drug elimination from the body is proportional to the amount of drug in the body (compartment) at that time.
Tumescent lidocaine satisfies the first requirement for a one-compartment model only because the blood-tissue equilibrium is “immediate” relative to the extremely slow rate of lidocaine absorption from tumescent fat. In reality, equilibrium between the lidocaine concentrations in blood and other tissues is not instantaneous. Limited by the rate of tissue perfusion, equilibrium is delayed 30 to 60 minutes after lidocaine enters the circulation. Relative to the many hours required for tumescent lidocaine to be absorbed from the subcutaneous space into the vascular space, however, blood-tissue equilibrium for lidocaine is achieved quickly.
Lidocaine also satisfies the second requirement. From experience with IV lidocaine used in treating cardiac dysrhythmias, lidocaine is indeed eliminated at a rate that is proportional to the total amount of lidocaine within the “body.” Lidocaine is said to be eliminated by a first-order process, which occurs when the rate of a drug’s elimination from the body is proportional to the amount of drug in the body.
In contrast, drug elimination is a zero-order process when the rate of drug elimination is constant and independent of the drug’s concentration in the body. Ethyl alcohol metabolism and elimination represent an example of a zero-order elimination process.
Tumescent lidocaine kinetics can be described by a one-compartment model, two-compartment model, or more elaborate multicompartment model. The simplest model that explains the clinically observed events is usually the preferred model.
Absorption, Distribution, and Elimination
Three different but overlapping phases of lidocaine movement occur through the body: absorption, distribution, and elimination. The profoundly slow rate of lidocaine absorption into the systemic circulation after tumescent infiltration is the key to understanding the unique safety of the tumescent technique for local anesthesia.
When lidocaine is given as an IV bolus to treat a cardiac dysrhythmia, absorption is instantaneous. The other two processes of distribution and elimination, however, occur sequentially over time. The situation with tumescent lidocaine kinetics is more complex. After tumescent infiltration of lidocaine, the processes of absorption, distribution, and elimination all occur simultaneously.
The absorption of tumescent lidocaine is exceptionally slow because of the following:
- By elevating interstitial hydrostatic pressure above capillary intraluminal pressure, tumescent infiltration compresses and collapses capillaries and venules. With virtually no blood flowing through the capillaries within the tumescent tissue, the rate of lidocaine absorption is minimized even before the onset of β-adrenergic vasoconstriction.
- The formation of the dilute lidocaine subcutaneous reservoir produces a physical separation of the lidocaine from the blood vessels, thus increasing the distance over which lidocaine must diffuse before it reaches a blood vessel.
- The dilution of lidocaine reduces the lidocaine concentration gradient across the capillary endothelial wall, thereby minimizing its rate of absorption.
- The profound capillary vasoconstriction minimizes capillary perfusion and thus decreases transcapillary absorption.
- The relative avascularity of adipose tissue limits vascular absorption.
- Because of the high lipid solubility of lidocaine, the subcutaneous fat acts as a reservoir for lidocaine and limits the amount of lidocaine available for absorption.
The sum of these additive effects accounts for the unprecedented slow rate of systemic lidocaine absorption. The combination of extremely slow systemic absorption of tumescent lidocaine, rapid hepatic metabolism, and swift renal elimination results in significantly low lidocaine blood levels and thus minimal risks of lidocaine toxicity.
Analogy: Slow-release Oral Tablet. The absorption of lidocaine from the subcutaneous deposit of tumescent anesthesia is analogous to the absorption of a slow-release tablet taken by mouth. When the anesthetic solution is in the subcutaneous tissue, it is isolated from the systemic circulation. Similarly, the drug contained within a slow-release tablet is not immediately absorbed into the systemic circulation. In both cases the drug is contained within an isolated reservoir, is released gradually, and is absorbed incrementally.
A slow-release tablet does not dissolve immediately on entering the gastrointestinal (GI) tract. Instead, the outer portion is slowly eroded, layer by layer. Over many hours the drug is gradually released in small increments from the tablet. Thus, at any point in time, very little drug is available for systemic absorption.
A similar situation occurs with the slow release of lidocaine, which is only being absorbed from the peripheral external surface of the mass of subcutaneous tumescent solution. This mass is isolated because of the intense vasoconstriction throughout the tumescent fatty tissue. The capillary bed within the central portion of the tumescent tissue is so completely constricted that there is no significant blood flow through, and thus no significant absorption from, the central portion of the tumescent tissue.
The infiltrated subcutaneous fat containing the deposit of tumescent lidocaine is similar to the stomach or GI tract containing the slow-release tablet. Although the drug is technically inside the body, the anatomic site of drug absorption is kinetically distinct and isolated from the rest of the body.
Thus the kinetics of lidocaine after tumescent delivery is analogous to the one-compartment model for oral administration of a slow-release tablet.
Significance of Area under Curve. By plotting the graph of plasma lidocaine concentration at different points in time after a subcutaneous injection, one obtains a curve, designated mathematically by the term Clido (t) (Figure 19-1). Measuring the area under the curve (AUC) can provide important pharmacokinetic information. In terms of formal mathematics, AUC is simply the following integral:
where plasma lidocaine concentration Clido (t) is a continuous function of time, over the time interval from when the dose is given at t = 0, to the time when Clido (t) returns to 0, here represented by t = ∞. The shape of the graph of C lido(t), together with AUC, can provide valuable clinical information about tumescent lidocaine kinetics.
With present technology, lidocaine concentration cannot be measured continuously over time. Instead, lidocaine plasma concentrations are determined by taking samples of venous blood at discrete times (e.g., 1, 2, 4, 8, 12, 16, 24, 36, and 48 hours) after initiating lidocaine infiltration. By plotting the measured values of the plasma lidocaine concentrations Clido(ti) at each time ti, then sequentially connecting the points with straight-line segments, one obtains a graph of Clido (t) based on real data (Figure 19-2, A). The area under this graph is an approximation or an estimate of the true AUC.
AUC is equivalent to the total milligram amount of lidocaine that is absorbed into the systemic circulation. Thus, if identical amounts of lidocaine are given by two different routes of delivery (e.g., IV bolus dose and subcutaneous dose) and each yields 100% absorption, the total AUC for each route of delivery will be equal. The shapes of the graphs, however, will not necessarily be the same (Figure 19-2, B to E).
Peak Concentration. The maximum lidocaine plasma concentration after any given dose (Cmax) is directly affected by factors that affect (1) rate of lidocaine absorption or (2) extent of lidocaine absorption (systemic bioavailability).
For any given dose of subcutaneous lidocaine, any factor that accelerates the rate of lidocaine absorption will result in a shorter time necessary to achieve Cmax and will increase its magnitude. Not surprisingly, anything that slows lidocaine absorption will also delay the time (Tmax) when Cmax occurs and will diminish its magnitude (Figure 19-3).
Two triangles of equal area do not necessarily have the same base and height. The area of a triangle equals ½BH, where B and H are the magnitude of the base and height, respectively. For two triangles having equal area, the triangle with the smallest base must have the greatest height. This concept provides the mathematic basis for using the AUC to help explain the relationship between a drug’s rate of absorption and its peak plasma concentration.
The rate of absorption determines the length of the base of the AUC. Rapid lidocaine absorption will have a short base, whereas slow absorption will have a long base. If the AUCs are equal for two methods of lidocaine delivery, the short base will have a high peak (and thus a relatively higher risk of toxicity), and the long base will have a low peak plasma level (and a relatively lower risk of toxicity).
Suppose Clido(t) represents the graph of plasma lidocaine concentration over time, and AUC is the area under this curve. If a certain route of delivery produces rapid lidocaine absorption, the geometric figure that represents the AUC under the graph of Clido(t) will have a relatively short base and a high peak. If the same amount of drug is given in such a manner that the absorption is much slower, the base of the AUC will be much wider, and the peak will be relatively low. Both graphs will have the same AUC because the same total milligram dose of lidocaine has been absorbed with either route of delivery, even though the shapes of the curves are different.
This inverse relationship between Cmax and the rate of absorption explains the safety of the relatively large doses of lidocaine that are used with tumescent liposuction. Suppose that an epidural dose of lidocaine is completely absorbed over 2 hours and that the corresponding peak lidocaine concentration is Cmax. If a tumescent dose of lidocaine requires 24 to 36 hours to be completely absorbed, and if the tumescent dose should achieve the same Cmax as the epidural dose, one can predict that the tumescent dose can be approximately 24 to 36 times greater than the epidural dose.
Absorption rate determines peak plasma concentration, which in turn determines probability of toxicity. Different routes of administration yield different rates of absorption and thus different likelihoods that plasma concentrations of the drug will exceed levels associated with toxicity. These concepts help in understanding how the slow rate of dilute lidocaine absorption associated with the tumescent technique allows higher doses of lidocaine with such a high degree of safety.
Duration of Toxicity. The rate of lidocaine absorption affects the length of time that the plasma lidocaine concentration remains above any specified concentration (Figure 19-4).
When a relatively small dose of lidocaine is absorbed rapidly, the peak level is achieved quickly, then the plasma concentration decreases rapidly. If a relatively small dose of lidocaine produces plasma concentrations that exceed the toxic threshold (6 μg/ml), toxicity is brief. After the rapid lidocaine absorption of an IV bolus dose, the pharmacokinetic behavior of lidocaine is a two-compartment model. The duration of toxicity after an IV bolus is relatively brief because of the rapid distribution of lidocaine into peripheral tissues. The plasma concentration rapidly achieves a peak in the central intravascular compartment, then rapidly decreases as the lidocaine is absorbed into the tissues of the peripheral compartment. The result is that lidocaine toxicity is brief with less risk of serious complications if it occurs after rapid absorption of a relatively small lidocaine dose.
In contrast, after prolonged absorption, lidocaine behaves as if the body were a one-compartment system. If toxic threshold concentration is exceeded after slow absorption, peripheral tissues will already be in equilibrium with the blood lidocaine, and no rapid decrease in plasma lidocaine concentration will occur. When lidocaine absorption is slow, a relatively large lidocaine dose may never exceed the toxic threshold. If toxicity does occur after prolonged absorption, however, toxicity will persist relatively longer.
Absorption Rate Paradox. Obese patients tolerate larger mg/kg doses of IV lidocaine than thinner patients, possibly because obese patients have a larger apparent volume of distribution (VD) for lidocaine. In other words, an obese patient has a greater amount of total body adipose tissue into which lidocaine can be partitioned.
For tumescent lidocaine the relative rate of absorption decreases with increasing obesity. In other words, for equal mg/kg doses of tumescent lidocaine, the greater the patient’s supply of subcutaneous fat, the slower is the rate of lidocaine absorption.
The phenomenon in which obese patients tolerate higher mg/kg doses of tumescent lidocaine than thin patients is an unexpected paradox. As shown next, this absorption rate paradox might have another explanation.
Let A = surface area and V = the corresponding volume of a mass of tumescent fat. Clearly, V is proportional to the total dose of lidocaine. Assume that the rate of lidocaine absorption is proportional to external A of a mass of tumescent fat. Then the ratio A/V is proportional to the rate of absorption per unit dose (mg) of lidocaine.
If the shape of a tumescent compartment of fat is cuboid, ellipsoid, or even spheric, a doubling (increasing by a factor of 2) of V of a mass of tumescent fat produces an increase by a factor of (approximately) 1.6 of A of that volume (see mathematics section at the end of this chapter).
Consider two spheres (or cubes) having volumes VII and VI, where VII is twice as large as VI. Thus VII = 2VI, or (VII/VI) = 2.
Let the surface areas of these volumes be AII and AI, where AII/AI = 1.5874 ≈ 1.6, or AII ≈ 1.6 AI.
Consider the ratio AII/VII and substitute the terms AII ≈ 1.6 AI and VII = 2VI:
AII/VII ≈ (1.6) AI/(2)VI = (0.8)AI/VI
Recalling that A/V is proportional to the rate of absorption per unit dose (mg) of lidocaine, we see that the rate of absorption per unit area for the larger volume (VII) will be merely 0.8 times as fast as the smaller volume (VI). Thus the geometric fact that VII = 2VI, implying AII ≈ 1.6 AI, might be a partial explanation for the absorption rate paradox.
Consider the following example. An obese patient weighs 100 kg and a thin patient 50 kg. The same areas of each patient are treated by tumescent liposuction, using identical concentrations of anesthetic solution. If the obese patient requires twice the total milligram dose of lidocaine as the thin patient, both patients will receive the same mg/kg dose of lidocaine. The obese patient will have a volume VII and the thin patient a volume VI of tumescent fat, where V II = 2VI. The rate of lidocaine absorption, which is assumed to be proportional to the surface area of tumescent fat, will be relatively slower in the obese patient by a factor of 0.8.
Thus, at the same mg/kg dosage of lidocaine, the rate of lidocaine absorption will be relatively slower in the obese patient and faster in the thin patient. Finally, in conclusion, obese patients should tolerate relatively higher mg/kg doses of lidocaine than thinner patients.
Infiltration Rate. At the relatively high concentrations of commercial formulations of lidocaine, rapid infiltration produces rapid systemic absorption. At the low lidocaine concentrations of tumescent preparations, any increased rate of lidocaine absorption caused by rapid infiltration is clinically insignificant.
At relatively high lidocaine concentrations, a rapid subcutaneous injection quickly achieves plasma concentrations that can exceed the threshold for potential toxicity. A rapid subcutaneous injection of 1350 mg of lidocaine (1% and 0.5%) with epinephrine (1:100,000) produced a plasma concentration of 6.3 mg/L within 15 minutes.4 Recall that 6.0 mg/L (6.0 μg/ml) of lidocaine is the recognized threshold for significant toxicity.
A slow injection of 1% lidocaine with epinephrine produces significantly lower and delayed peak blood levels. Thus 1000 mg of lidocaine (1%) with epinephrine (1:100,000) slowly injected subcutaneously over 45 minutes produced a Cmax of 1.5 mg/L, which occurred 9 hours later (Figure 19-5).
A slow subcutaneous infiltration of lidocaine with epinephrine always slows the rate of lidocaine absorption. This effect is most important at the relatively high concentrations of commercial 1% lidocaine with epinephrine. Initiating a local anesthetic infiltration by first giving a slow injection of a relatively small volume of lidocaine with epinephrine, then allowing some vasoconstriction to occur before injecting a more significant volume, will reduce the absorption rate for both lidocaine and epinephrine. The result is a reduction of both the peak plasma lidocaine concentration and the incidence of tachycardia related to epinephrine.
For dilute tumescent solutions of lidocaine and epinephrine, lidocaine absorption is always rather slow. Surgeons who use systemic anesthesia for liposuction tend to accomplish the tumescent infiltration rapidly. It appears that lidocaine toxicity is not a significant risk despite rapid infiltration.
Nevertheless, a rapid infiltration of a tumescent solution of lidocaine and epinephrine does result in a rapid appearance of a small, brief peak in plasma lidocaine concentration. This transient early peak is the result of a delayed onset of vasoconstriction, which allows a brief interval for relatively rapid absorption of a small amount of lidocaine. The tumescent lidocaine diffusion rate across capillary endothelium is not rapid enough to cause toxicity, since the lidocaine concentration gradient is already relatively low because of the dilution inherent to the tumescent technique.
Surgeons must remember that rapid infiltration can be more uncomfortable than slow infiltration. Very rapid tumescent infiltration is usually done only when the liposuction patient is under systemic anesthesia.
Dilution. A volunteer study showed that 1% lidocaine was absorbed faster and had a higher peak than did 0.1% lidocaine, with total dose and infiltration rate held constant. In each case the total dose of lidocaine was 1000 mg and the total dose of epinephrine 1 mg; the time allowed for infiltration was exactly 45 minutes. For 1% lidocaine the magnitude of Cmax was 1.5 μg/ml, which occurred at Tmax of 9 hours. For 0.1% lidocaine, Cmax was 1.2 μg/ml and Tmax 14 hours (Figure 19-6).
The effect of a tenfold dilution of lidocaine on systemic absorption rate after a subcutaneous injection cannot be generalized to epidural spinal anesthesia. At higher absolute concentrations and in highly vascular tissues, dilution does not significantly delay lidocaine absorption. For example, there was no significant difference in the rate of lidocaine absorption when 1% and 10% concentrations of lidocaine were injected into the highly vascular tissue for epidermal anesthesia.5
Vascularity. Tissue vascularity affects the rate of lidocaine absorption. Absorption is slower from relatively avascular fat compared with highly vascular tissue of the gingiva or epidural space. A high blood flow rate through highly vascular tissue maintains the high concentration gradient across the vascular wall.
An injection of lidocaine and epinephrine into the highly vascular gingival mucosa for dental anesthesia may result in rapid epinephrine absorption and a brief but alarming tachycardia. Although patients typically interpret the experience as an allergic reaction, it is not an immune-mediated event but merely a predictable pharmacologic effect of epinephrine.
Lidocaine toxicity can also occur after rapid subcutaneous injection of commercial formulations of lidocaine. I once watched a surgeon infiltrate 1% lidocaine subcutaneously in an infant for local anesthesia before laser treatment of a hemangioma. The degree of vascularity of the site was one of the factors in the resulting lidocaine toxicity, as manifested by a generalized seizure.
Vasoconstriction. Epinephrine-induced vasoconstriction slows the rate at which blood can transport lidocaine away from the site of injection. The vasoconstriction induced by epinephrine is as vital for the safety of the tumescent technique as the dilute nature of tumescent local anesthesia. Vasoconstriction not only prolongs the duration of local anesthesia, but more importantly slows the rate of systemic absorption of lidocaine and thus significantly reduces the magnitude of Cmax (Figure 19-7).
Lidocaine is a capillary vasodilator that has a rapid onset of approximately 1 minute. This is evidenced by the rapid appearance of erythema after a simple 0.1-ml intradermal injection of lidocaine (1%) without epinephrine. The vasodilator effect of lidocaine is caused by blockage of adrenergic neurotransmission and inhibition of vascular smooth muscle contraction.6
Epinephrine is a capillary vasoconstrictor requiring approximately 3 to 6 minutes for onset of action and about 10 to 15 minutes for maximal effect. The vasoconstriction of epinephrine takes longer to become clinically apparent than the vasodilation caused by lidocaine. Eventually the vasoconstriction of epinephrine overcomes the vasodilation of lidocaine. This phenomenon is seen clinically when a 0.1-ml intradermal injection of lidocaine (1%) with epinephrine (1:100,000) initially produces erythema, followed by blanching several minutes later.
After Bolus Infusion. The pharmacokinetic process can be simplified by focusing on the fate of lidocaine after a rapid IV bolus dose. Most knowledge about the time-dependent fate of lidocaine in the body is the result of studying lidocaine kinetics after an IV bolus in human volunteers and animals.
When given as an IV bolus, systemic lidocaine absorption is instantaneous. When studying the distribution kinetics of lidocaine as it spreads throughout the body, the process of absorption can be eliminated as a confounding variable by focusing on the distribution process after an IV bolus. The changes in lidocaine blood levels over time will reflect only the processes of distribution and elimination. Lidocaine distribution and elimination are independent of the absorption process, and therefore it is the same for an IV bolus as for subcutaneous tumescent infiltration.
In a mathematical model where no tissue-drug binding exists, one can assume that the rate of achieving blood-tissue equilibrium is a function of the rate of tissue perfusion. In this perfusion rate–limited model, drug concentration in a tissue is the same as its concentration in the venous blood leaving the tissue. Lidocaine distribution pharmacokinetics is considered to be perfusion rate limited.7 For an IV bolus dose the kinetic model is a perfusion rate–limited, two-compartment model.
The fate of an IV bolus of lidocaine has two phases: (1) the distribution phase, or α-phase, and (2) the elimination phase, or β-phase. Immediately after an IV bolus of lidocaine, during the α-phase, a large proportion of the dose is rapidly redistributed out of the vascular space and absorbed into the peripheral tissues. The highly perfused organs, such as the lungs, kidneys, and spleen, followed by muscle, are the first tissues to achieve equilibrium with intravascular lidocaine. The lidocaine half-life during this distribution phase is approximately 8 minutes.8 It takes more than 30 minutes for the levels of lidocaine in the blood to reach an equilibrium with lidocaine concentration in the myocardium and brain.
After distribution of lidocaine into peripheral tissues, the plasma lidocaine concentration is lowered as a result of elimination by hepatic metabolism during the β-phase (Figure 19-8).
Adipose tissue requires more time than other tissues to absorb enough lidocaine to achieve an equilibrium with blood because of the sparse vascularity of fat. Also, because lidocaine is highly lipophilic, fat has a relatively high capacity to store lidocaine.
After Tumescent Infiltration. The lidocaine distribution kinetics of slow IV infusion and that of the tumescent technique are similar. In either situation the lidocaine concentration in the blood increases so slowly that an equilibrium is maintained continuously between blood and peripheral tissues. Peak tissue and blood concentrations are achieved simultaneously. The rate of tissue perfusion is relatively fast compared with the rate of lidocaine absorption. Thus lidocaine distribution after tumescent delivery is not perfusion rate limited.
Simultaneous Metabolic Activities
As noted earlier, the key to understanding the pharmacokinetics of tumescent lidocaine is the interaction between (1) the rate of lidocaine absorption from the tumescent fat and (2) the rate of systemic elimination.
Tumescent absorption is slow and continuous, similar to a slow, continuous IV infusion. Six to eight hours after initiating a slow IV infusion of lidocaine, an equilibrium is reached between the lidocaine concentration in blood and that in peripheral tissues. When a slow IV infusion is discontinued, the residual of lidocaine in the body is eliminated at a rate identical to the elimination β-phase that follows an IV bolus dose. The half-life of this elimination phase is about 2 hours. Tumescent absorption cannot be terminated as abruptly as turning off an IV infusion; rather, it continues for more than 18 to 36 hours.
The rate of increase and then decrease of lidocaine concentration is determined by a complex interplay between simultaneous tumescent absorption and hepatic metabolism. The complexity of these two concurrent processes becomes apparent when one observes the qualitative differences between the graphs of Clido(t) for a low dose (15 mg/kg), a medium dose (35 mg/kg), and an exceptionally high dose (60 mg/kg) of tumescent lidocaine (Figure 19-9).
Smaller Tumescent Doses. With a relatively small tumescent dose of lidocaine, 15 to 35 mg/kg, the rate of lidocaine absorption increases to a well-defined Cmax at Tmax and then decreases. At these doses the range of Tmax is approximately 8 to 14 hours after initiating the infiltration.
As a first-order process, the rate of hepatic elimination of lidocaine increases and decreases in proportion to the plasma lidocaine concentration. Initially the absorption rate is much faster than the rate of elimination, and thus the lidocaine concentration increases. The rate of hepatic elimination is maximal when the plasma concentration achieves its maximal value, Cmax.
Mathematically, Tmax is exactly the point in time when the rate of absorption equals the rate of elimination. Before Tmax the rate of lidocaine absorption from the tumescent fat is greater than the rate of hepatic elimination. After Tmax the rate of lidocaine absorption from the tumescent fat slows down and is less than the rate of elimination (Figure 19-10).
Larger Tumescent Doses. Large doses of tumescent lidocaine behave differently than small doses. Thus, after tumescent liposuction, a graph of Clido(t) is qualitatively different from that at a smaller dose of lidocaine.
With relatively small doses of tumescent lidocaine (less than 35 mg/kg) the plasma lidocaine concentration reaches a well-defined peak at approximately 10 to 12 hours after beginning the infiltration. At relatively large doses, however, instead of a distinct peak, the lidocaine concentration seems to achieve a broad, level plateau that is maintained for 16 hours or more before declining. With a 60-mg/kg tumescent dose of lidocaine, a plateau is reached within 8 hours and persists for at least another 16 hours (Figure 19-11).
With continued absorption the amount of lidocaine remaining at the site of absorption decreases steadily. Subsequently, hepatic metabolism significantly reduces lidocaine blood levels, which approach 0 mg/L by 48 hours after beginning the tumescent infiltration.
The existence of a concentration plateau shows that, during the time that the lidocaine blood levels remain constant, the rate of lidocaine absorption is in a state of constant equilibrium with the rate of lidocaine elimination. Specifically, the rate of lidocaine absorption is exactly equal to the rate of lidocaine elimination. The concentration plateau indicates that the absorption rate from the tumescent tissues is constant and independent of the amount of lidocaine remaining at the absorption site.
Zero-Order or First-Order Processes
When a drug is absorbed at a constant rate, independent of the amount of drug remaining at the absorption site, the process is said to be a zero-order absorption process. An example is the long-acting oral tablet designed to dissolve on the outer surface of the tablet and thus slowly release drug at a constant rate for absorption into the systemic circulation. Thus, with tumescent liposuction, lidocaine absorption behaves as a zero-order absorption process, which is unique to the tumescent technique for subcutaneous injection.
In contrast, the absorption of oral drugs in a rapidly disintegrating dosage form that quickly dissolves into solution, as well as most injections into subcutaneous tissue and muscle, often approximates first-order kinetics. A first-order absorption process is characterized by an absorption rate that decreases over time and is proportional to the amount of drug that remains at the absorption site. This process is characterized by an absorption rate constant (ka) and a corresponding absorption half-life.
The phenomenon of zero-order lidocaine absorption is paramount in explaining the safety of the tumescent technique. The unexpected zero-order absorption of tumescent lidocaine explains how the large doses of subcutaneous lidocaine are consistently associated with a low risk of toxicity.
The terminology referring to first-order and zero-order processes is derived from the differential equations that describe these two processes (see section at the end of this chapter). Pharmacokinetic studies of IV lidocaine given by rapid bolus or slow infusion provide much information about the elimination kinetics for lidocaine, with estimates for the volume of distribution (V), clearance (Cl), elimination half-life (t1/2), and elimination rate constant (k). Also, systemic elimination of lidocaine is a first-order process.
Cytochrome P450 3A4. Lidocaine elimination by hepatic enzyme cytochrome P450 3A4 (CYP3A4) is a first-order process. In healthy volunteers, lidocaine is so efficiently and rapidly metabolized by the hepatic enzymes that the rate of elimination is limited only by the rate of hepatic perfusion. In healthy patients, hepatic capacity to metabolize lidocaine is not saturated, and the rate of lidocaine elimination is proportional to lidocaine concentration in the blood. The greater the amount of lidocaine within its volume of distribution, the higher is the plasma concentration and the higher the rate of hepatic metabolism.
If the rate of lidocaine metabolism is reduced by 50%, Cmax is approximately doubled. The relative safety of the tumescent technique for local anesthesia depends on the normal, high rate of liver metabolism of lidocaine (see Chapter 17). Anything that decreases the rate of lidocaine metabolism will increase Cmax and increase the risk of toxicity. The following factors can reduce the rate of lidocaine metabolism:
- Decreased CYP3A4 enzymatic activity caused by competitive drug interaction that inhibits CYP3A4
- Decreased blood flow to the liver caused by decreased cardiac output from either excessive IV fluids precipitating congestive heart failure or drug-induced impaired cardiac output (e.g., with propranolol)
- Impaired hepatic function resulting from hepatitis or cirrhosis
Drugs such as ketoconazole (Nizoral) or sertraline (Zoloft) can inhibit or reduce the enzymatic function of CYP3A4. Even with drugs that inhibit CYP3A4, little (if any) evidence indicates that the hepatic enzymes responsible for lidocaine metabolism become saturated (see Chapter 18). Although a drug may inhibit CYP3A4 and slow the rate of lidocaine metabolism, this rate remains a linear function of plasma lidocaine metabolism and rate of hepatic blood flow.
After Bolus Infusion. Once again, consider the example of a rapid IV bolus dose of lidocaine. An equilibrium is quickly established between lidocaine in the blood and in the lipids of peripheral tissues. From this point the rate of decreasing plasma lidocaine concentration slows noticeably. During the entire β-phase the slow decrease of the lidocaine concentration is essentially 100% attributable to hepatic metabolism. The half-life of lidocaine as a result of this β-phase elimination is 100 to 120 minutes, or about 2 hours.
Lidocaine is rapidly and almost entirely metabolized by the liver. Less than 5% of lidocaine is cleared by the kidneys. For a 70-kg person the clearance (blood volume per minute) of lidocaine is 640 ± 170 ml/min, approximately 700 ml/min/70 kg, or more generally 10 ml/min/kg. This approximates the plasma flow to the liver.9,10
The liver is so efficient at metabolizing lidocaine that most of the lidocaine that passes through the hepatic circulation is removed (Figure 19-12). Lidocaine is said to have a hepatic extraction ratio of 0.7, which means that 70% of lidocaine entering the liver exits as metabolite. In other words, for every liter of blood that passes through the liver, 70% of its lidocaine is metabolized, whereas only 30% survives unchanged. More precisely, the hepatic extraction ratio for lidocaine is reported to be 62% to 81%.
After Tumescent Infiltration. Elimination of lidocaine after tumescent delivery is significantly different from the process of elimination after an IV bolus dose. For example, the total amount of lidocaine in a tumescent dose, up to 50 mg/kg, is significantly larger than the typical IV bolus dose of 1 to 2 mg/kg.
The absorption half-life of tumescent lidocaine is much longer (approximately 8 to 12 hours) than the elimination half-life for lidocaine (2 hours). Tumescent lidocaine is absorbed so slowly that much of the drug remains to be absorbed well beyond the Tmax when Cmax is reached. At any particular time, most of the infiltrated tumescent lidocaine either is in the tumescent fat waiting to be absorbed or has been eliminated. Little of the total dose is in the systemic circulation, or the volume of distribution, at any given time.
After tumescent infiltration the process of lidocaine elimination is prolonged by the continuous, slow, systemic absorption of tumescent lidocaine and persists up to 48 hours. Elimination of lidocaine after tumescent infiltration is not much different from the rate of lidocaine absorption from the tumescent fat. In fact, when the rate of lidocaine absorption is exactly equal to the rate of lidocaine elimination, the plasma lidocaine concentration is constant. When lidocaine absorption and elimination are equal, lidocaine concentration as a function of time is a constant plateau (see Figure 19-11).
Clearance and Half-life. The systemic clearance (total body clearance) and elimination half-life of lidocaine provide a quantitative measure of the rate of liver metabolism.
In young, healthy male volunteers, mean systemic clearance and elimination half-life of lidocaine after a single IV bolus dose are 15.6 mL/min/kg and 1.6 hours, respectively.
Young female volunteers seem to have an increased clearance and half-life and a larger volume of distribution than young, healthy males. In general, therefore, young females can tolerate larger doses of tumescent lidocaine than young males.
Elderly men and women have reduced clearance and prolonged half-life compared with young adult controls.11 Thus the recommended maximum dose for tumescent lidocaine should be reduced by 10% to 25% for older patients.
Young obese volunteers have a prolonged half-life and an increased volume of distribution. Again, compared with thin patients, obese patients should be better able to tolerate a higher tumescent dosage of lidocaine.12
Bioavailability of a drug is defined as the fraction of a given dose that ultimately reaches a particular targeted tissue. A dose of a drug might have different degrees of bioavailability for different organ tissues. Thus a large percentage of an oral antifungal drug may reach the liver, lungs, and kidneys, but only a small fraction may penetrate the blood-brain barrier and enter the central nervous system.
The concept of bioavailability is different from that of absorption. Drug absorption involves the fraction absorbed from the site of administration and the rate at which a drug diffuses away from its site of administration and into the body’s systemic circulation. Bioavailability involves the fraction of dose that reaches the site of action. A drug’s bioavailability depends on both its absorption and its ability to penetrate certain barriers and to avoid metabolism or elimination on its journey to the site of drug action.
Bioavailability depends on the following:
- Site of administration
- Extent of absorption from the site of administration
- Physiologic and pathologic states that affect metabolism
- Amount of absorbed drug that is eliminated before it can reach the targeted site of action
For example, the bioavailability of a hydrocortisone ointment topically applied to the skin might only be 1%. Thus, if 100 μg of hydrocortisone is applied to the skin dissolved in an ointment base, only 1 μg is ultimately absorbed through the stratum corneum, epidermis, and dermis and then enters the systemic circulation, eventually being metabolized and finally excreted.
For another example, after a 4-mg sedative is taken by mouth, 2 mg is actually absorbed from the GI tract into the portal circulation, of which 1 mg is metabolized by the liver. Thus only 1 mg of the original 4 mg actually enters the systemic circulation and eventually reaches the central nervous system. The bioavailability is (1 mg)/(4 mg) = 0.25, or 25%.
It is typically an advantage to maximize bioavailability when a drug is targeted at the parenchyma of an internal organ. When a potentially toxic drug is targeted at subcutaneous or external (epidermal or mucosal) body tissue, however, it may be an advantage to minimize systemic bioavailability. Examples include a topical anticandidiasis cream or an antihelminthic drug for intraluminal intestinal parasites (the GI tract’s mucosal surface is topologically an external body surface).
Tumescent liposuction is unusual in that the site of action is the local subcutaneous fat targeted for liposuction. Optimal local bioavailability requires a certain time for the tumescent solution to be dispersed by bulk flow throughout the targeted compartment and for lidocaine to diffuse into sensory nerves. To minimize lidocaine toxicity, one must lessen systemic bioavailability by minimizing systemic absorption.
Lidocaine delivered by the tumescent technique is targeted at localized tissues. It is a therapeutic advantage to maximize the local effects of tumescent lidocaine and to minimize its systemic effects. The safety of tumescent liposuction is the result of (1) reducing the rate of lidocaine absorption (by means of extreme dilution and profound vasoconstriction) and (2) reducing the systemic bioavailability (by open drainage and bimodal compression after liposuction).
Lidocaine toxicity is reduced by minimizing the amount of lidocaine absorbed into the systemic circulation. The goal with tumescent liposuction is to maximize local bioavailability and minimize systemic bioavailability of lidocaine.
Liposuction removes a percentage of lidocaine and thus reduces the systemic bioavailability of lidocaine. Without liposuction the systemic bioavailability of lidocaine after tumescent infiltration would be 100%. Because of the slow rate of tumescent lidocaine absorption, however, high doses of lidocaine are safe even without liposuction. If liposuction cannot be completed after tumescent infiltration, the risk of lidocaine toxicity is minimal if total dosage is below the recommended maximum safe dosage of 50 mg/kg.
With liposuction the margin for safety for tumescent lidocaine is even greater. The systemic bioavailability of lidocaine with tumescent liposuction can be reduced by two distinct processes that physically remove lidocaine from the body. First, liposuction reduces the systemic bioavailability of lidocaine by about 20% simply by aspirating lidocaine along with fat. Second, open drainage with bimodal compression further reduces the amount of systemic lidocaine absorption by increasing the amount of lidocaine that drains out of the body after surgery.
Accelerated drainage of residual tumescent anesthetic solution is accomplished by using adits (punch biopsy holes 1.0, 1.5, or 2.0 mm in diameter) instead of incisions. If incisions are used, drainage is maximized by allowing incision sites to remain open (not closing incisions with sutures). Finally, applying a high degree of uniform compression over the treated areas encourages a maximum volume of drainage.
Maximum Safe Dose. After tumescent infiltration has been completed and before liposuction can be initiated, something may force the patient or surgeon to cancel the surgery, resulting in 100% lidocaine bioavailability and an increased risk of systemic toxicity.
Thus any estimate of a maximum safe dose of lidocaine for tumescent liposuction must assume 100% systemic bioavailability. One cannot assume that liposuction will always be accomplished after tumescent infiltration is completed, nor can one assume that the systemic bioavailability will be substantially less than 100%.
Sequestered Lidocaine Reservoir
Delayed lidocaine absorption is key to the safety and efficacy of very dilute (tumescent) solutions of lidocaine. This delayed absorption seems to result from a reservoir effect; lidocaine is sequestered within the infiltrated adipose tissue and unavailable for immediate absorption in the systemic circulation. The actual site of this reservoir is not critical to the pharmacokinetics of tumescent lidocaine.
With an idealized one-compartment model for tumescent lidocaine, no pharmacokinetic distinction exists between lidocaine that is bound or unbound to tissue. The proportion of bound and unbound lidocaine is assumed to be constant. Also, any change in concentration of the unbound lidocaine is instantly reflected in a proportionate change in the bound fraction. As soon as unbound tissue lidocaine diffuses into the systemic circulation, a proportionate amount of the lidocaine bound to subcutaneous tissue instantaneously becomes unbound.
An ideal pharmacokinetic model also assumes that the bound fraction is not displaced from its binding site by anything other than a change in the concentration of the unbound fraction. In other words, the assumption is that no drugs or processes might displace bound lidocaine from its binding sites and change the proportionality between the bound and unbound fractions.
The lidocaine reservoir may be the result of (1) pools of tumescent anesthetic solution loculated within vasoconstricted fatty tissue and (2) binding of dilute lidocaine to adipose tissue in general and to adipocyte lipids in particular. The relative importance of these sites of lidocaine sequestration is not certain.
When lidocaine is added to a mixture of equal volumes of water and lipids, a greater proportion of the lidocaine is dissolved within the lipid fraction. De Jong3 favors the direct binding of lidocaine to adipose tissue as the source of the reservoir effect for subcutaneous lidocaine. He has proposed that the ratio of unbound/bound lidocaine within adipose tissue is a function of the concentration of lidocaine in the local anesthetic solution.
It is unlikely that the explanation for slow systemic absorption of tumescent lidocaine is an intense binding of lidocaine to lipids within tumescent fat or the sequestration of lidocaine within the interstitium of tumescent tissue. If the explanation were as simple as that, one would expect more lidocaine to be removed by liposuction.
Tumescent lidocaine pharmacokinetics is best represented by a one-compartment model. Tumescent absorption is a zeroorder process. The rate of lidocaine absorption from tumescent tissue is constant and independent of the amount of lidocaine remaining at the site of absorption. Tumescent lidocaine resembles the absorption characteristics of a slow-release tablet in the GI tract. The rate of hepatic elimination of tumescent lidocaine is proportional to the concurrent plasma lidocaine concentration and is thus a first-order elimination process.
Large doses of tumescent lidocaine in the range of 50 to 55 mg/kg appear to be safe in most patients. Impaired hepatic metabolism of lidocaine can predispose a patient to lidocaine toxicity. The peak plasma concentration typically reaches a plateau within 8 to 12 hours and can persist for more than 24 hours, before diminishing to zero at about 48 hours.
Tumescent pharmacokinetics might have application beyond local anesthesia. The slow rate of absorption and prolonged concentration plateau associated with extreme dilution might prove advantageous for drug delivery in other areas of medicine, such as oncology. Treatment of breast cancer by the local infiltration of a chemotherapeutic agent may allow a prolonged local uptake of the drug by the proximal lymphatics.
The mathematics of pharmacokinetics
The following sections provide more detailed analyses of concepts discussed in this chapter.
Derivation of Surface Area/Volume Ratio
The following calculations demonstrate the relationship between the ratios of surface area (A) to volume (V) for two spheres, where the volume of one sphere is twice a large as the volume of the other. Interestingly, the same relationship between A/V ratios holds for two cubes, where one has twice the volume of the other.
Conjecture. Suppose that volume VII is twice as large as volume VI, that is, VII/VI = 2. If AII and AI represent the surface of VII and VI, respectively, then AII/AI @ 1.6, and A/V ratios for these two volumes are related by the equation AII/VII – (0.8)AI/VI.
Proof (Spheres). The volume of a sphere of radius r is (4/3)πr3, and its surface area is 4πr2. Now suppose VII – 2VI, where R is the radius of the larger sphere, and r is the radius of the smaller sphere. Thus VII – (4/3)πR3, and VI – (4/3)πr3.
Because VII = 2VI, then (4/3)πR3 = VII = 2VI = 2(4/3)πr3. Solving for R yields R3 = 2 r3, and therefore R = (2)1/3r. From the classic formula for the surface area of a sphere, AII = 4πR2, and AI = 4πr2. Substituting R = (2)1/3r in the equation yields the surface area for AII:
AII = 4πR2 = 4π[(2)1/3r]2 = (2)2/3 4πr2 = (2)2/3 AI
Thus the ratio of the two surface areas is as follows:
AII/AI = (2)2/3 = (22)1/3 = (4)1/3 = 1.5874 @ 1.6
By assumption, VII = 2VI, or VII/VI = 2. Therefore, if AII/AI is divided by VII/VI:
[AII/AI]/[VII/VI] @ (1.6)/2 = 0.8
After rearranging the terms, we may conclude the following:
AII/VII @ (0.8) AI/VI
Proof (Cubes). A similar calculation holds true when the volumes are cubes (cuboid) rather than spheres (spheric). Suppose VII and VI represent the volume of the two cubes, where the volume of the larger cube is twice the volume of the smaller cube; thus VII = 2 VI. Let E and e represent the length of an edge of the large and small cube, respectively. Then the volumes can be expressed as VII – E3 and VI – e3. Because VII – 2VI, then E3 – VII – 2VI – 2e3. Solving this algebraic equation for E yields E3 – 2 e3, and therefore E – (2)1/3 e.
If AII and AI represent the surface area of the respective cubes, AII = 6E2, and AI = 6e2. Substituting E = (2)1/3e into AII = 6E2:
AII = 6E2 = 6[(2)1/3e]2 = 6(2)2/3e2
Thus the ratio of the two surface areas is as follows:
AII/AI = [6(2)2/3e2]/6e2 = (2)2/3 = (4)1/3 = 1.5874 @ 1.6
By assumption, VII = 2VI, or VII/VI = 2. Therefore, if AII/AI is divided by VII/VI:
[AII/AI]/[VII/VI] ≈ (1.6)/2 = 0.8
After rearranging the terms, we may conclude the following:
AII/VII ≈ (0.8) AI/VI
Discussion. Let us assume that a volume (V) of tumescent fat is roughly spheric. If the concentration of the tumescent anesthetic solution is constant, the volume of the sphere will proportional to the total dose (milligrams) of lidocaine, and thus:
V is proportional to the total dose of lidocaine.
If we assume the systemic absorption of lidocaine only occurs from the surface of the sphere, the rate of absorption is proportional to the surface area (A) of the sphere, and thus:
A is proportional to the rate of lidocaine absorption.
Finally, the surface area/volume term is as follows:
A/V is proportional to the rate of lidocaine absorption per total dose of lidocaine.
This conclusion is derived from elementary geometry and from the assumption that tumescent lidocaine absorption is proportional to the surface area of the mass of tumescent fat. This relation between A and V, where AII/VII @ (0.8) AI/VI, helps to explain why an obese patient tolerates a larger dose of tumescent lidocaine better than a relatively thin patient.
Suppose patient PII weighs 100 kg and patient PI weighs 50 kg. If each receives the same mg/kg dose of lidocaine, then VII = 2 VI, where VII and VI represent the volume of tumescent fat in each patient, respectively. The rate of absorption per total dose is less for the obese patient than the thin patient by a factor of 0.8.
Estimating Time for Lidocaine Clearance
Using standard values for lidocaine clearance and other clinical values yields calculations consistent with observed pharmacokinetic parameters. For example, consider a 70-kg patient who received a 50-mg/kg dose of tumescent lidocaine. The total dose of lidocaine is 50 mg/kg = 70 kg = 3500 mg. From clinical experience, I know that this dosage will yield an average peak plateau of peak plasma concentration of approximately 2.0 mg/L.
Also, from data published by others, lidocaine clearance in a 70-kg patient is 700 ml/min. In other words, the liver will clear 700 ml of lidocaine per minute. If the blood contains 2.0 mg/L, then 700 ml of blood must contain 1.4 mg. Because the liver clears 700 ml/min, the liver must metabolize or eliminate 1.4 mg/min of lidocaine. By simple multiplication we calculate that the liver will metabolize lidocaine at a rate of 1.4 mg/min = 84 mg/hr. Finally, we can calculate that the number of hours necessary to metabolize 3500 mg of lidocaine is (3500 mg)/(84 mg/hr) = 41.6 hours.
Thus, knowing that a 3500-mg dose of lidocaine will typically yield a peak plasma lidocaine concentration 2.0 mg/L, and using standard average value of 700 ml/min for lidocaine clearance in a healthy patient, we can derive an estimate of the time required to metabolize and eliminate the entire 3500-mg dose of lidocaine: 41.6 hours.
The actual time for complete lidocaine metabolism depends on the validity of several assumptions. For example, because plasma concentrations are not a constant 2.0 mg/L, the actual time for complete clearance may be greater than 41.6 hours. On the other hand, because liposuction will reduce lidocaine bioavailability, not all 3500 mg of the infiltrated lidocaine will be absorbed into the systemic circulation. Thus the time required to metabolize all the tumescent lidocaine is less than 41.6 hours. This time is consistent with the observed values of 36 to 48 hours for complete lidocaine clearance after a tumescent dose of 50 mg/kg for liposuction.
A few simple calculations demonstrate the internal consistency of the estimated values for the various pharmacokinetic parameters, using the previous example. At steady state, rate of elimination = RE = RA = rate of tumescent lidocaine absorption. Since RE = 1.4 mg/min = 84 mg/hr, we can conclude that RA = 84 mg/hr.
Systemic clearance (Cl) can be viewed as a proportionality constant in the relationship between RA and steady-state plasma concentration (CSS). Thus RA = Cl · CSS. Substituting the appropriate values:
1.4 mg/min = (0.7 L/min)(2.0 mg/L)
Mathematical Description of Tumescent Lidocaine Kinetics
All drugs exhibit undesirable and toxic effects. Clinical pharmacokinetics helps to determine the optimal dosage regimen for any particular drug. This section provides a more rigorous discussion of some basic pharmacokinetic principles as applied to the tumescent technique.
The apparent volume of distribution (V) is a theoretic concept that allows one to express the (total amount of drug in the body) = (X) in terms of the (concentration of drug in the blood) = (C). This theoretic V is a tool that simplifies the mathematical modeling of complex pharmacokinetic processes.
When a drug enters the body, it is distributed into various tissues in different concentrations. If the degree of drugtissue binding is independent of concentration, the ratio of the concentrations in the various tissues is constant. By making this theoretic assumption, one can express the ratio between the (C) and (X) by a simple proportionality equation, C = (1/V) · X, where (1/V) can be regarded as a constant of proportionality.
Knowing both X (e.g., total IV dose) and C (measured from a blood sample), one can express concentration (C) as the total amount (X) of drug per apparent volume (V):
C = X/V
X = V · C
The theoretic number V represents the hypothetic volume that would be necessary to contain all the drug present in the body at exactly the same concentration as found in the blood.
Lidocaine: Rate of Elimination. The rate of elimination of lidocaine from the body is known from the change of lidocaine blood levels over time after a simple IV bolus injection. By measuring lidocaine blood levels sequentially over time and plotting these levels on a graph, one can show that the rate of elimination of lidocaine from the body is proportional to the concentration (C) of lidocaine in the body.
A pharmacokinetic elimination process for a given drug is defined as a first-order process when the drug’s rate of elimination is directly proportional to the drug’s plasma concentration. Thus, by definition, lidocaine elimination via hepatic metabolism is a first-order process that is mathematically described by a simple, linear differential equation. This differential equation can be written in different ways, each equivalent to the others:
where (C) = X/V), X is amount of drug currently in the body, V is hypothetic apparent volume of distribution, and K is linear elimination rate constant.
This equation can be expressed as follows: the rate of decrease in the amount of lidocaine in the body is directly proportional to the amount in the body. The negative sign (–) indicates that a negative change is occurring, that is, X is decreasing with time. So far we have two proportionality equations: X = V · C and dX/dt = –KX. From elementary calculus we can solve the differential equation as follows:
dX/X = –K dt
Taking the integral of each side:
∫dX/X = ln X – ln X0 = ln(X/X0)
∫–K dt = –K · t = K · 0 = –K · t
Then equating the results:
ln X – ln X0 = –K · t
ln(X) = ln(X0) – (K · t)
Converting this natural logarithm to an exponential, one obtains an expression of the amount of drug in the body as a function of time:
exp [ln(X)] = exp[ln(X0)–(K · t)]
This is equivalent to the following:
X = X0 · exp(–Kt) (1)
Finally, because X = V · C, we can write V · C = X = (X0) exp(–Kt). After a rearrangement of terms, we can now have an equation that expresses blood concentration C(t) of lidocaine after IV bolus injection as a function of time:
C(t) = (X0/V)[exp(–Kt)]
Finding Experimental Value of C0 and V. By experimentally measuring the plasma concentration C of lidocaine at various times, we can determine experimental estimates for the values of K, the elimination rate constant, and V, the apparent volume of distribution.
Numeric calculations and drawings of graphs are easier using common logarithms to the base of 10 rather than natural logarithms to the base e. By definition:
Y = log10X (2)
if and only if:
10Y = X (3)
We can express Y in terms of natural logarithm to the base e by taking the natural logarithm of both sides of equation 3:
In X = ln 10Y = Y ln 10 (4)
After rearranging the terms, we have:
Y = (ln X)/(ln 10) (5)
By equating equations 1 and 4, we have:
log10X = (ln X)/(ln 10) (6)
Because ln (10) = 2.303, or equivalently, e2.303 = 10, equation 6 can be written as:
log10(X) = ln(X)/2.303
ln(X) = (2.303)log10(X) (7)
By taking the natural logarithm of both sides of equation 1, X = X0 · exp(–Kt), we have:
ln(X) = ln(X0) – (K · t) (8)
Substituting equation 7 into equation 8, we have:
log X = (log X0) – (K · t/2.303)
Because X = VC, and X0 · VC0, we derive:
log C(t) = (log C0) – (K/2.303) · t (9)
By measuring the plasma lidocaine concentration C(t) at various times and then plotting a graph of the data log C(t), which is the same as plotting C(t) using semilog graph paper, the data should fall along a straight line described by the equation for log C(t), where –K/2.303 is the slope of the line. By extrapolating back to time t = 0, we obtain:
log C(0) = log C0 – (K · 0/2.303) = log C0
This is an experimental estimate for the value of C0.
Now we can estimate for the apparent volume of distribution V = X0/C0, where X0 is the IV dose and C0 has been derived experimentally. For lidocaine, experimental data published by several investigators suggest that a reasonable estimate of the apparent volume of distribution V for a 70-kg person is 77 (± 28) liters, or 1.1 L/kg.
Experimental Estimate of K
Method 1. An experimental estimate for the value of K, the apparent first-order elimination rate constant, can be determined from the relationship C(t) = C0 at time t = 0, and C(t1/2) = C0/2 at time t1/2, where t1/2, the half-life of C(t), is the length of time required for C(t) to decrease from C0 to (C0)/2. We can easily determine t1/2 by simply plotting the graph of C(t), the plasma concentration of lidocaine, as a function of time following an IV bolus dose.
Substituting C(t1/2) = C0/2 in equation 9, we have:
log(C0/2) = log C0 – [K · t1/2]/2.303 (10)
After rearranging the terms, we derive:
[log(C0/2) = log C0 ]/t1/2= -[K]2.303 (11)
where –[K]/2.303 is equal to the slope of the line C(t) between t = 0 and t = t1/2. Thus, by estimating C0 and measuring C0/2 and t1/2, one can determine the numeric value of the slope = [K]/2.303 and therefore the number K.
Method 2. From equation 1 we have:
X = X0 · exp(–Kt)
If X = (1/2)X0, equation 1 becomes X0/2 = X0 · exp(–Kt1/2). Thus, [1/2] = exp(–Kt1/2), or equivalently, 2 = exp[Kt1/2], and ln(2) = K · t1/2, and finally:
K = ln(2)/t1/2 = 0.693/t1/2 (12)
Thus, by measuring the half-life of C(t), one can calculate the value of K.
Absorption. The process of drug absorption is a zeroorder process when the drug enters the systemic circulation at a constant rate. Thus dX/dt = k0 describes a zero-order process of absorption.
After tumescent infiltration of a large volume of dilute lidocaine and epinephrine into subcutaneous fat, the majority of the lidocaine is sequestered inside the tumescent subcutaneous tissue. Only the lidocaine near the peripheral “surface” of the infiltrated tissue is available for absorption. The profound degree of tumescent vasoconstriction in effect isolates the lidocaine that is contained deep within the tumescent tissue.
Thus, once a given dose XI of tumescent lidocaine at a concentration C has been infiltrated, the lidocaine absorption rate k1 is approximately a constant. When a larger dose of tumescent lidocaine X2 having the identical concentration C is infiltrated, the rate of absorption will be a constant k2. However, k1 and k2 are not necessarily equal.
Simultaneous Absorption and Elimination. From the previous discussion, we know that lidocaine is eliminated by a first-order process, and therefore dX/dt = –KX.
In reality, after tumescent infiltration of lidocaine, the plasma concentration depends on both the rate of absorption and the rate of elimination. The differential equation that describes the simultaneous absorption and elimination of lidocaine is as follows:
dX/dt = k0 –KX
where X is the amount of lidocaine in the body, and k0 is the constant rate of absorption (units of mg/sec). The solution of this differential equation is as follows:
X = (k0/K)[1 –exp(–Kt)]
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Figure 19-1 Graph of plasma lidocaine concentration, Clido(t), as a function of time after subcutaneous tumescent infiltration. Area under the curve (AUC) is equivalent to total amount of lidocaine absorbed over time into systemic circulation. Maximum or peak concentration of plasma lidocaine is designated by Cmax. The term Tmax is the exact point in time when Cmax occurs. For a fixed value of AUC, the smaller the value of Tmax, the greater is the value of Cmax. Any factor that delays lidocaine absorption will decrease magnitude of peak concentration.
Figure 19-2 Kinetics of tumescent lidocaine and tumescent saline. On two separate occasions, 75-kg female had tumescent infiltration of 2625 mg of lidocaine (35 mg/kg) in 5 L of normal saline. On the first occasion, no liposuction was done. Two weeks later, infiltration was repeated using identical volume of saline and identical dosage of lidocaine, followed by tumescent liposuction of 1500 ml of supranatant fat. (Redrawn from Klein JA: Plast Reconstr Surg 92:1085-1098, 1993.) A, Effect of liposuction on concentration of plasma lidocaine. Two graphs of concentration (Clido) of plasma lidocaine (μg/ml) as a function of time (t) are shown. The tallest graph, with largest area under curve (AUC), is a plot of sequential determinations of plasma lidocaine concentration after tumescent infiltration of 2625 mg of lidocaine in 5 L of solution without liposuction. Second graph has smaller AUC and represents sequential plasma lidocaine concentrations resulting from identical infiltration but differing from first because of liposuction. Difference in magnitude between two AUCs is attributed to effects of liposuction. Liposuction is responsible for reducing systemic absorption of tumescent lidocaine by approximately 20%. When this study was done, all incisions were closed with suture, with no open drainage. If open drainage had been used to remove additional lidocaine, reduction of AUC would have been more significant. Liposuction and open drainage contribute to reduced bioavailability and increased safety of tumescent lidocaine. B, Hematocrit changes after tumescent infiltration. Sequential measurement of hematocrit after tumescent infiltration of 5 L of saline with dilute epinephrine (0.5 mg/L) reveals much about systemic absorption of tumescent saline. Because hematocrit returns to preoperative value within 48 hours, change of hematocrit cannot be attributed to blood loss. No evidence indicates that tumescent liposuction produces hemoconcentration or that intravascular fluid deficit exists. Tumescent technique produces significant hemodilution with virtually no IV fluids. In this example, 10% decrease in hematocrit is consistent with 10% increase in volume of intravascular fluid compartment from hemodilution. Volume of intravascular fluid is maximum at same time (Tmax) that concentration of tumescent lidocaine achieves its maximum, approximately 12 hours after beginning infiltration. Rate and magnitude of intravascular fluid augmentation and change of hematocrit are independent of whether liposuction is performed. Thus a decline in hematocrit in immediate postoperative period does not correlate with amount of surgical blood loss caused by liposuction. C, Patient’s weight after infiltration and liposuction. At 48 hours after tumescent infiltration, patient’s weight returns to preinfiltration value. Without liposuction, weight is increased by 5 kg, which corresponds to 5 L of saline infused. Patient drank fluids without restriction. After gaining approximately 1 kg/L of tumescent infiltration, all tumescent fluid remaining in patient after liposuction is eliminated via kidneys. The 48-hour interval is typical for a return to preoperative weight, with or without liposuction. D, Cumulative urine volume after tumescent liposuction. Patient’s urine output was consistently greater than 70 ml/hr, with and without liposuction. This is a common threshold, below which physician becomes increasingly concerned about possible intravascular fluid deficiency, inadequate renal perfusion, renal insufficiency, or cardiac impairment. Patients are fully alert during tumescent liposuction and can drink clear liquids during and after surgery. No need exists for IV infusion of fluids because patients can drink fluids and because renal perfusion is adequate, as evidenced by continuously good urine output. E, Hourly urine specific gravity after tumescent liposuction. Typically, patient’s urine specific gravity decreases after tumescent infiltration. This decreased urine specific gravity shows patient is well hydrated. Because tumescent infiltration produces relative systemic fluid overload, routine administration of IV fluids is potentially dangerous.
Figure 19-3 Rate of lidocaine absorption affects risk of toxicity. Consider hypothetic patient who, on two separate occasions, is given identical doses of lidocaine that differ only in concentration and site of injection. On each occasion, sequential lidocaine plasma concentrations are determined over ensuing 48 hours. Because two doses are of equal magnitude with 100% systemic absorption, their areas under curve (AUCs) of plasma lidocaine concentration are equal. Suppose dose A is epidural injection of concentrated lidocaine (2% = 20 mg/ml) and epinephrine that is completely absorbed into systemic circulation and completely eliminated in approximately 12 hours. Suppose dose B is injection into subcutaneous fat of very dilute lidocaine (0.1% = 1mg/ml) and epinephrine that is completely absorbed into systemic circulation and completely eliminated in approximately 36 hours. Because AUCs are equal, graph of dose A, with the shortest base, must have the highest peak. Similarly, graph of dose B, with the longest base, must have the lowest peak. Because magnitude of peak plasma lidocaine concentration is correlated with risk of toxicity, a more rapid rate of absorption carries a greater risk of toxicity.
Figure 19-4 Graph of dose A, with small AUC, represents relatively small dose of lidocaine that is rapidly absorbed. For example, if small epidural dose of lidocaine rapidly absorbed into systemic circulation produces toxicity, one can expect toxicity to be of short duration. Graph of dose B, with large AUC, represents relatively large dose of lidocaine that is slowly absorbed. Consider the example of a large dose of subcutaneous tumescent lidocaine that is slowly absorbed. If plasma lidocaine concentration exceeds toxic threshold, toxicity will be of relatively long duration.
Figure 19-5 Rate of lidocaine infiltration can affect rate of absorption. Rapid infiltration of 1% and 0.5% lidocaine increases risk of toxicity. When combined 1% and 0.5% lidocaine, each with epinephrine concentration of 1:100,000, is infiltrated into subcutaneous fat within a short period (less than 5 minutes), systemic absorption can be rapid. Rapid infiltration of undiluted commercial concentrations of lidocaine with epinephrine can produce a peak plasma lidocaine concentration in excess of the 6 μg/kg threshold for potential lidocaine toxicity. Black straight line (●) represents serum lidocaine concentrations sampled at 15 and 30 minutes after total of 1350 mg of lidocaine had been infiltrated into targeted fat just before liposuction. Other straight line (■) represents similar result in another patient who received rapid injection of 800 mg of lidocaine. Gently curved graph (▲) represents much slower systemic absorption of tumescent lidocaine. After incremental infiltration over 45 minutes of 1000 mg of lidocaine (1%) with epinephrine, peak plasma lidocaine concentration was only 1.4 μg/ml. (Data for ■ from Piveral K: Plast Reconstr Surg 80:643, 1987 [letter].)
Figure 19-6 Concentration of lidocaine can affect rate of absorption. Dilution slows rate of lidocaine absorption. When 1 g of dilute lidocaine (1 g/L) and epinephrine (1 mg/L) is slowly injected into subcutaneous fat over 45 minutes, Tmax = 14 hours and Cmax = 1.2 μg/ml. Two weeks later, when 1 g of undiluted commercial concentration of lidocaine (1 g/100 ml) and epinephrine (1 mg/100 ml) was slowly injected into subcutaneous fat, rate of absorption was more rapid, with Tmax = 9 hours and Cmax = 1.5 μg/ml.
Figure 19-7 Tumescent solution without epinephrine. During infiltration for tumescent liposuction, there was no clinical evidence of blanching vasoconstriction, and blood-tinged anesthetic oozed from needle puncture sites. Patient had received 17.8 mg/kg of lidocaine when it was determined that epinephrine had been omitted from anesthetic solution. Sequential plasma samples were obtained over 18 hours after initiation of infiltration. Tmax occurred in less than 3 hours, much sooner than usual 8 to 14 hours. Also, Cmax of 2.1 μg/ml was unusually high.
Figure 19-8 Pharmacokinetics of IV bolus of lidocaine. Graph represents plasma lidocaine concentration as it changes over time beginning immediately after IV bolus dose. Initial rapid decrease in lidocaine concentration primarily results from rapid removal of lidocaine from plasma as it is distributed (α-phase) into other tissues. After lidocaine has achieved equilibrium concentration among all body tissues, rate of declining plasma concentration principally results from more gradual process of elimination (β-phase) by hepatic metabolism (see text).
Figure 19-9 Total lidocaine dose determines its plasma concentration–time profile. Relationship between total dose of tumescent lidocaine and maximum plasma lidocaine concentration (Cmax) is not linear. With increasing dosages (mg/kg) of tumescent lidocaine, shape of the graph of plasma lidocaine concentration as a function of time, Clido(t), tends to change. At lower dosages Cmax appears as distinct peak; at high dosages Cmax tends to become a plateau that may persist for several hours. ○, 15 mg/kg; □, 35 mg/kg; ∆, 60 mg/kg.
Figure 19-10 Maximum lidocaine concentration (Cmax) occurs when rate of absorption equals rate of elimination. When rate of lidocaine absorption exceeds rate of elimination, plasma lidocaine concentration (○) is an increasing function of time. When rate of lidocaine elimination is greater than rate of absorption, plasma lidocaine concentration decreases with time. When rate of absorption equals rate of elimination, concentration = Cmax.
Figure 19-11 After liposuction using large dosages of tumescent lidocaine, plasma lidocaine concentration typically achieves extended Cmax plateau rather than single peak maximum value.
Figure 19-12 Lidocaine is rapidly metabolized in liver. When 1 L of blood passes through liver, approximately 700 ml of blood is completely cleared of all lidocaine by hepatic cytochrome P450 3A4 metabolism. As blood flows through liver, 70% of blood lidocaine content is eliminated.
|TABLE 19-1 Lidocaine Pharmacokinetic Parameters|
|Fe (fraction of drug excreted unchanged)||0.02 ± 0.01|
|kn (elimination rate constant)||0.39/hr|
|Oral availability (%)||35 ± 11|
|Urinary excretion (%)||2 ± 1|
|Bound in plasma (%)||70 ± 5|
|Clearance in a 70-kg person||640 ± 170 ml/min/70 kg|
|@ 700 ml/min/70 kg|
|= 10 ml/min/kg|
|Volume of distribution (L)||1.1 L/kg|
|70-kg person||77 ± 28|
|Redistribution (α) half-life||8 min|
|Elimination (β) half-life||1.8 ± 0.4 hr|
|Toxic concentration||> 6 μg/ml|