The need to reduce the dose of intravenous anesthetic in the setting of hypovolemic shock has long been recognized by anesthesiologists. The famous observation in the aftermath of the attack on Pearl Harbor is a sobering, historical example of this firmly entrenched clinical dogma. Noting the severe cardiovascular depression that can result when intravenous anesthetics are administered to patients in shock, Dr Francis John Halford, a surgeon, concluded that intravenous anesthetics “are an ideal form of euthanasia”1 in this setting. Although the number of deaths has almost certainly been exaggerated,2 it is widely believed that the hemodynamic depression associated with thiopentone anesthetic induction in US Naval hospitals at Pearl Harbor contributed to combat-related deaths.
Hypovolemia secondary to hemorrhagic shock is a common sequelae of trauma; serious hemorrhage also sometimes complicates otherwise routine or complex elective procedures. The hemodynamic changes associated with severe hemorrhage, including altered distribution of blood flow and decreased perfusion to metabolic organs, can profoundly influence the pharmacokinetics (PK) of intravenous anesthetic drugs. To a lesser extent, the altered physiology of hemorrhagic shock can also influence the pharmacodynamics (PD) behavior of intravenous anesthetics.
Knowledge of how hemorrhagic shock impacts intravenous anesthetic pharmacologic behavior should inform the rational selection and administration of these agents. The aim of this review is to examine the hemodynamic alterations of hemorrhage as they relate to drug disposition and effect, to consider findings from animal models and human reports for individual anesthetic drugs, and to discuss the clinical implications of this body of knowledge in humans.
SHOCK PHYSIOLOGY RELATING TO CLINICAL PHARMACOLOGY
Hemorrhagic shock results in a major redistribution of blood flow. Circulatory system adaptation to severe hemorrhage maintains blood flow to core organs (ie, central nervous system, heart), while blood is shunted away from other vascular beds (eg, skin, skeletal muscle, gut, kidney) which can more readily tolerate periods of ischemia. These local and systemic compensatory changes mitigate the damage caused by hemorrhage. Locally, collateral vessels dilate to oxygenate hypo-perfused tissue, whereas damaged vessels constrict to reduce hemorrhage.3 Systemically, norepinephrine from the peripheral nerves, epinephrine from the adrenal medulla, and nonadrenergic biochemicals (ie, angiotensin and vasopressin) are released with the net result of systemic arterial vasoconstriction to decrease nonvital organ blood flow to maintain perfusion pressure to the brain and heart.4 This increased sympathetic activity also serves to increase cardiac chronotropy and ionotropy as an additional compensatory measure.5 The cardiovascular effects of many of the commonly used intravenous anesthetic agents counteract many of the adaptations of shock to the body.
The hemorrhage-induced changes in regional blood flow decrease the perfusion of the primary metabolic organs (ie, liver and kidney). Blood flow to the liver in the setting of shock is somewhat difficult to determine, in part due to the duplicity of its blood supply. However, it is clear from both human and animal data that in the initial stages of hemorrhagic shock, liver blood flow is decreased,6 although not to the same degree as the skin, muscle, or gut, enabling continued liver function to some degree, especially in the production of glucose via gluconeogenesis.7 The kidney (and gut) also suffer a reduction in blood flow during severe hemorrhage, but these tissues are able to “hibernate” through periods of ischemia by decreasing the energy consumption associated with membrane transport.8 In animal models, liver cytochrome P450 enzyme metabolic capacity appears to be largely preserved after crystalloid resuscitation from severe hemorrhage.9
Hemorrhage-induced neuroendocrine responses are also significant. Hemorrhagic shock activates the endogenous opioid system.10 In animal models, beta-endorphin levels increase by 4-fold in severe hemorrhage11; these levels of endogenous opioid produce clear analgesic effects.12 Interestingly, naltrexone administration before hemorrhage affords the animals some protection against hypotension, indicating that the endogenous opioids may be contributing to hypotension, perhaps conferring some evolutionary survival value.11
Taken together, these circulatory and neuroendocrine responses to severe hemorrhage have clear implications on the clinical pharmacology of intravenous anesthetics. Viewed within the framework of a traditional 3 compartment mammillary model, these shock-induced changes will necessarily impact the PK profile of a drug by altering the distribution of drug to peripheral compartments, and also by decreasing the clearance of drug from the central compartment. Moreover, the neuroendocrine adaptations to hemorrhage could theoretically alter the PD profile of intravenous anesthetics by exerting synergistic effects via the endogenous opioids.
ANIMAL MODELS IN HEMORRHAGIC SHOCK
Because of both ethical considerations and logistical challenges, the influence of hemorrhagic shock on the clinical pharmacology of intravenous anesthetics is largely studied using animal models. Investigators have developed numerous models for the study of shock, including fixed-pressure, fixed-volume, and uncontrolled hemorrhage models, each with pros can cons as they relate to the study of shock-induced pharmacologic changes.13
The 2 most commonly used large animal models in the study of anesthetics are the isobaric hemorrhage model14–18 and the isovolemic hemorrhage model.19–27 The isobaric hemorrhage model allows researchers to accurately determine the point in time where the shock process transitions from compensated to uncompensated. Shock investigators have pointed out the obvious correlation between the length of the compensatory phase in animal models and the “golden hour” of trauma care, a concept that is well-entrenched clinical dogma, though somewhat controversial.28 The isovolemic model, on the other hand, better mimics an actual massive hemorrhage scenario. For a more thorough explanation of hemorrhage models, readers are directed to Supplemental Digital Content, Document, https://links.lww.com/AA/D6.
INFLUENCE OF SHOCK ON ANESTHETICS
Using the animal models described, many of the intravenous drugs commonly used in anesthesia have been studied to determine the influence shock has on their disposition and effects. Although the clinical pharmacology profile of each drug during severe bleeding is somewhat different, general patterns clearly emerge from this body of investigation. Studies and sporadic reports in humans generally confirm the more sophisticated observations made in carefully controlled animal models.
Opioids
Opioids exhibit shock-induced changes in pharmacologic behavior. Animal studies demonstrate the need for a dosage reduction for morphine, fentanyl, and remifentanil on the basis of PK changes; opioid PD is unchanged.
In the absence of hemorrhage, when administered alone, opioids have only moderate effects on hemodynamics. The fentanyl congeners produce a centrally mediated increase in vagal tone that reduces heart rate.29,30 Morphine-induced histamine release reduces systemic vascular resistance (SVR) and can sometimes cause hypotension.31 Methadone produces a prolongation of the time from the start of the Q wave to the end of the T wave (QT interval) independent of mu-receptor action.32 These opioid effects on cardiovascular physiology can be synergized when the opioids are combined with other intravenous anesthetics.33–36
In animal models, an identical opioid dose yields higher concentrations during hemorrhagic shock. Concentrations of morphine and its major metabolite morphine-3-glucuronide were higher in bled rats.23 Egan et al37 reported fentanyl concentrations increased 2-fold in bled versus unbled pigs (Figure 1) and that shock increased the context-sensitive half-time. Both studies speculate that the observed decrease in distribution and clearance are attributable to altered blood flow patterns and a reduction in flow to metabolic organs.23,37 Interestingly, Johnson et al17 showed that remifentanil, a drug which does not require metabolism by liver or kidney,38,39 also has more than 2-fold increase in concentration during hemorrhagic shock. This surprising finding can perhaps be explained by recognizing that for remifentanil, many capillary beds express esterases and thus contribute to its metabolism. The context-sensitive half-time of remifentanil in the setting of shock is not prolonged to the same extent as fentanyl.17
;)
Figure 1.: The influence of hemorrhagic shock on fentanyl pharmacokinetics. A, Fentanyl plasma concentrations versus time are plotted after a brief infusion in shock (red) versus control (blue) swine in an experiment using an isobaric hemorrhage model. Fentanyl concentrations are substantially higher in the shock animals throughout the experiment. B, A pharmacokinetic simulation of the plasma concentrations resulting from a typical fentanyl dosage scheme for shock (red) and (blue) control animals. After the same dose, shock animals exhibit substantially higher concentrations. The vertical axis for both plots is on a log scale. Adapted with permission from Egan TD, Kuramkote S, Gong G, Zhang J, McJames SW, Bailey PL, "Fentanyl Pharmacokinetics in Hemorrhagic Shock: A Porcine Model,"
Anesthesiology, 1999, 91, 156–166.
37When remifentanil and propofol are infused simultaneously in swine, both drugs increase in concentration during hemorrhagic shock. However, the rate of increase in remifentanil concentration is 3 times higher than that of propofol.24 The difference in the rate of change in concentration of the 2 drugs during shock is of note as the ratio of hypnotic to opiate influences the depth of anesthesia.40 In these investigations, the stage of shock also influences the magnitude of the PK changes.24,27 As Kurita et al24 note, the strong inverse relationship between remifentanil concentration and cardiac output (ie, decreased clearance in the setting of decreased cardiac output) suggests that hydrolysis in tissue, rather than plasma, is the main contributor to the metabolism of remifentanil. This assertion is consistent with in vitro evidence.41 So while remifentanil could be expected to be resistant to the PK changes secondary to decreased liver blood flow during shock, significant PK changes have been observed presumably due to a global decrease in tissue perfusion and metabolism and a resultant decrease in the volume of distribution.
Neither rodent nor large mammal models demonstrated changes in opioid PD. The analgesic effect of morphine is increased during shock in a rodent model, but these changes are attributable to increased drug concentration rather than increased potency.23 Similarly, in a large mammal model, Johnson et al17 reported that remifentanil exhibits no changes in potency during shock; bled swine had C50s similar to their unbled counterparts.
Propofol
In contrast to opioids, the clinical behavior of propofol is more substantially altered by hemorrhage; both its PK and PD are affected. This leads to an increase in the effects of propofol, including its well-documented hemodynamic effects.42,43 In the absence of bleeding, propofol mediates blunting of sympathetic and baroreceptor activity and decreases arterial blood pressure and cardiac output.44,45 These hemodynamic effects are more pronounced in elderly and severely ill patients.46
Hemorrhage potentiates the hypotensive effects of propofol, partly through changes in PK. De Paepe et al47 showed that mean arterial pressure (MAP) significantly decreased with propofol infusion in hypovolemic rats compared to controls. PK analysis confirmed decreased central compartment clearance and increased half-times for the hypovolemic rats, which led to higher drug concentrations at equal doses.47 In addition, the dose required to produce equivalent slowing in the electroencephalogram (EEG) was substantially reduced (ie, 60%) in hypovolemic rats. Johnson et al15 also described changes in propofol PK in the setting of shock; mean propofol plasma concentrations in bled swine to the onset of cardiovascular decompensation were 2.5-fold greater than the control group (Figure 2).15 The PK changes are accounted for by the shock-induced decrease in volume of distribution. Although they did not directly measure hepatic or renal blood flow, these PK changes may also be due to decreased clearance of propofol resulting from alteration of blood distribution, particularly to liver and kidney, which are vital for elimination of the drug.48,49
Figure 2.: The influence of hemorrhagic shock on propofol pharmacokinetics and pharmacodynamics. A, Simulation of the predicted effect-site propofol concentrations that result from a 500 µg·kg
−1·min
−1 infusion for 60 min in control and shock swine in an experiment using an isobaric hemorrhage model. The faded lines indicate the effect-site concentration that produces 50% of the maximal effect on the BIS for the shock (red) and control (blue) swine. After the same dose, shock animals exhibit substantially higher concentrations. The lower
C 50 (concentration that produces 50% of the maximal effect) in shock animals substantially amplifies the magnitude and duration of effect in the shock group. B, Mean processed electroencephalogram (BIS) changes versus time during and after a brief propofol infusion for shock (red) and control (blue) animals. BIS indicates bispectral index. Adapted with permission from Johnson KB, Egan TD, Kern SE, et al, "The Influence of Hemorrhagic Shock on Propofol: A Pharmacokinetic and Pharmacodynamic Analysis,"
Anesthesiology, 2003, 99, 409–420.
15Kazama et al27 further characterized the effect of hemorrhage on propofol PK by measuring concentrations during compensated and uncompensated stages of hemorrhage. They removed decreasing amounts of blood from swine until circulatory collapse. They found that during compensated shock, the increase in propofol concentration was <20% greater than the prehemorrhagic baseline; when hemorrhage was uncompensated, the plasma concentration of propofol was elevated to life-threatening concentrations that were nearly 4 times greater than prehemorrhage.27 Johnson et al15 describe changes in PD of propofol during shock, something that the studies of De Paepe et al47also suggest. De Paepe et al47 observed a significant reduction (ie, 23%) in the predicted effect-site concentrations at the return of the righting reflex, indicating a left shift in the concentration-effect relationship using this clinical effect measure. The C50 (concentration required for 50% of maximal effect) of propofol in bled swine, as determined using the processed EEG, commonly the bispectral index (BIS), was reduced by more than half in bled swine, indicating that increased end-organ sensitivity was contributing to the increased drug effect, not just an increase in drug concentrations (Figure 2). These shock-associated PD changes were confirmed by Kurita et al18 in an experiment studying the immobilizing effects of propofol. They showed that the C50 for immobility in bled swine was significantly less (ie, 23%) than in controls, indicating a similar increase in drug potency for this clinical end point.
The importance of the PD changes of propofol are highlighted by a Johnson et al14 experiment examining the behavior of propofol in the more clinically relevant scenario of hemorrhagic shock followed by crystalloid resuscitation. When animals from the hemorrhage group reached peak shed blood volume using the isobaric hemorrhage model, lactated Ringer’s solution was reinfused with a new target MAP of 70 mm Hg followed by infusion of propofol. Resuscitation partially restored hemodynamic function (eg, return of central venous pressure and cardiac index to baseline). It did not, however, entirely reverse the metabolic effects of shock (eg, persistent lactic academia and base deficit)14 and bled animals were still more sensitive to the cardiovascular depressive effects of propofol 42,44,50 than controls. More important, as shown in the simulations presented in Figure 3, resuscitation essentially reversed the PK changes previously observed in bled animals; resuscitated and control animals had no significant differences in plasma propofol concentrations when given equivalent doses.14 In a similar study conducted by Takizawa et al,51 isovolemic hemorrhage followed by crystalloid resuscitation also reversed the PK changes induced by hemorrhage. The restoration of normal cardiac output after resuscitation may be one of the key factors contributing to the restoration of a normal PK profile.52
Figure 3.: The influence of hemorrhagic shock on the pharmacokinetics and pharmacodynamics of propofol after crystalloid resuscitation in an isobaric hemorrhage model in swine. The plots are simulations of the predicted effect-site concentrations that result from a 200 µg·kg
−1·min
−1 infusion for 60 min. A, Control group. Propofol concentrations are shown in blue. The processed electroencephalogram (BIS) is shown in purple. The
C 50 (the concentration that produces 50% of the maximal effect) is shown in faded blue. B. Shock-resuscitation group. Propofol concentrations are shown in red. The processed electroencephalogram (BIS) is shown in purple. The
C 50 is shown in faded red. Resuscitation nearly reverses the expected bleeding-induced rise in propofol concentrations, but the lower
C 50 persists. BIS indicates bispectral index. Adapted with permission from Johnson KB, Egan TD, Kern SE, McJames SW, Cluff ML, Pace NL, "Influence of Hemorrhagic Shock Followed by Crystalloid Resuscitation on Propofol: A Pharmacokinetic and Pharmacodynamic Analysis,"
Anesthesiology, 2004, 101, 647–659.
14However, despite the reversal of shock-induced PK changes, resuscitated swine had a more pronounced decrease in BIS during propofol infusion compared to controls,14 indicating persistent PD changes as shown in the simulations of Figure 3. Johnson et al14 reported a 1.5-fold decrease in the C50 following resuscitation, which is somewhat less than the 2.7-fold decrease in C50 for bled, unresuscitated swine.
Takizawa et al51 demonstrated the effects of resuscitation on the PK and PD of propofol in 10 human patients undergoing elective surgery. Patients received equal infusions of propofol during surgery and drug concentration was measured at progressively more severe degrees of hemorrhage (ie, an isovolemic hemorrhage model), which was followed by crystalloid resuscitation to maintain hemodynamic stability.51 They showed that total propofol concentration did not significantly vary between prehemorrhage and maximum hemorrhage with resuscitation, confirming that resuscitation prevents shock-induced PK changes.51 Despite unchanged concentrations of propofol, however, the EEG was significantly more depressed during hemorrhage with resuscitation compared to the prehemorrhage baseline.51 Considered collectively, these studies demonstrate that resuscitation almost completely reversed the PK changes induced by hypovolemia, but the PD changes, at least partially, persist.
The mechanism for increased potency of propofol in the setting of shock is unclear. Hypotheses to explain the increased potency include synergy with endogenous opiates released during shock, alteration of the metabolic milieu in shock modulating the end-organ response, and altered protein binding of propofol during shock. Propofol is very highly protein bound (ie, >95%).53 Thus, even small increases in free drug concentration can be clinically relevant.48 De Paepe et al47 reported that bled and control rats had no significant difference in the free fraction of propofol. However, in 4 patients with major hemorrhage and resuscitation during liver transplantation, Takizawa et al54 show total propofol concentrations increased 2-fold during hemorrhagic shock, while unbound propofol concentrations increased 4-fold.
The major difference between these seemingly conflicting reports is resuscitation. Hiraoka et al48 described an increase in unbound propofol secondary to lower albumin concentrations as a consequence of crystalloid resuscitation, which they have proposed as the mechanism for the increased potency of propofol.54,55 A study of propofol PK and PD in humans following hemorrhage and resuscitation during surgery provides corroborating evidence that an increase in unbound propofol associated with albumin dilution contributes to the increased potency of propofol despite unchanged total concentrations of propofol.51
De Paepe et al20 demonstrated that the increased potency of propofol during shock is unlikely to be mediated by synergy with endogenous opiates as antagonism with naloxone does not decrease the C50 of propofol. Further study of the mechanism of persistent end-organ sensitivity to propofol in the setting of shock may augment understanding of the mechanism of action of propofol in normal conditions, as well as why some other anesthetic agents do not exhibit such behavior.
Etomidate and Ketamine
Etomidate and ketamine are viewed favorably by clinicians when treating patients with hemodynamic instability given that they have minimal cardiovascular effects.56–58 The findings from animal studies generally support this clinical dogma.
Etomidate has little effect on cardiovascular variables in hemodynamically stable patients, mild tachycardia being the only significant effect.56 When compared directly to propofol by Brussel et al,50 etomidate, unlike propofol, showed minimal changes in the heart rate, cardiac output, blood pressure, SVR, or pulmonary capillary wedge pressure of dogs. The cardiovascular stability associated with etomidate during induction of anesthesia, even in patients with cardiac disease, is thought to be due to an interaction of etomidate with peripheral α2B-adrenoceptors leading to vasoconstriction, opposing hypotensive effects, including those of other coadministered agents.59 De Paepe et al19 found etomidate infusion to decrease MAP and heart rate in hypovolemic rats. Johnson et al16 also describe a decrease in MAP and increase in SVR for swine with etomidate infusion. These findings highlight the potential advantage of etomidate over other induction agents as proposed by a number of authors.60–62 Etomidate does have the notable adverse effect of adrenal suppression.63–65 New etomidate derivatives, with less adrenal suppressive effects,66–69 are promising substitutes for etomidate, but appear to be associated with neuroexcitatory activity that may prevent their successful clinical development.70
Like propofol, the PK profile for etomidate is changed by hemorrhagic shock, although not nearly to the same degree. De Paepe et al19 show that the dose required to suppress EEG signal is almost 40% lower in hypovolemic rats compared to controls. They attribute this increased hypnotic effect to PK changes induced by hemorrhage given that the maximal plasma concentrations of etomidate did not differ between bled and unbled groups, despite the bled group receiving a lower dose. Volume of distribution at steady state was also decreased by almost 30%. In addition, they demonstrated that the increased effect of etomidate was not due to changes in protein binding induced by hypovolemia.19 Johnson et al16 also report changes in PK of etomidate in hemorrhagic swine (Figure 4), though their study showed even less effect than the De Paepe rodent study.19 They report near equivalent concentrations of etomidate between bled swine and controls until the end of drug infusion when maximal concentrations in the bled swine were minimally elevated above controls. However, in their study, hemorrhagic shock did not reduce the clearance of etomidate as it does for other intravenous (IV) anesthetics. They speculate that cardiovascular compensation was sufficient with etomidate to preserve hepatic blood flow enough to not slow etomidate metabolism. Differences in the hemorrhage model, as well as study species, make it difficult to determine the effect of the hemorrhage on clearance of etomidate. However, that the PK profile of etomidate during shock is only moderately impacted compared to other IV anesthetics is clear.
Figure 4.: The influence of shock on the pharmacokinetics and pharmacodynamics of etomidate in an isobaric hemorrhage model in swine. A, The etomidate plasma concentrations versus time after a brief infusion. B, The processed electroencephalogram (BIS) versus time. Control animals are represented in blue, and shock animals in red. There are minimal differences between the shock and control groups in both concentration and effect. BIS indicates bispectral index. Adapted with permission from Johnson KB, Egan TD, Layman J, Kern SE, White JL, McJames SW, "The Influence of Hemorrhagic Shock on Etomidate: A Pharmacokinetic and Pharmacodynamic Analysis,"
Anesth Analg., 2003, 96, 1360–1368.
16Shock-associated PD changes for the behavior of etomidate are also minimal compared to propofol. De Paepe et al19 reported a very small decrease in the predicted etomidate effect-site concentration at the return of the righting reflex for hypovolemic rats compared to controls, indicating a possible small increase in potency. They conclude that the increased hypnotic effect of etomidate during hypovolemia is mainly attributable to PK changes. Johnson et al16 report no difference in the BIS data between bled and unbled swine (Figure 5). They conclude that hypovolemia has no effect on the PD of etomidate.
Figure 5.: A summary of the dosage reductions necessary in the context of severe hemorrhagic shock compared to the nonshock state for bolus (solid red) and infusion (hatched red) administration for several commonly used intravenous anesthetic agents based on pharmacokinetic and pharmacodynamic parameters from animal models. Adapted with permission from Shafer SL, "Shock Values,"
Anesthesiology, 2004, 101, 567–568.
85Ketamine has minimal to no depressive cardiovascular effects in hemodynamically stable animals or humans without the steroid suppressive effects of etomidate. In fact, many hemodynamic variables increase with ketamine in euvolemic patients,57,58 mostly due to increased sympathetic activity,22 despite ketamine being a direct myocardial depressant.57,71 However, in the setting of hypovolemia, ketamine infusion decreases heart rate, MAP, and cardiac output. Weiskopf et al72 speculate that the usual catecholamine surge from ketamine elicits minimal hemodynamic effect in hypovolemia because of the prominent compensatory sympathetic activity induced by hemorrhage; thus the depressive effects of ketamine dominate in hypovolemia.72 Englehart et al22 demonstrate in a hemorrhagic shock and resuscitation swine model that a ketamine-based total intravenous anesthesia (TIVA) regimen produces significantly less hypotension than an isoflurane maintenance regimen. Likewise, Brezina et al21 demonstrate that when compared to propofol-remifentanil anesthetized minipigs, ketamine-medetomidine infusion results in higher blood pressure and decreased heart rate despite a higher shed blood volume (ie, 53% compared to 45%).
A literature search for relevant terms fails to reveal any studies directed at elucidating the effects of hemorrhagic shock on the PK and PD of ketamine. More research is needed to inform our clinical thinking on this important drug in the setting of hemorrhage.
OTHER INTRAVENOUS DRUGS AND INHALATION AGENTS
Some other intravenous anesthetics have been studied and exhibit a general pattern consistent with the more recent, more sophisticated studies focused on intravenous anesthetic agents in common contemporary use (eg, propofol, etomidate, fentanyl, remifentanil). Benzodiazepines exhibit both PK and PD changes in shock.25,73 Lidocaine also exhibits PK changes,74 as does thiopental72,75 and gamma-hydroxybutyrate.26
Although beyond the scope of this review, a few nuances relating to inhalation agents during hemorrhage deserve emphasis. Because inhalation agents are delivered in the concentration domain via a vaporizer and are minimally metabolized, they are not expected to exhibit higher concentrations during shock (ie, the vaporizer sets an upper limit above which the concentration cannot rise and reduced blood flow to metabolic organs has minimal influence on concentration).76 Nonetheless, shock-induced changes in cardiac output and blood flow patterns alter inhaled agent uptake and distribution.77 Investigators using large mammal models have also observed some changes in inhalation agent PD in the setting of shock, depending on the effect measure used and the degree of shock. Hemorrhage with crystalloid resuscitation does not alter the hypnotic effects of isoflurane as measured by the EEG,77 but does slightly decrease MAC (minimal alveolar concentration).78 The reduction in MAC may be due to endogenous opioid activity in response to shock because the PD change is reversed by naloxone.79 Decompensated shock does, however, alter the electroencephalographic effect of isoflurane, regardless of fluid resuscitation, though the change seems to be minimal, in contrast to several intravenous anesthetics.79,80 In a sheep hemorrhage model, isoflurane inhibits intravascular volume expansion by transcapillary refill, impeding the compensatory defenses of the body against hemorrhage.81 These observations about the clinical pharmacologic behavior of inhalation agents during shock must be considered in the context of the significant cardiovascular effects of these agents in the absence of shock.
ADDITIONAL HUMAN DATA
Because of obvious bioethical and logistical constraints, human studies examining the influence of shock on the PK and PD of intravenous anesthetic are scarce. However, the available data support conclusions drawn from the animal models. Takizawa et al51 present perhaps the most compelling human data addressing the influence of hemorrhagic shock on the PK and PD of intravenous anesthetics by at least partially corroborating the findings from animal models for propofol. In a small cohort of elective surgery patients undergoing major operations, they demonstrated that ongoing crystalloid resuscitation in the face of significant hemorrhage is not associated with an increase in total propofol concentration; this observation is consistent with the data from animal models.14 Importantly, they observed a substantial rise in the free propofol concentrations and a commensurate increase in the EEG effect of propofol with progressive blood loss despite a constant propofol infusion rate throughout the anesthetic. They speculate that dilution of plasma protein during hemorrhage and resuscitation may be responsible for the rise in free propofol concentration, explaining the increased propofol effect notwithstanding a constant propofol infusion rate.51 This is consistent with the observation that the increased propofol potency demonstrated in animal models is not reversed by naloxone.20
In a case report, Honan et al82 describe an instance in which occult hemorrhage is preceded by an abrupt decrease in BIS and an unexpected increase in propofol concentration.82 The 70-year-old female patient was anesthetized with alfentanil and propofol administered by target-controlled infusion (TCI) for an elective abdominal aortic aneurysm repair that was complicated by major, ultimately lethal retroperitoneal hemorrhage after removal of the aortic cross-clamp. Blood samples drawn throughout the case, obtained due to the patient’s serendipitous participation in an unrelated clinical study, revealed propofol concentrations near target levels before the major hemorrhage (4.71 μg/mL with a target of 5), which more than doubled during the time of hemorrhage (7.15 μg/mL with a target of 3). The abrupt drop in the processed EEG (BIS) at the onset of hemorrhage was thought to indicate a change in the disposition of propofol resulting in acutely increased concentrations. Honan et al82 note the consistency of their experience with the findings from animal studies. The cerebral hypoperfusion that eventually accompanies lethal hemorrhage may complicate the interpretation of the decrease in BIS observed in this case.83 Understanding of the altered behavior of propofol during hemorrhage and the need for cautious dosing has led some clinicians to change practice; processed EEG monitoring, for example, has been used as a surrogate to monitor for clinical deterioration or changes in depth of anesthesia84 that may be brought on by unintended increase of the effect of propofol—such as that described in the Honan et al82 case report.
CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS
Considered collectively, this body of information drawn from animal and human data informs the rational selection and administration of intravenous anesthetics in the setting of hemorrhagic shock. Viewed from the framework of a compartmental model, hemorrhage shock decreases the size of the central compartment and lowers central clearance for most intravenous anesthetics, leading to an altered dose-concentration relationship. These PK changes result in substantially higher concentrations and increased effect (including increased adverse cardiovascular effects) for most intravenous agents. Etomidate is a notable exception to this general rule; etomidate does not exhibit substantially increased drug concentrations during bleeding. These bleeding-induced changes in PK are nearly completely reversed by crystalloid resuscitation.
Hemorrhagic shock, for the most part, does not greatly alter the PD of intravenous anesthetics or opioids with the notable exception of propofol. Propofol exhibits increased potency during hemorrhagic shock physiology, even after crystalloid resuscitation; this increased potency may be due to an increase of free propofol concentrations.
Shafer85 performed a series of simulations to summarize the clinical implications of this body of work characterizing the influence of hemorrhagic shock on the disposition and effects of commonly used intravenous anesthetics. As shown in Figure 5, substantial dosage reductions are necessary for most drugs when administered either by bolus or infusion. Etomidate is a clear outlier. Without resuscitation, propofol doses must be reduced by 80%–90% to achieve a specified level of effect! Many clinicians may find that degree of dosage reduction surprising. Crystalloid resuscitation reduces the propofol dosage reduction necessary to around 50%. For the opioids fentanyl and remifentanil, a dosage reduction of approximately 50% is required; the impact of crystalloid resuscitation on the dosing scheme for these opioids is unknown, but the evidence for the other drugs suggests that resuscitation will substantially mitigate the shock-induced PK changes.
Several clinically relevant key points emerge from this body of work. The well-entrenched clinical dogma that etomidate is a preferred induction agent in patients suffering from hemorrhagic shock is firmly supported by the evidence from sophisticated animal models. In addition, propofol is a poor choice for induction or maintenance of anesthesia in severely bleeding patients, even after crystalloid resuscitation. Opioid doses must be decreased by at least 50% in such patients. These key clinical features are summarized in the Table.
Table. -
Summary of Changes in Pharmacokinetics and Pharmacodynamics During Hemorrhage and Resuscitation on Intravenous Anesthetics
| Drug |
PKa Changes With Hemorrhage |
PK Changes With Hemorrhage and Resuscitation |
PDb Changes With Hemorrhage |
PD Changes With Hemorrhage and Resuscitation |
| Sedative hypnotics |
|
|
|
|
| Propofol |
+++15,27,47 |
+14,51 |
+++15,18 |
+14,51 |
| Etomidate |
+16,19 |
No data |
016,19 |
No data |
| Ketamine |
+72 |
No data |
No data |
No data |
| Opioids |
|
|
|
|
| Remifentanil |
+++17,24 |
No data |
017 |
No data |
| Fentanyl |
+++37 |
No data |
No data |
No data |
| Morphine |
++23 |
No data |
No data |
No data |
+++, large change; ++, moderate change; +, small change; 0, no change.
Abbreviations: PK, pharmacokinetics; PD, pharmacodynamics.
aAll PK changes are increased drug levels per given dose.
bAll PD changes are the increased effect per given dose.
Several shortcomings of this literature deserve emphasis. First, much of the relevant information emanates from animal models and thus may not be fully applicable to humans, although the more limited human data are consistent with conclusions drawn for the animal work. In addition, the shock models commonly applied may not be fully relevant to clinical practice; most of the studies examine severe forms of hemorrhage, which are perhaps not applicable to more quotidian bleeding observed in routine, elective cases. Moreover, most of the literature study the drugs in isolation, which is not representative of the multidrug anesthetics commonly administered in contemporary anesthesia practice. And while some drugs have been studied with crystalloid resuscitation, not all of the drugs have been studied in this clinical context; none of the studies included resuscitation with blood products.
These shortcomings present opportunities for further research. The interaction between opioids and hypnotics during hemorrhage and resuscitation is an obvious area for investigation. Investigation is needed into why etomidate does not exhibit the PK changes associated with the other agents, as well as why the PD of etomidate does not change in contrast to propofol despite having a similar mechanism. Further investigation to clarify why propofol has increased potency during shock is also warranted. Perhaps the biggest gap in the evidence base is the lack of human studies, which is obviously complicated by ethical and logistical challenges.
DISCLOSURES
Name: Ezekiel D. Egan, BA.
Contribution: This author made substantial contributions to the conception and design of the work, the acquisition, analysis, and interpretation of data for the work, and drafting the work.
Name: Ken B. Johnson, MD.
Contribution: This author made substantial contributions to the conception and design of the work, the analysis and interpretation of data for the work, and the critical revising of the work for important intellectual content.
This manuscript was handled by: Markus W. Hollmann, MD, PhD.
REFERENCES
1. Halford FJ. A critique of intravenous anesthesia in war surgery. Anesthesiology. 1943;4:67–69.
2. Kidd AG, Restall J. Thiopentone anaesthesia at Pearl Harbor. Br J Anaesth. 1995;75:823.
3. Collins JA. The pathophysiology of hemorrhagic shock. Prog Clin Biol Res. 1982;108:5–29.
4. Libert N, Harrois A, Duranteau J. Haemodynamic coherence in haemorrhagic shock. Best Pract Res Clin Anaesthesiol. 2016;30:429–435.
5. Dark PM, Delooz HH, Hillier V, Hanson J, Little RA. Monitoring the circulatory responses of shocked patients during fluid resuscitation in the emergency department. Intensive Care Med. 2000;26:173–179.
6. Helling TS. The liver and hemorrhagic shock. J Am Coll Surg. 2005;201:774–783.
7. Maitra SR, Geller ER, Pan W, Kennedy PR, Higgins LD. Altered cellular calcium regulation and hepatic glucose production during hemorrhagic shock. Circ Shock. 1992;38:14–21.
8. Reilly PM, Bulkley GB. Vasoactive mediators and splanchnic perfusion. Crit Care Med. 1993;21:S55–S68.
9. Kumar A, Remmel RP, Mann HJ, Beilman GJ. Drug metabolism in hemorrhagic shock: pharmacokinetics of selective markers of cytochrome-P450 2C9, 2D6, and 3A4 enzyme activities in a porcine model. J Surg Res. 2011;167:e231–e243.
10. Molina PE. Stress-specific opioid modulation of haemodynamic counter-regulation. Clin Exp Pharmacol Physiol. 2002;29:248–253.
11. Molina PE. Opiate modulation of hemodynamic, hormonal, and cytokine responses to hemorrhage. Shock. 2001;15:471–478.
12. Molina PE. Endogenous opioid analgesia in hemorrhagic shock. J Trauma. 2003;54:S126–S132.
13. Lomas-Niera JL, Perl M, Chung CS, Ayala A. Shock and hemorrhage: an overview of animal models. Shock. 2005;24(Suppl 1):33–39.
14. Johnson KB, Egan TD, Kern SE, McJames SW, Cluff ML, Pace NL. Influence of hemorrhagic shock followed by crystalloid resuscitation on propofol: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology. 2004;101:647–659.
15. Johnson KB, Egan TD, Kern SE, et al. The influence of hemorrhagic shock on propofol: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology. 2003;99:409–420.
16. Johnson KB, Egan TD, Layman J, Kern SE, White JL, McJames SW. The influence of hemorrhagic shock on etomidate: a pharmacokinetic and pharmacodynamic analysis. Anesth Analg. 2003;96:1360–1368.
17. Johnson KB, Kern SE, Hamber EA, McJames SW, Kohnstamm KM, Egan TD. Influence of hemorrhagic shock on remifentanil: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology. 2001;94:322–332.
18. Kurita T, Takata K, Morita K, et al. The influence of hemorrhagic shock on the electroencephalographic and immobilizing effects of propofol in a swine model. Anesth Analg. 2009;109:398–404.
19. De Paepe P, Belpaire FM, Van Hoey G, Boon PA, Buylaert WA. Influence of hypovolemia on the pharmacokinetics and the electroencephalographic effect of etomidate in the rat. J Pharmacol Exp Ther. 1999;290:1048–1053.
20. De Paepe P, Van Sassenbroeck DK, Belpaire FM, Buylaert WA. Influence of naloxone on the increased sensitivity to propofol during hypovolemia in the rat. Crit Care Med. 2001;29:997–999.
21. Brezina A, Drabek T, Riha H, Schreiberova J, Hess L. The effect of medetomidine-ketamine anesthesia on hemodynamic parameters during hemorrhagic shock in minipigs. Physiol Res. 2010;59:703–710.
22. Englehart MS, Allison CE, Tieu BH, et al. Ketamine-based total intravenous anesthesia versus isoflurane anesthesia in a swine model of hemorrhagic shock. J Trauma. 2008;65:901–908.
23. De Paepe P, Belpaire FM, Rosseel MT, Buylaert WA. The influence of hemorrhagic shock on the pharmacokinetics and the analgesic effect of morphine in the rat. Fundam Clin Pharmacol. 1998;12:624–630.
24. Kurita T, Uraoka M, Morita K, Suzuki M, Morishima Y, Sato S. Influence of haemorrhage on the pseudo-steady-state remifentanil concentration in a swine model: a comparison with propofol and the effect of haemorrhagic shock stage. Br J Anaesth. 2011;107:719–725.
25. Klockowski PM, Levy G. Kinetics of drug action in disease states. XXV. Effect of experimental hypovolemia on the pharmacodynamics and pharmacokinetics of desmethyldiazepam. J Pharmacol Exp Ther. 1988;245:508–512.
26. Van Sassenbroeck DK, De Paepe P, Belpaire FM, Boon PA, Buylaert WA. Influence of hypovolemia on the pharmacokinetics and electroencephalographic effect of gamma-hydroxybutyrate in the rat. Anesthesiology. 2002;97:1218–1226.
27. Kazama T, Kurita T, Morita K, Nakata J, Sato S. Influence of hemorrhage on propofol pseudo-steady state concentration. Anesthesiology. 2002;97:1156–1161.
28. Rogers FB, Rittenhouse KJ, Gross BW. The golden hour in trauma: dogma or medical folklore? Injury. 2015;46:525–527.
29. Bovill JG, Sebel PS, Stanley TH. Opioid analgesics in anesthesia: with special reference to their use in cardiovascular anesthesia. Anesthesiology. 1984;61:731–755.
30. Reitan JA, Stengert KB, Wymore ML, Martucci RW. Central vagal control of fentanyl-induced bradycardia during halothane anesthesia. Anesth Analg. 1978;57:31–36.
31. Rosow CE, Moss J, Philbin DM, Savarese JJ. Histamine release during morphine and fentanyl anesthesia. Anesthesiology. 1982;56:93–96.
32. Tung KH, Angus JA, Wright CE. Contrasting cardiovascular properties of the µ-opioid agonists morphine and methadone in the rat. Eur J Pharmacol. 2015;762:372–381.
33. Kern SE, Xie G, White JL, Egan TD. A response surface analysis of propofol-remifentanil pharmacodynamic interaction in volunteers. Anesthesiology. 2004;100:1373–1381.
34. Wiczling P, Bieda K, Przybyłowski K, et al. Pharmacokinetics and pharmacodynamics of propofol and fentanyl in patients undergoing abdominal aortic surgery - a study of pharmacodynamic drug-drug interactions. Biopharm Drug Dispos. 2016;37:252–263.
35. Mertens MJ, Olofsen E, Engbers FH, Burm AG, Bovill JG, Vuyk J. Propofol reduces perioperative remifentanil requirements in a synergistic manner: response surface modeling of perioperative remifentanil-propofol interactions. Anesthesiology. 2003;99:347–359.
36. Vuyk J. Pharmacokinetic and pharmacodynamic interactions between opioids and propofol. J Clin Anesth. 1997;9:23S–26S.
37. Egan TD, Kuramkote S, Gong G, Zhang J, McJames SW, Bailey PL. Fentanyl pharmacokinetics in hemorrhagic shock: a porcine model. Anesthesiology. 1999;91:156–166.
38. Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology. 1993;79:881–892.
39. Michelsen LG, Hug CC Jr.. The pharmacokinetics of remifentanil. J Clin Anesth. 1996;8:679–682.
40. Beydon L, Desfontis JC, Ganster F, et al. BIS response to tamponade and dobutamine in swine varies with hypnotic/opiate ratio. Ann Fr Anesth Reanim. 2009;28:650–657.
41. Davis PJ, Stiller RL, Wilson AS, McGowan FX, Egan TD, Muir KT. In vitro remifentanil metabolism: the effects of whole blood constituents and plasma butyrylcholinesterase. Anesth Analg. 2002;95:1305–1307.
42. Goodchild CS, Serrao JM. Propofol-induced cardiovascular depression: science and art. Br J Anaesth. 2015;115:641–642.
43. Sahinovic MM, Struys MMRF, Absalom AR. Clinical pharmacokinetics and pharmacodynamics of propofol. Clin Pharmacokinet. 2018;57:1539–1558.
44. Goodchild CS, Serrao JM. Cardiovascular effects of propofol in the anaesthetized dog. Br J Anaesth. 1989;63:87–92.
45. Ebert TJ. Sympathetic and hemodynamic effects of moderate and deep sedation with propofol in humans. Anesthesiology. 2005;103:20–24.
46. Hug CC Jr, McLeskey CH, Nahrwold ML, et al. Hemodynamic effects of propofol: data from over 25,000 patients. Anesth Analg. 1993;77:S21–S29.
47. De Paepe P, Belpaire FM, Rosseel MT, Van Hoey G, Boon PA, Buylaert WA. Influence of hypovolemia on the pharmacokinetics and the electroencephalographic effect of propofol in the rat. Anesthesiology. 2000;93:1482–1490.
48. Hiraoka H, Yamamoto K, Okano N, Morita T, Goto F, Horiuchi R. Changes in drug plasma concentrations of an extensively bound and highly extracted drug, propofol, in response to altered plasma binding. Clin Pharmacol Ther. 2004;75:324–330.
49. Takizawa D, Hiraoka H, Goto F, Yamamoto K, Horiuchi R. Human kidneys play an important role in the elimination of propofol. Anesthesiology. 2005;102:327–330.
50. Brüssel T, Theissen JL, Vigfusson G, Lunkenheimer PP, Van Aken H, Lawin P. Hemodynamic and cardiodynamic effects of propofol and etomidate: negative inotropic properties of propofol. Anesth Analg. 1989;69:35–40.
51. Takizawa E, Takizawa D, Hiraoka H, Saito S, Goto F. Disposition and pharmacodynamics of propofol during isovolaemic haemorrhage followed by crystalloid resuscitation in humans. Br J Clin Pharmacol. 2006;61:256–261.
52. Upton RN, Huang YF. Influence of cardiac output, injection time and injection volume on the initial mixing of drugs with venous blood after i.v. bolus administration to sheep. Br J Anaesth. 1993;70:333–338.
53. Cockshott ID, Douglas EJ, Plummer GF, Simons PJ. The pharmacokinetics of propofol in laboratory animals. Xenobiotica. 1992;22:369–375.
54. Takizawa D, Takizawa E, Miyoshi S, Kawahara F, Hiraoka H. The increase in total and unbound propofol concentrations during accidental hemorrhagic shock in patients undergoing liver transplantation. Anesth Analg. 2006;103:1339–1340.
55. Takizawa D, Sato E, Kurosaki D, Hiraoka H, Horiuchi R, Goto F. Pharmacodynamics of propofol during hemorrhagic shock. Anesthesiology. 2005;102:1068–1069.
56. Gooding JM, Corssen G. Effect of etomidate on the cardiovascular system. Anesth Analg. 1977;56:717–719.
57. Traber DL, Wilson RD, Priano LL. Differentiation of the cardiovascular effects of CI-581. Anesth Analg. 1968;47:769–778.
58. Virtue RW, Alanis JM, Mori M, Lafargue RT, Vogel JH, Metcalf DR. An anesthetic agent: 2-orthochlorophenyl, 2-methylamino cyclohexanone HCl (CI-581). Anesthesiology. 1967;28:823–833.
59. Paris A, Philipp M, Tonner PH, et al. Activation of alpha 2B-adrenoceptors mediates the cardiovascular effects of etomidate. Anesthesiology. 2003;99:889–895.
60. Smith DC, Bergen JM, Smithline H, Kirschner R. A trial of etomidate for rapid sequence intubation in the emergency department. J Emerg Med. 2000;18:13–16.
61. Jellish WS, Riche H, Salord F, Ravussin P, Tempelhoff R. Etomidate and thiopental-based anesthetic induction: comparisons between different titrated levels of electrophysiologic cortical depression and response to laryngoscopy. J Clin Anesth. 1997;9:36–41.
62. Bergen JM, Smith DC. A review of etomidate for rapid sequence intubation in the emergency department. J Emerg Med. 1997;15:221–230.
63. Sprung CL, Annane D, Keh D, et al.; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111–124.
64. Morris C, Perris A, Klein J, Mahoney P. Anaesthesia in haemodynamically compromised emergency patients: does ketamine represent the best choice of induction agent? Anaesthesia. 2009;64:532–539.
65. Cuthbertson BH, Sprung CL, Annane D, et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med. 2009;35:1868–1876.
66. Wang B, Chen S, Yang J, Yang L, Liu J, Zhang W. ET-26 hydrochloride (ET-26 HCl) has similar hemodynamic stability to that of etomidate in normal and uncontrolled hemorrhagic shock (UHS) rats. PLoS One. 2017;12:e0183439.
67. Wang B, Yang J, Chen J, et al. An etomidate analogue with less adrenocortical suppression, stable hemodynamics, and improved behavioral recovery in rats. Anesth Analg. 2017;125:442–450.
68. Yang J, Kang Y, Wang B, Yang L, Liu J, Zhang W. Metabolite-inactive etomidate analogues alleviating suppression on adrenal function in Beagle dogs. Eur J Pharm Sci. 2017;99:343–349.
69. Campagna JA, Pojasek K, Grayzel D, Randle J, Raines DE. Advancing novel anesthetics: pharmacodynamic and pharmacokinetic studies of cyclopropyl-methoxycarbonyl metomidate in dogs. Anesthesiology. 2014;121:1203–1216.
70. Valk BI, Absalom AR, Meyer P, et al. Safety and clinical effect of i.v. infusion of cyclopropyl-methoxycarbonyl etomidate (ABP-700), a soft analogue of etomidate, in healthy subjects. Br J Anaesth. 2018;120:1401–1411.
71. Goldberg AH, Keane PW, Phear WP. Effects of ketamine on contractile performance and excitability of isolated heart muscle. J Pharmacol Exp Ther. 1970;175:388–394.
72. Weiskopf RB, Bogetz MS, Roizen MF, Reid IA. Cardiovascular and metabolic sequelae of inducing anesthesia with ketamine or thiopental in hypovolemic swine. Anesthesiology. 1984;60:214–219.
73. Adams P, Gelman S, Reves JG, Greenblatt DJ, Alvis JM, Bradley E. Midazolam pharmacodynamics and pharmacokinetics during acute hypovolemia. Anesthesiology. 1985;63:140–146.
74. Benowitz N, Forsyth RP, Melmon KL, Rowland M. Lidocaine disposition kinetics in monkey and man. II. Effects of hemorrhage and sympathomimetic drug administration. Clin Pharmacol Ther. 1974;16:99–109.
75. Price HL. A dynamic concept of the distribution of thiopental in the human body. Anesthesiology. 1960; 21:440–445.
76. Egan TD. Total intravenous anesthesia versus inhalation anesthesia: a drug delivery perspective. J Cardiothorac Vasc Anesth. 2015;29(Suppl 1):S3–S6.
77. Kurita T, Morita K, Fukuda K, et al. Influence of hypovolemia on the electroencephalographic effect of isoflurane in a swine model. Anesthesiology. 2005;102:948–953.
78. Kurita T, Takata K, Uraoka M, et al. The influence of hemorrhagic shock on the minimum alveolar anesthetic concentration of isoflurane in a swine model. Anesth Analg. 2007;105:1639–1643.
79. Kurita T, Morita K, Fukuda K, et al. Influence of hemorrhagic shock and subsequent fluid resuscitation on the electroencephalographic effect of isoflurane in a swine model. Anesthesiology. 2005;103:1189–1194.
80. Kurita T, Uraoka M, Morita K, Sato S. Influence of progressive hemorrhage and subsequent cardiopulmonary resuscitation on the bispectral index during isoflurane anesthesia in a swine model. J Trauma Acute Care Surg. 2012;72:1614–1619.
81. Hahn RG, Brauer L, Rodhe P, Svensén CH, Prough DS. Isoflurane inhibits compensatory intravascular volume expansion after hemorrhage in sheep. Anesth Analg. 2006;103:350–358.
82. Honan DM, Breen PJ, Boylan JF, McDonald NJ, Egan TD. Decrease in bispectral index preceding intraoperative hemodynamic crisis: evidence of acute alteration of propofol pharmacokinetics. Anesthesiology. 2002;97:1303–1305.
83. Cavus E, Meybohm P, Doerges V, et al. Effects of cerebral hypoperfusion on bispectral index: a randomised, controlled animal experiment during haemorrhagic shock. Resuscitation. 2010;81:1183–1189.
84. Lichtor JL. Depth of anesthesia monitors and shock. Anesthesiology. 2005;102:1068.
85. Shafer SL. Shock values. Anesthesiology. 2004;101:567–568.
