The clinical relevance of accounting for differences in body mass is a result of the prevalence of obesity in the Western culture. Obesity is a major public health problem throughout the developed world. Since the early 1970s, the proportion of the American population that is overweight has steadily increased.55 Among US adults ages 20 to 74 years, approximately 25% are overweight with a slightly higher prevalence among women.56 Almost 5% of US adults are morbidly obese (ie, they weigh twice their ideal body weight [IBW]). Anesthesia providers thus frequently encounter obese patients in everyday practice.
Many investigators have explored the impact of weight on drug dosing for opioids46,57-59 and sedatives60 and have offered strategies on how doses should be formulated for patients who are overweight. Nonetheless, despite the high prevalence of obesity, practitioners often formulate dosage regimens for many drugs based on total body weight (TBW). Dosing according to TBW in obese patients, however, can lead to large doses and prolonged or toxic effect. Clinicians should recognize that most studies designed to determine appropriate doses of IV anesthetics have been conducted in healthy patients or volunteers at or near their IBW. A unique attribute of IBW is that it represents an estimate of appropriate body weight based on height only. For example, a popular formula to estimate IBW is 49.9 + 0.89 × (Height – 152.4) kg for men and 45.4 + 0.89 × (Height – 152.4) kg for women.61
To illustrate the resultant weights using these formulas, IBWs for several common heights are presented in Table 40-5. It is important to point out that when using these formulas for any given height, the IBW is the same regardless of weight. Formulating a dose according to the IBW for patients of equivalent height that are 70, 100, and 150 kg would be the same. By contrast to dosing patients according to their TBW, dosing according to the IBW has the potential for significant underdosing.
To get around the limitations of IBW for dosing anesthetics, investigators have used lean body mass (LBM) instead. Advantages of LBM are that it excludes weight associated with adipose tissue and accounts for patient height and TBW. For example, LBM has been used to scale pharmacokinetic parameters (ie, volumes and clearances) for remifentanil to predict drug levels in lean and obese patients (Table 40-6).57
Using these weight-adjusted pharmacokinetic parameters, simulations of remifentanil effect site concentrations in obese and lean patients can be compared when dosed according to TBW versus LBM (Fig. 40-21). This set of simulations was performed for a lean woman (125 lb) and an obese woman (220 lb) of the same height (5 ft, 5 in). The simulations used dosing regimens typical for remifentanil as part of a combined technique with a potent inhaled agent, nitrous oxide, or a continuous infusion of a sedative hypnotic. The dosing scheme included a bolus dose (1 μg/kg) followed by a continuous infusion at 0.25 μg/kg/min for 20 minutes and then 0.15 μg/kg/min for 60 minutes.
Key points illustrated by these simulations include (1) Dosing obese patients according to their TBW can yield remifentanil effect site concentrations that are substantially higher than equivalently dosed lean patients. The peak effect site concentrations after 20 minutes of the anesthetic were 9.5 and 5.4 ng/mL for the obese and lean patient, respectively. (2) With the dosing scaled to LBM, the resultant simulated effect site concentrations for both the lean and obese patients were lower than the effect site profile for a lean patient dosed to her TBW. These simulations suggest that dosing IV anesthetics to LBM, similar to IBW, may lead to significant underdosing.
LBM has an additional limitation. When a patient's weight approaches morbid obesity, dosing according to the LBM becomes increasingly inaccurate.62 A unique and somewhat worrisome feature to the LBM equation is that for any given height, there is a maximum LBM. For TBWs that are above the maximum LBM, the LBM decreases. In Fig. 40-22, an LBM normogram, the LBM estimates that correspond to TBWs in which the LBM decreases with increasing TBW are plotted as a gray dashed line. This is most likely an artifact of the LBM equation. If not accounted for, very large patients would receive smaller doses than patients of equivalent height who are not as large. Another limitation of using the LBM normogram for dosing is that the LBM reports the patient mass in the absence of any fat tissue.
The LBM is always lower than the IBW. This is illustrated in the normogram with solid gray lines. These lines point out the resultant LBM for an IBW for a man who is 6 ft, 1 in tall and a woman who is 5 ft, 9 in tall. Because even lean people have some fat, this suggests that using the LBM for dosing anesthetics, as observed in Fig. 40-21, leads to some degree of underdosing. Hence, for clinical purposes, the LBM equation is perhaps only useful until reaching the maximum LBM for a given height with the expectation that many patients may require additional anesthetic.
With this limitation in mind, Bouillon and Shafer62 recommended that estimates of the ideal dosing weight from which to formulate dosing regimen use a modified normogram of LBM. Their modified normogram uses the following guidelines: (1) Conventional LBM scales are adjusted to IBW (in other words, for a patient who is at his or her IBW, the LBM at a given height should be the IBW). In effect, this shifts the original normograms presented in Fig. 40-22 up and to the left. (2) The scaled or modified LBM normograms are truncated at the maximal estimates of LBM. This approach relies on the assumptions that recommended doses printed in package inserts are appropriate for patients who are at their IBW. The scaled normogram of LBM is presented in Fig. 40-23. Again, the gray dashed lines represent the point where the scaled LBM decreases with increasing weight. Scaled LBM estimates in this region should not be used to estimate the proper dosing weight.
Using this scaled normogram for dosing remifentanil when a person's weight is at or below his or her IBW is unnecessary. Using the person's actual weight will suffice. When a person's weight is above his or her IBW, using the normogram in Fig. 40-23 may be useful but probably not immediately practical if not readily available in a clinical setting. A more simplified approach based on the normograms presented in Fig. 40-23 is to use a patient's IBW or if approaching morbid obesity, consider using their IBW plus some fraction of the difference between TBW and IBW.62 A simplified summary of scaled LBM normograms is presented by gender in Table 40-7. To account for height and weight, suggested scaled weights to use for dosing are presented as a function of the body mass index (BMI).
In Fig. 40-21, the green line represents the resultant remifentanil effect site concentration when dosing the 5-ft, 5-in (165-cm), 220-lb (100-kg) patient according to the suggested dosing weight in Table 40-6. Her IBW is 57 kg. Her BMI was calculated as 37. Twenty percent of the difference between the TBW and IBW is 8.6 kg. The suggested dosing weight is therefore 65.6 kg. The resultant effect site concentrations are in between the concentrations when dosing her according to her TBW and LBM, respectively. Using this approach, the inherent risks of underdosing using the LBM and overdosing using the TBW as well as avoiding the limitations of dosing according to the IBW are avoided.
Age and Intravenous Anesthetic Pharmacology: Developing Rational Dosing Strategies
Considering the aging of the world's population, the clinical significance of age in the practice of anesthesia is obvious. Practitioners are frequently faced with the clinical challenge of anesthetizing older adults, sometimes even patients in their ninth or tenth decades of life. Clinicians have long recognized that elderly patients usually require smaller dosages of most IV anesthetics to produce the desired therapeutic effect while minimizing adverse effects.
Of the frequently considered patient covariates (eg, gender, age, body weight, kidney function, hepatic function), age is perhaps one of the most valuable in terms of developing a therapeutic, nontoxic dosage strategy for many IV anesthetics. Age is easily measured (ie, just ask the patient), and its influence on the pharmacokinetics and pharmacodynamics of many IV anesthetics has been described in some detail.
With regard to age, both remifentanil and propofol can serve as prototypes to examine the impact of age on anesthetic pharmacology. Studies specifically designed to assess the influence of age on remifentanil and propofol pharmacokinetics and pharmacodynamics have been conducted, and complex models have been constructed that characterize the influence of age in quantitative terms.11,32,60,62,63
With regard to remifentanil, it is clear that the elderly do indeed require less drug to produce the desired spectrum of opioid effects. The reduced dosage requirement is a function of both pharmacokinetic and pharmacodynamic mechanisms, although pharmacodynamic factors dominate.11 The concentration of remifentanil necessary for 50% of maximal effect as measured by the EEG is markedly decreased in elderly adults (C50 for EEG changes); in addition, remifentanil's clearance and volume of distribution are also decreased.11 These age-related changes translate clinically into the need for a very substantial dosage reduction in elderly adults that is based largely on the increased potency of remifentanil in older patients (ie, a pharmacodynamic difference).
Using the pharmacokinetic–pharmacodynamic parameters from age-adjusted pharmacologic models of propofol and remifentanil, computer simulations can be performed to explore the suitability of various dosage schemes. Fig. 40-24 presents a set of simulations of propofol's pharmacologic behavior after an induction dose of propofol. Using age-adjusted pharmacokinetic and pharmacodynamic parameters,32,60 4 simulations of a 2-mg/kg propofol bolus for a 20-, 40-, 60-, and 80-year-old patient demonstrate that with the same dose, there is a subtle rise in the peak propofol effect site concentration and a small delay in reaching the peak with increasing age. By contrast, the concentration at which there is a 50% probability of losing unresponsiveness (C50 for unresponsiveness) drops by 50% from age 20 to 80 years (Table 40-8). Combining the pharmacokinetic and pharmacodynamic models, the duration of propofol effect (ie, the time above the effect site concentration associated with a loss of responsiveness) substantially increases with increasing age.
This plot illustrates a combined pharmacokinetic and pharmacodynamic simulation of the propofol effect site concentration that results from a 2-mg/kg bolus. The simulated patient is an 80-kg, 183-cm-tall man. Simulations were performed for patients of age 20, 40, 60, and 80 years old. The horizontal lines represent the effect site concentrations (Ces) associated with a 50% probability of loss of responsiveness. They are 1.7, 1.4, 1.1, and 0.8 μg/mL for ages 20, 40, 60, and 80 years, respectively. Pharmacokinetic and pharmacodynamic parameters for propofol by age were adapted for simulation from Schnider et al.32,60
Table 40‐8 Influence of Age on the Pharmacologic Behavior of a 2‐mg/kg Bolus of Propofol and a 1-Hour Remifentanil Infusion Set at 0.2 mcg/kg/Min ||Download (.pdf)
Table 40‐8 Influence of Age on the Pharmacologic Behavior of a 2‐mg/kg Bolus of Propofol and a 1-Hour Remifentanil Infusion Set at 0.2 mcg/kg/Min
| Peak propofol Ce (mcg/mL)||6.5||7.0||7.6||8.2|
| Time to peak Ce (min)||1.7||1.8||2.0||2.0|
| C50 for LOR (mcg/mL)||1.7||1.4||1.1||0.8|
| Time above the C50 for LOR (min)||9||10||12||14|
| Percent reduction in dose (%)||0||25||56||65|
| Remifentanil Ce (ng/mL) upon termination of the infusion||5.6||6.6||8.0||10.2|
| C50 for analgesia (ng/mL)||2.0||1.6||1.3||0.9|
| Upon termination of the infusion, time above the C50 for analgesia (min)||8||13||19||29|
| Percent reduction in dose (%)||0||18||37||55|
Similarly, Fig. 40-25 is an illustration of simulations of remifentanil's pharmacologic behavior after a 1-hour infusion. Using age-adjusted pharmacokinetic and pharmacodynamic parameters,11,63 4 simulations are presented of a 1-hour continuous infusion at a rate of 0.2 μg/kg/min for a 20-, 40-, 60-, and 80-year-old patient. With the same infusion rate, the remifentanil effect site concentration develops a substantial increase over time with increasing age (Table 40-8). Estimates of the C50 for analgesia allow for the prediction of duration of analgesic effect after termination of the 1-hour infusion. In Fig. 40-25, the C50 for each simulated age is presented as a horizontal line. After termination of the infusion, the duration of analgesic effect markedly increases with age (>3-fold increase from age 20-80 years).
This plot illustrates a combined pharmacokinetic and pharmacodynamic simulation of the remifentanil effect site concentration (Ce) that results from a 1-hour infusion set at 0.2 μg/kg/min. The simulated patient is an 80-kg, 183-cm-tall man. Simulations were performed for patients of age 20, 40, 60, and 80 years old. The horizontal lines represent the effect site concentrations associated with a analgesia. The analgesic levels are 2, 1.6, 1.3, and 0.9 ng/mL for ages 20, 40, 60, and 80 years, respectively. Pharmacokinetic and pharmacodynamic parameters for propofol by age were adapted for simulation from Minto et al.11,63
Additional simulations can be used to estimate the percent reduction in dose as a function of age for both propofol and remifentanil. As is illustrated in Table 40-8, achieving equipotent doses in 20- and 80-year-old adults requires that an 80-year-old patient receive a dose that has been reduced by 55% to 65% of that which would be given to a 20-year-old patient. These simulations emphasize the importance of considering age when formulating an appropriate dose in elderly patients.
Although physiologic mechanism of the pharmacodynamic changes in elderly people remains largely unexplored, the pharmacokinetic changes may be at least attributable to decreased cardiac output. The lower cardiac output associated with advanced age64 presumably results in slower drug mixing and therefore higher peak concentrations after a bolus dose.65-67 Lower cardiac output may also decrease drug delivery to metabolic organs, resulting in lower clearance for some drugs.
When generalizing to other drugs, whether reduced cardiac output is the primary underlying mechanism responsible for the pharmacokinetic changes observed in elderly adults, it is consistent with the observation that many IV anesthetics (thiopental, propofol, etomidate) appear to have a smaller distribution volume or slower clearance in elderly adults.10,60,68,69
It is, however, important to point out that reduced cardiac output is not a ubiquitous finding in elderly adults, particularly in the absence of heart disease in well-conditioned individuals.70 Recognizing this has perhaps led to the common clinical notion of identifying a patient's "physiological" age instead of relying on chronological age alone.71,72 Significant reductions in dosage may not therefore be necessary for physically robust elderly patients with normal body habitus and without substantial coexisting disease.
It is more difficult to generalize with regard to age-induced pharmacodynamic changes to other IV anesthetics. Although elderly adults clearly have a "left-shifted" concentration–effect relationship for opioids (ie, the opioids are more potent in elderly patients11,73), a good deal of data suggest that older patients are not more pharmacodynamically sensitive to the sedative–hypnotics. For example, there is no difference between old and young in terms of the EEG C50 for etomidate or thiopental.10,68,69 On the other hand, recently published data suggest that both propofol and midazolam are more potent in elderly patients.32,74 Thus, although there is certainly general consensus that elderly patients require less medication than younger patients, whether this reduced dosage requirement can be attributed to pharmacokinetic or pharmacodynamic mechanisms remains unclear for some individual agents.
Blood Volume and Intravenous Anesthetic Pharmacology: Developing Rational Dosing Strategies
Dr Halford, a surgeon, wrote a letter to the editor of Anesthesiology after caring for several trauma victims after the attack on Pearl Harbor in 1941. He noticed that anesthetists had started using the IV anesthetic sodium pentothal. His comments included: "Then let it be said that intravenous anesthesia is also an ideal form of euthanasia… .With this heterogeneous mass of emergency anesthetists, it is necessary to choose an anesthetic involving the WIDEST MARGIN OF SAFETY for the patient… . Stick with ETHER."75
Anesthesiologists have long recognized the need to select certain IV anesthetics over others, to incrementally dose these anesthetics, and to moderate the overall dose for patients who have significant blood loss before or during surgery. Through experience, clinicians have learned that a full dose of selected IV anesthetics can lead to pronounced and often unwanted side effects with potentially disastrous consequences.
In the recent past, several researchers have attempted to quantify how the extent of blood loss impacts IV anesthetic pharmacokinetics and pharmacodynamics to include work with opioids,76-78 sedative–hypnotics,79-83 benzodiazepines,84,85 and local anesthetics.86 The most important finding consistent throughout this body of work is that equivalent dosing leads to higher drug concentrations with severe blood loss compared with control participants without bleeding. In addition, although derived volumes and clearances from pharmacokinetic analyses do not reflect true organ drug distribution and clearance, they do indicate that in severe blood loss, blood flow to muscle, gut, liver, and connective tissue is markedly decreased such that anesthetics delivered IV are most likely pumped straight to the brain in higher concentrations. This phenomenon leads to higher brain concentrations of anesthetic drugs and a more pronounced or prolonged anesthetic effect.87
As an example, Fig. 40-26 illustrates the differences in blood concentrations that result from identical doses of remifentanil in bled and unbled swine.78 After severe blood loss (42 mL/kg), resultant remifentanil blood levels were 2-fold higher during and after a 10-minute remifentanil infusion. Of note in this study, the dose (10 μg/kg/min) is approximately 50- to 100-fold more than a typical dose of 0.1 to 0.2 μg/kg/min, yet all animals survived despite losing more than half of their blood. A decrease in blood volume and cardiac index (5-1.7 L/min/m2) along with compensatory changes in regional blood flow are the likely physiologic mechanisms explaining these pharmacokinetic changes. Pharmacokinetic analyses revealed that the volumes of distribution and clearances were decreased in bled animals compared with unbled control subjects. Spectral edge changes in the EEG were used to measure drug effect. By contrast to the pharmacokinetic analysis, there was no difference observed in the pharmacodynamics between groups. As has been observed with fentanyl77 and morphine,76 these findings with remifentanil corroborate the relative forgiving posture of high-dose opioids on cardiovascular function even when used in hemorrhagic shock.
Resultant mean blood drug concentrations versus time from equivalent dosing of remifentanil in bled (42 mL/kg) and unbled swine. The red and blue lines represent the mean levels for bled and unbled animals, respectively. The blue box at the lower left corner represents the duration of the 10-μg/kg/min remifentanil infusion. The error bars indicate the standard error. The vertical axis is on the log scale. Cp, plasma concentration.
In contrast to opioids, blood loss has a more worrisome impact on propofol pharmacokinetics and pharmacodynamics. Similar to the experimental design used with remifentanil described above, investigators have bled animals and then administered propofol. Two major differences were observed when compared with remifentanil. First, the administration of propofol after severe hemorrhage (42 mL/kg) led to certain cardiovascular collapse. Second, the dose found to elicit a pharmacologic effect (ie, a change in the BIS of at least 50) in unbled animals was in no way tolerated in bled animals. To conduct experiments in bled animals, the propofol dose had to be reduced by more than 50%, and the extent of hemorrhage had be markedly reduced to 30 mL/kg. In this case, hemorrhage led to a decrease in the cardiac index from 5 to 2.6 L/min/m2. Subsequently, animals received a 10-minute propofol infusion at 200 μg/kg/min. Of interest, with equivalent dosing, the hemorrhaged animals exhibited approximately 2-fold greater plasma concentrations of propofol throughout the study period. A pharmacokinetic analysis revealed that similar to remifentanil, propofol compartmental clearances and volumes were decreased in bled animals.
The BIS was used as a surrogate measure of propofol effect. As expected, changes in the BIS lagged behind the changes in plasma propofol concentrations. These data were used to estimate the keo for bled and unbled animals and construct previously described pharmacodynamic models to include estimates of the C50 and γ. Comparison of pharmacodynamic parameters between bled and unbled animals revealed a similar keo and γ but a 2.7-fold decrease in the C50 (4.6 μg/mL vs 1.7 μg/mL for the control and shock groups, respectively). This is emphasized by the leftward shift (green arrow) in the C50 for each study group in Fig. 40-27.
The concentration–effect relationship of propofol to the bispectral index scale (BIS) in bled (30 mL/kg) and unbled swine as characterized by a pharmacodynamic model. The blue and red lines represent the mean change in BIS over a range of propofol effect site concentrations (Ces) for unbled and bled swine, respectively. The green arrow illustrates the shift in the C50 between groups.
Perhaps one of the more dangerous uses of IV anesthetics is during the induction of anesthesia. Here bolus doses are used to rapidly render a patient analgesic or unconscious, but these doses can be associated with significant morbidity if dosing does not account for large changes in blood volume. For purposes of discussion, consider an induction dose of propofol. The pharmacokinetic and pharmacodynamic findings related to propofol during blood loss described previously will be used to illustrate how blood loss impacts conventional dosing of sedative hypnotics.
In Fig. 40-11, using pharmacokinetic parameters previously described in humans,3 the onset and duration of loss of responsiveness after a propofol bolus of 2 mg/kg were 1 and 8 minutes, respectively, assuming that the necessary propofol effect site concentrations required for loss of responsiveness near 1.8 μg/mL.25 Conducting a propofol bolus simulation after moderate blood loss (35% of the blood volume) yields a significantly different result (Fig. 40-28). Based on the impact of blood loss on propofol pharmacokinetics and pharmacodynamics, this simulation takes in account the 2.5-fold increase in effect site propofol concentration and the 2.7-fold decrease in concentration required for loss of responsiveness.
Combined pharmacokinetic and pharmacodynamic simulations of a propofol bolus dose 2 mg/kg under normal hemodynamic conditions and after moderate blood loss. The blue and red lines represent the effect site concentrations (Ces) under normal and hypovolemic conditions. The gray solid and dashed lines represent the propofol effect site concentration associated with a loss of responsiveness under normal and hypovolemic conditions.
With this simulation, the impact of moderate blood loss on the duration of effect is easily appreciated. Of note, with blood loss, there is more than a 5-fold increase in the duration of effect (8-44 minutes). These simulations suggest that propofol should be used, if at all, with extreme caution! Estimating the dose that would provide an equivalent effect in a person with severe blood loss compared with a person with normal cardiovascular physiology yields a propofol dose reduction of 80% (eg, 0.4 mg/kg). Although the impact of blood loss on propofol is dramatic, it is important to recognize that this simulation is of a single propofol bolus and does not reflect the common practice of combining propofol with an opioid during the induction of anesthesia. In this scenario, it is likely that the pronounced increase in peak effect and duration of effect would only be larger and potentially more dangerous.
Perhaps the most important consequence of blood loss on propofol behavior is the exaggerated hemodynamic response after a bolus dose. Propofol is a peripheral vasodilator and suppresses contractility.88 As observed in these simulations, a propofol bolus dose yields higher effect site concentrations that remain elevated for a prolonged period of time, thus amplifying propofol's cardiovascular depression. Sodium thiopental has a similar profile of cardiovascular depression, and this likely explains why Dr Halford was so adamant about the dangers associated with the induction of anesthesia with sodium pentothal.
What about resuscitation? Does volume resuscitation restore drug disposition and effect to baseline? In typical clinical practice, some fluid resuscitation is usually under way before the administration of an anesthetic. Based on the premise that resuscitation will restore cardiac output and systemic blood flow, the shock-induced pharmacokinetic and pharmacodynamic changes may be reversed. In a similar set of experiments, a comparison was made between unbled control subjects and bled and then partially resuscitated swine.89 Hemorrhage was severe (42 mL/kg), and resuscitation constituted an infusion of crystalloid to maintain a mean arterial blood pressure of 70 mm Hg for 60 minutes. This resulted in a resuscitation volume of 59 mL/kg.
After a 10-minute high-dose (750 μg/kg/min) propofol infusion, the propofol plasma concentrations were nearly identical. Resuscitation restored the shock-induced changes in propofol pharmacokinetics to near baseline values. The pharmacodynamic parameters, however, remained altered. As with severe blood loss, the C50 was decreased 1.5-fold after hemorrhage and resuscitation. Although the mechanism for this phenomenon is not well understood, one explanation for the increase in end-organ sensitivity to propofol may be at least partly attributable to an unrecognized increase in unbound propofol. Thus, the leftward shift in the C50 of propofol may represent an undetected pharmacokinetic difference between groups. Although the plasma propofol levels were similar between the bled and then resuscitated animals and the unbled animals, the amount of unbound propofol available to exert a pharmacologic effect may have been increased.90 After removing more than 50% of the estimated blood volume and replacing it with crystalloid, plasma protein content would most likely be decreased. Furthermore, alterations in organ blood flow, capillary wall integrity, and plasma pH may influence the levels of unbound propofol. Given that plasma protein content, propofol-plasma protein binding, or unbound propofol levels were not measured or estimated, the extent that changes in unbound propofol played in altering the observed differences in end-organ sensitivity remains unknown.
With this protocol, 60% of the estimated blood volume was removed. A total of 140% of the shed blood volume was replaced with lactated Ringer solution to maintain a near-normotensive blood pressure. The near-normal blood pressure was deceiving! Although hemodynamic function appeared near normal (ie, the central venous pressure and cardiac index were similar to those in unbled animals), the cardiovascular response to propofol remained exaggerated. During the propofol infusion, the cardiac index decreased by 1.7 L/min/m2 in the shock-resuscitation group but only by 0.2 L/min/m2 in the control group. The large hemodynamic changes in the shock-resuscitation group illustrate how severe blood loss followed by partial resuscitation can lead to potentially large cardiovascular changes with the administration of propofol. In fact, a significant clinical correlate from this analysis is that despite a near-normal hemodynamic profile after partial resuscitation for severe blood loss, resuscitation should continue to minimize the potentially severe hemodynamic depression that can be associated with the administration of propofol.
Fig. 40-29 represents a simulation of the propofol effect site concentration after a propofol bolus dose in a patient with severe blood loss followed by partial resuscitation with crystalloid (1.5 mL of crystalloid per 1 mL of estimated blood loss). This simulation accounts for the pharmacodynamic changes as manifest by a 1.5-fold decrease in the effect site concentration required for loss of responsiveness. The duration of effect increases from 8 to 11 minutes.
Combined pharmacokinetic and pharmacodynamic simulation of a 2-mg/kg propofol bolus dose after severe blood loss and resuscitation. The solid and dashed gray lines represent the effect site concentrations (Ces) at which there is a loss of responsiveness under normal and bled and then resuscitated conditions. Emax, maximal effect.
Compared with propofol, both ketamine and etomidate have greater acceptance among clinicians who care for patients with significant blood loss. This is largely because the cardiovascular depression known to be exaggerated with propofol and sodium pentothal is not as apparent with etomidate and even to a lesser extent with ketamine. Although etomidate is known to produce mild cardiovascular depression, prior work surprisingly has revealed minimal cardiovascular change after a high-dose brief continuous etomidate infusion81,83 during moderate hemorrhagic shock (30 mL/kg). In a similar fashion, the pharmacokinetic and pharmacodynamic profile of etomidate after blood loss was also minimally influenced by blood loss. This suggests that dosing requirements for etomidate do not require adjustment after moderate blood loss. This finding goes along with the widely held view that etomidate is a good choice in hemodynamically unstable patients.
What remains unknown is the impact of blood loss on ketamine. Preliminary work has revealed that, similar to etomidate, blood loss does not significantly impact the pharmacokinetics of ketamine. Ketamine is known to increase sympathetic tone, serve as a potent analgesic, and perform favorably in patients with poor cardiovascular function. These preliminary findings support the widely held view that ketamine is an important drug to maintain in our pharmacologic armamentarium when caring for patients with life-threatening blood loss.
The pharmacodynamic properties of ketamine, however, are difficult to assess. This is largely because ketamine is a racemic mixture that, when metabolized, has an active metabolite, norketamine. Hence, the contribution of both enantiomers and norketamine must be considered when assessing the overall drug effect of ketamine. An additional difficulty with measuring ketamine's drug effect is that it is difficult to identify surrogate measure for ketamine's effect. For example, the BIS is not a reliable measure of ketamine's sedative effects.
In summary, as clinicians manage patients with blood loss through often perilous anesthetics, hemorrhage and even hemorrhage followed by resuscitation that appears to restore hemodynamic function to near normal can lead to dramatic alterations in the pharmacologic behavior of commonly used sedative hypnotics and opioids. Duration of effect, peak effect site concentrations, and extent of cardiovascular depression should all be considered when selecting an IV anesthetic and formulating an appropriate dose. Hemodynamically compromised patients are especially susceptible to the cardiovascular suppression of selected sedative hypnotics, but other sedative hypnotics appear to be much safer. Propofol and sodium pentothal are especially poor choices even after some degree of resuscitation. By contrast, ketamine and etomidate tend to be immune to the deleterious effects of moderate to severe blood loss on their pharmacokinetic profiles. Severe blood loss alters opioid pharmacokinetics, leading to higher plasma concentrations, but opioids, in contrast to propofol and sodium pentothal, enjoy a wider therapeutic margin in the presence of blood loss. What remains unexplored, however, is the impact blood loss has on the resultant effect from the simultaneous administration of multiple drugs. As illustrated in the drug synergism section of this chapter, opioids and sedative–hypnotics can dramatically influence one another. How this interaction behaves in the presence of intravascular volume depletion remains unknown.
One of the most vexing problems facing anesthetists is satisfactorily caring for patients who chronically consume opioids (see Chapter 24 for a general review of substance abuse and anesthesia practice). With chronic consumption of opioids, tolerance develops, and more drug is required to achieve a desired analgesic effect. This becomes especially problematic in the perioperative period when opioid dosing requirements for these patients often reach thresholds associated with significant morbidity in the nonopioid-tolerant population. Out of concern for patient safety, opioid doses are often administered in more conventional doses to avoid unwanted side effects associated with opioid toxicity, leading to often dramatically poor pain control in the postoperative period. In these types of patients, the population-based pharmacodynamic models used to describe opioid concentration–effect relationships become obsolete. Performing simulations to estimate opioid behavior either alone or in combination with other types of anesthetics using pharmacodynamic models built from studies evaluating an opioid-naïve population is bound to provide a faulty estimate of drug effect in patients who chronically consume opioids. The essential problem is that the magnitude of the right shift in the C50 and C95, which are key parameters used to build the pharmacodynamic models, is unknown (Fig. 40-30).
The effect of opioid tolerance on the concentration–effect relationship characterized by pharmacodynamic modeling. The C50 and C95 are shifted to the right indicating that the more drug is required to achieve the same level of drug effect.
With the widespread use of oral short-acting and time-contingent opioids, transdermal opioid delivery systems, and implantable opioid infusion pumps, opioid tolerance is recognized as a growing challenge in the perioperative environment. Nevertheless, there is a paucity of literature examining the phenomenon of opioid tolerance as a covariate in pharmacodynamic models. One potential reason for this is that opioid tolerance is a difficult feature of drug behavior to quantify and most likely varies substantially from person to person based on duration of opioid consumption and opioid dose.
With this problem in mind, investigators have explored methods of identifying the concentration—effect relationship for opioid on an individual basis.91-93 Using principles of pharmacokinetics and pharmacodynamics, a technique has been developed called the fentanyl challenge. The fentanyl challenge was designed for use in patients with a known history of chronic opioid consumption who are scheduled to undergo surgical procedures associated with significant postoperative pain that will require a general anesthetic and are of moderate to long duration (ie, multilevel lumbar spine instrumentation). The fentanyl challenge protocol calls for a rapid continuous infusion of fentanyl (2 μg/kg/min) to be administered until the onset of respiratory depression in the absence of any other sedatives, anxiolytics, or opioids (Fig. 40-31). The optimal setting in which to perform the challenge is just before the induction of general anesthesia. The onset of respiratory depression as defined within the fentanyl challenge is a respiratory rate less than 6 breaths/min. A critical component of the challenge is to measure the time from the onset of the fentanyl infusion until the onset of respiratory depression.
Computer simulation of the fentanyl challenge. The plot illustrates the fentanyl effect site concentration (Ce) that results from a continuous infusion of 2 μg/kg/min. This plot is used to estimate the fentanyl effect site concentration at the onset of respiratory depression. For example, if 8 minutes elapse before the onset of respiratory depression (ie, a respiratory rate <6 breaths/min), the associated fentanyl effect site concentration is approximately 20 ng/mL.
With the duration of the high-dose fentanyl infusion until respiratory depression identified, a pharmacokinetic simulation of the infusion is made to identify the fentanyl effect site concentration that is associated with respiratory depression. This process redefines the pharmacodynamic relationship between fentanyl effect site concentrations and drug effect that is unique to a particular patient. A major assumption of this protocol is that more drug will be required to achieve analgesia.
As previously described in the pharmacodynamic section, there are a series of pharmacodynamic relationships over an array of noxious stimuli encountered in the perioperative environment (Fig. 40-10). One interesting feature of this array of concentration relationships is that they can be quantified in terms of a percentage of the amount of drug required to elicit EEG changes.26 For example, the fentanyl effect site concentration associated with C50 for changes in the spectral edge, a measure of EEG activity is approximately 9 ng/mL.35,73,94,95 The fentanyl effect site concentration C50s associated with analgesia and respiratory depression are 1.6 and 5.4 ng/mL, respectively. Hence, the fentanyl effect site concentrations for analgesia and respiratory depression are 17% and 60%, respectively, of the C50 for EEG changes. Taking advantage of this linearity, the analgesic fentanyl effect site concentrations are approximately 30% of those associated with respiratory depression.96,97
Although not well established, preliminary work has indicated that the linear relationship between analgesia, respiratory depression, and EEG changes remains intact despite a rightward shit in the concentration effect relationships associated with opioids in chronic opioid-consuming patients.91-93 Using this linearity, the fentanyl challenge is able to predict analgesic effect site concentrations from estimated concentrations of fentanyl required to produce respiratory depression. For example, the fentanyl effect site concentration associated with analgesia is 30% of the effect site concentration associated with respiratory depression regardless of whether the fentanyl effect site concentration is required to achieve respiratory depression.
With the analgesic effect site concentration identified as a percentage of the concentration required for respiratory depression, the next step is to develop fentanyl dosing regimens to achieve and maintain analgesia. Dosing goals may be directed at providing intraoperative analgesia as part of a combined anesthetic technique or postoperative analgesia until the patient is able to take oral analgesics. Additional simulations are used to identify optimal infusion rates that will produce the target analgesic effect during the course of the anesthetic and into the postoperative period.
Unique features of fentanyl pharmacokinetics that are important to consider when initiating an infusion following a fentanyl challenge include
With prolonged continuous infusions (ie, >2 hours), effect site concentrations continue to rise. Simulations of continuous infusions reveal that effect site concentrations do not reach near steady state for at least 24 hours. Thus, it is important to anticipate the duration of a postoperative continuous fentanyl infusion and select an infusion rate that will not exceed the effect site concentrations associated with respiratory depression.
Upon completion of the fentanyl challenge before the induction of anesthesia, a significant amount of fentanyl can be delivered depending on the duration of the challenge. For example, an 8-minute infusion at 2 μg/kg/min in a 90-kg patient will result in the delivery of 1440 μg (29 mL) of fentanyl. This initial dose should be accounted for when formulating an intraoperative fentanyl infusion rate.
In Fig. 40-32, a set of simulations illustrate the fentanyl effect site concentrations that result from a fentanyl challenge. In this case, an 8-minute infusion was required to reach the onset of respiratory depression. After the challenge are 6 simulations of a fentanyl infusion ranging from 1 to 6 μg/kg/h for a 6-hour anesthetic. At 8 minutes, the fentanyl effect site concentration associated with respiratory depression is 20 ng/mL, giving a target effect site concentration of 6 ng/mL (ie, 30% of 20). Using this simulation, the fentanyl infusion that best approximates the target effect site concentration of 6 ng/mL is a continuous infusion at 3 μg/kg/h.
Computer simulation of the fentanyl challenge (2 μg/kg/min) for 8 minutes followed by continuous infusions at various rates for 6 hours. This plot is used to estimate the fentanyl infusion rate necessary to achieve analgesia. The target effect site concentration (Ce) is estimated as 30% of the fentanyl Ce associated with the onset of respiratory depression (20 ng/mL). For a 5-hour anesthetic, a continuous infusion of 3 μg/kg/h best achieves the target Ce.
Information obtained from pharmacokinetic simulations after a fentanyl challenge can be used to improve intraoperative dosing of fentanyl to ensure adequate analgesia in the early postoperative period. In addition, this same information can be used to identify IV fentanyl dosing regimens for the first 24 to 48 hours after selected surgical procedures associated with significant postoperative pain and no or inadequate ability to use oral analgesics.
To improve intraoperative dosing of fentanyl, prior work has found that administering a continuous infusion of fentanyl that maintains the analgesic effect site concentration throughout the duration of a surgical procedure leads to an adequate level of analgesia in the early postoperative period yet allows for timely emergence from anesthesia in patients who chronically consume opioids.92 With regard to postoperative dosing of fentanyl, information gained from the fentanyl challenge can be used to identify dosing regimens for patient-controlled analgesia (PCA) combined with a basal continuous infusion to maintain analgesia while avoiding respiratory depression.91-93 Infusion rates (in μg/kg/h) used intraoperatively to target the fentanyl concentrations associated with analgesia are divided in half. Half the infusion rate is administered as a continuous infusion, and the other half is administered as intermittent boluses using a PCA.
Preliminary exploration into the efficacy and safety of this technique has been encouraging. In a cohort of patients who reported chronic consumption of opioids, a fentanyl challenge was used to identify the intraoperative and postoperative dosing regimens for fentanyl. The number of interval doses delivered via the PCA was used as a metric of pain control. Interval dose requirements of 2 doses or fewer per hour were considered to provide adequate analgesia. No use of the PCA over a 4-hour period was considered to be an aggressive basal infusion and was decreased by 20%. PCA usage more than twice an hour was considered in inadequate basal infusion and was increased by 20%. After 24 hours of this dosing regimen, measures of respiratory function, arterial PCO2 levels, and pain control were made. In all subjects, respiratory rates and blood oxygenation were normal. Arterial PCO2 levels ranged from 40 to 47 mm Hg. PCA usage was within 1 to 2 doses per hour.
A computer simulation of a fentanyl challenge followed by the intraoperative and postoperative course is presented in Fig. 40-33. In this example, an 80-kg patient known to chronically consume opioids required 10 minutes to achieve the onset of respiratory depression. The corresponding fentanyl effect site concentration at this time was 27 ng/mL. The target effect site concentration for analgesia was therefore 30% of 27 or approximately 8 ng/mL. Subsequently, a basal infusion of fentanyl was administered during the 4-hour intraoperative period at 5 μg/kg/h as part of a combined technique with a potent inhaled agent. Upon completion of the intraoperative period, the patient was allowed to emerge from anesthesia. In the postoperative phase, a basal infusion was started at 2.5 μg/kg/h. In addition to the basal infusion, the PCA was set to deliver a demand dose of 50 μg every 15 minutes (2.5 μg/kg/h if using all 4 doses). The basal infusion and PCA were used for 36 hours after the anesthetic. The average PCA usage was 2 demand dose per hour. No adjustments were made in the PCA.
Computer simulation of the intraoperative and postoperative course after a fentanyl challenge for an 80–kg, 180-cm patient. The fentanyl challenge (2 μg/kg/min) required 10 minutes to achieve respiratory depression (respiratory rate <6 breaths/min). The fentanyl effect site concentration (Ce) at 10 minutes was 27 ng/mL. Subsequently, a fentanyl infusion was run at 5 μg/kg/h (8 mL/h) for 4 hours with a target analgesic concentration of 8 ng/mL. Upon completion of the anesthetic, a basal infusion at 2.5 μg/kg/h (4 mL/h) and a patient-controlled analgesia (PCA) pump with a 50-μg bolus dose on a 15-minute lockout were started. The average PCA dose was 1 bolus per hour.
Several points of clinical interest are illustrated by this simulation. By starting a fentanyl infusion rate at 5 μg/kg/h immediately after the fentanyl challenge, the resultant effect site concentrations were well above the target concentration for nearly 90 minutes. This is an important feature to consider when delivering anesthetics of shorter duration. Also of interest, by the end of the 4-hour anesthetic, the effect site concentration was beginning to climb above 8 ng/mL. If an anesthetic requires more time, perhaps a more moderate infusion rate would be prudent (ie, 4 μg/kg/h). In the postoperative phase, the simulation reveals that the basal infusion rate in combination with the PCA maintained the target concentration well. On being turned off, the fentanyl effect site concentrations drop fairly slowly. The time required for the fentanyl effect site levels to drop by half is more than 5 hours. This dissipation time may be important to consider when initiating oral analgesic therapy after terminating a PCA and basal infusion.