JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Memtsoudis, S. G.
Right arrow Articles by Heerdt, P. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Memtsoudis, S. G.
Right arrow Articles by Heerdt, P. M.
Related Collections
Right arrow Cardiovascular
Right arrow Pharmacology

Anesth Analg 2005;100:111-115
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000140242.25232.41

ANESTHETIC PHARMACOLOGY

Autonomic Mechanisms in the Age-Related Hypotensive Effect of Propofol

Stavros G. Memtsoudis, MD, PhD*,{dagger}, Andrew H. S. The, BS*, and Paul M. Heerdt, MD, PhD*,{dagger}

Departments of *Anesthesiology and {dagger}Pharmacology, Weill Medical College of Cornell University, New York, NY.

Address correspondence to Stavros G. Memtsoudis, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hopsital, 75 Francis Street, Boston, MA 02115. Address e-mail to smemtsoudis{at}partners.org


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We hypothesized that age-related differences in cardiovascular regulatory processes play a role in the augmented vasodepressor response to anesthetic induction with propofol in older subjects. To test this hypothesis, differences in baroreceptor responsiveness (BR) were first demonstrated in young adult (6–12 mo, n = 12) and aged (>42 mo, n = 12) New Zealand rabbits, and then the vasodepressor effect of propofol was compared in both the absence and presence of ganglionic blockade. For each age group, half of the animals were pretreated with 20 mg/kg IV hexamethonium (HEX) with the remaining half designated as controls. BR was first assessed by plotting cardiac cycle length as a function of the decline in mean arterial blood pressure (MAP) produced by multiple IV boluses of tri-nitroglycerine. Propofol was then given as an IV bolus of 4.5, 6.4, or 8.4 mg/kg over 3 s. Each animal was studied three times, receiving a single dose in variable order with at least 7 days between injections. In control animals, marked age-related differences in BR were evident and propofol produced larger peak decreases in MAP in older rabbits at all doses. HEX pretreatment abolished BR for both young and aged rabbits. However, after HEX administration the vasodepressor response to propofol in young animals was enhanced by 150% at 4.5, 125% at 6.4, and 61% at 8.4 mg/kg, respectively, whereas the impact in aged animals was only 25%, 30%, and –10%, respectively. These data support the hypothesis that age-related enhancement of propofol-induced hypotension is largely a reflection of diminished BR.

IMPLICATIONS: Clinical experience suggests that aged individuals exhibit larger hypotensive effects after induction doses of propofol compared with young adults. The mechanism behind this observation remains largely unstudied. Our data gathered in a rabbit model suggest that age-related reduction in sensitivity of autonomic reflexes may contribute substantially to the increased hypotensive effect of propofol in the aged.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Both clinical experience and laboratory data indicate that induction of anesthesia with a variety of drugs, including propofol, causes hypotension more frequently in elderly subjects than in young adults (1,2). Although it is well established that the aging process influences cardiovascular control mechanisms via effects on peripheral sensors, central integration/processing, and end-organ responsiveness (3,4), it remains unclear whether age-dependent hypotension from bolus injection of propofol primarily reflects structural and/or functional changes (5) or alterations in pharmacodynamics and/or pharmacokinetics (6,7).

To determine if age-dependent dampening of baroreceptor-mediated reflex regulation of mean arterial blood pressure (MAP) is a significant contributor to enhanced propofol-induced hypotension with aging, the present study characterized the MAP change produced by bolus injection of propofol in relation to baroreceptor responsiveness (BR) in young adult (6–12 months) and aged (>42 months) rabbits. We hypothesized that if diminution of BR with aging is a significant component of systemic hypotension, then the dose-response effects of propofol will be enhanced to a greater degree in young animals by ganglionic blockade compared with aged animals. To test this hypothesis, the cardiovascular response to propofol of young and aged rabbits was compared in the presence and absence of hexamethonium (HEX) pretreatment.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After protocol approval by the Institutional Animal Care and Use Committee, 24 New Zealand white rabbits were used for the study. Animals were fasted overnight before experimentation. For all procedures, arterial and venous catheters (22-gauge) were inserted into ear vessels for MAP measurement and drug injection, respectively, after local anesthesia with a prilocaine/lidocaine emulsion. During each procedure, the animals were placed in a heated Lucite box and MAP and heart rate (HR) continuously recorded. Arterial oxygen saturation was monitored with a pulse oxymetry probe attached to each rabbit’s ear. Before propofol injection, oxygen was administered with a flow-by device at 3 L/min.

The rabbits were equally divided into control and ganglionic blockade groups, with six young and six aged animals in each group. Control animals received no pretreatment whereas those in the ganglionic blockade group received 20 mg/kg IV HEX followed by a 10-min equilibration period. With the animals awake in a quiet, dimly lit room, BR was first assessed by injecting multiple IV bolus doses (10–40 µg) of tri-nitroglycerin, allowing a return to baseline between doses. The resulting peak decline in cardiac cycle length was plotted as a function of the maximal decrease in MAP for each animal. Using least squares regression, the slope of this relationship for all tri-nitroglycerine doses given to each individual animal over the study protocol (at least six) was determined and the mean value for all animals in a group then used to compare BR between young and aged animals.

After BR testing, animals received 1 of 3 different doses of propofol per study session: 4.5, 6.4, or 8.4 mg/kg as an IV bolus over 3 s. The doses were chosen on the basis of previously reported data for induction of anesthesia with propofol in rabbits (8) and reflect 70, 100, and 130% of the reported ED95 for tracheal intubation, respectively. Each animal was studied three times, receiving one dose per study session with 1 wk between sessions.

Differences between the groups in regard to age, weight, baseline hemodynamic variables, and BR slopes were determined by analysis of variance and the Newman-Keuls test where appropriate. The propofol dose-response data were examined in two steps. First, results were analyzed in a repeated-measures general linear model to account for the impact of age (aged versus young), treatment (control versus HEX), and propofol dose (4.5 versus 6.4 versus 8.4 mg/kg), respectively. The within-subject factor was propofol dose, and between-subject factors were age and treatment. Second, differences between the young and aged hemodynamic response to each propofol dose within the control and HEX groups were determined by Student’s t-test. For all statistical tests, a value of P ≤ 0.05 was considered to be significant. All data are presented as mean values and standard deviation from the mean.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
As shown in Table 1, in comparison to young rabbits, aged animals were on average four times older and 25% heavier in both the control and the HEX groups. At baseline (conscious), the HR of aged animals tended to be slightly more rapid then among young rabbits. After HEX administration, HR increased ~50% in both age groups with abolition of the age-related difference. In contrast, baseline MAP was the same in both age groups regardless of whether or not HEX pretreatment had been given.


View this table:
[in this window]
[in a new window]
  		Table 1. Baseline Characteristics of Sample Population
 
In control animals, the mean BR slope was 6.2 ± 0.3 ms/mm Hg for young animals and 4.0 ± 1.5 ms/mm Hg for aged rabbits (P < 0.05). In contrast, after HEX administration BR was abolished for both young (slope 0.2 ± 0.1 ms/mm Hg) and aged animals (slope 0.4 ± 0.1 ms/mm Hg, P > 0.05). Figure 1 depicts the distinct age-related difference in the {Delta} cardiac cycle length/{Delta} MAP relationship in the control group, and abolition in the HEX group, when the response to all tri-nitroglycerine injections was pooled.



View larger version (19K):
[in this window]
[in a new window]
  		Figure 1. Pooled data from all animals showing changes in cardiac cycle length plotted as a function of changes in mean arterial blood pressure (MAP) after IV boluses of tri-nitroglycerine. A, an age-related difference in the {Delta} cardiac cycle length/{Delta} mean AP slope in control animals (r2 for aged 0.244, for young 0.690); B, age-independent abolition of the {Delta} cardiac cycle length/{Delta} MAP relationship in animals pretreated with hexamethonium (r2 < 0.05 for both aged and young).

 
Two animals died after injection of the final propofol dose (one young HEX, one aged control). Hemodynamic data after these doses were not included in the analysis but data obtained in the remaining experiments were. Application of the repeated-measures general linear model demonstrated significant effects of age (P ≤ 0.002) and treatment (P ≤ 0.05) on the change in MAP after propofol administration. In addition, the effect of propofol was dose-dependent (P ≤ 0.005), with differences found between 4.5 and 8.4 mg/kg as well as 6.4 and 8.4 mg/kg but not 4.5 and 6.4 mg/kg. For HR data, the administration of HEX was associated with a decreased response to propofol (P < 0.0001). No effect of age and dose was detected.

As shown in Figure 2, in aged rabbits propofol produced a decrease in MAP that was more than that observed in young animals at all three doses. In contrast, within the HEX group, the decrease in MAP produced by propofol was the same for both age groups at all doses, reflecting the fact that relative to control, the hypotensive response was enhanced by 150% at 4.5, 125% at 6.4, and 61% at 8.4 mg/kg in young animals but only by 25%, 30%, and –10%, respectively, in aged rabbits. As also shown in Figure 2, there were no age-related differences in the HR response to propofol in either the control or the HEX group.



View larger version (34K):
[in this window]
[in a new window]
  		Figure 2. Maximum changes in mean arterial blood pressure (MAP) and heart rate (HR) in response to IV boluses of propofol. A, age-related differences in the propofol dose-MAP response in control rabbits. B, the propofol dose-MAP response in animals pretreated with hexamethonium; in contrast to control animals, response is similar at all doses. C and D, the age-independent propofol dose-HR response in control and with hexamethonium pretreated animals, respectively. An asterisk indicates P < 0.05 between aged and young.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The aging process affects autonomic cardiovascular control mechanisms, even in healthy individuals (3,4). Changes in baroreflex control in particular may result from alterations at any level of the arc, including the baroreceptors themselves, vessel wall distensibility, central integration, afferent or efferent autonomic pathways, or a combination of these factors (2,4,9–11). The present study demonstrates that, as with humans, cardiovascular control mechanisms in aged rabbits are attenuated in comparison with young animals. Our data also demonstrate that bolus doses of propofol cause a more pronounced decrease in MAP in aged rabbits in comparison with young animals. However, after ganglionic blockade and abolition of BR to vasodilation, young animals display vasodepressor responses to bolus injections of propofol that are remarkably similar to those evident in aged animals. Accordingly, these data support the hypothesis that age-dependent dampening of reflex regulation of MAP contributes to the enhanced potency for hypotension in the aged.

Most studies of the mechanisms behind the hemodynamic response to propofol have been conducted during steady-state anesthesia and without regard for advanced age. These investigations have established a variety of direct effects on myocardial contractility (12–15), vascular tone (16,17), and baroreceptor function (18,19) that can individually and/or collectively contribute to hypotension. Although the present study does not allow for defining the relative impact of these or other effects on age-related hypotension after bolus dosing of propofol, the data do establish that in this animal model young animals will respond virtually the same as aged animals when ganglion-mediated reflex responses to direct vasodepressor stimuli are blocked.

Results of the study should be interpreted within the context of several limitations. The first relates to the animal model itself. Although the data demonstrate age-related differences in the hemodynamic response to bolus doses of propofol, they were obtained from a relatively small sample size of purebred rabbits with a maximum age of 4 years. Although rabbits of this age range have been used as an experimental model for cardiovascular aging (20), clinical applicability has been questioned based on the argument that 4-year-old rabbits may not be a real parallel for "elderly" humans (21). Nevertheless, our data clearly demonstrate an age-related dampening of BR, thus rendering the model suitable for the current study, regardless of whether the animals are truly elderly or simply "mature." Ultimately, however, caution must be exercised in extrapolating our findings to different species and/or subjects that are undeniably senescent. The second limitation relates to the singular use of HEX for blunting reflex-mediated responses to hypotension. Had the study included assessment of the reflex response to vasopressors or had the goal been to produce total autonomic blockade, HEX alone would have been inadequate because of incomplete parasympatholysis (22) and lack of effect on peripheral adrenergic receptors. However, as the study goal was to examine the predominantly sympathetic reflex response to vasodepression and HEX has been shown to effectively block this pathway (23), treatment with HEX alone was chosen to avoid the possibility that adding specific adrenergic antagonists would complicate data interpretation. Third is the relatively narrow scope of the study. Because MAP and HR are the most commonly measured hemodynamic variables before and during induction of anesthesia, the study was designed to focus on these indices of cardiovascular function. Although the MAP response to induction of anesthesia with propofol was clear and age-related, the data do not allow for dissociation of vascular and cardiac effects, thus leaving the question of age-related differences in the fundamental mechanism of the hypotensive stimulus unresolved. Furthermore, whether age-related differences reflect pharmacodynamics or pharmacokinetics is unclear.

We conclude that reflex regulation of cardiovascular function declines as a consequence of aging in humans as a result of alterations in both peripheral sensing mechanisms and end-organ responsiveness. Accordingly, baroreceptor-mediated responses to vasodepressor stimuli become blunted in elderly individuals. The present study demonstrated a similar age-related diminution of BR in aged rabbits, which coincided with enhancement, relative to young animals, of the maximal decrease in MAP produced by bolus injection of propofol. However, in the presence of ganglionic blockade, the vasodepressor effect of propofol was essentially the same for both age groups owing to a markedly increased response in young animals. Thus, young rabbits became "aged" in terms of MAP response after HEX administration, suggesting that in this age group intact reflex regulation of MAP is largely responsible for limiting the magnitude of hypotension produced by induction of anesthesia with propofol.


   Acknowledgments
 
The authors would like to acknowledge Drs. S. Body, S. Desai and E. Schernhammer from the Brigham and Women’s Hospital in Boston, Massachusetts as well as Dr. K. Pryor from the New York-Presbyterian Hospital in New York, New York for their assistance in the statistical analysis of our data.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Merin RG. Effects of anesthesia on the aging heart. In: Stephen CR, Assaf RAE eds. Geriatric anesthesia. Boston: Butterworths Publishers, 1986: 219–42.
  2. Skues MA, Prys-Roberts C. The pharmacology of propofol. J Clin Anesth 1989; 1: 387–400.[Medline]
  3. Duke PC, Wade JG, Hickey RF, Larson CP. The effects of age on baroreceptor reflex function in man. Can Anaesth Soc J 1976; 23: 111–24.[ISI][Medline]
  4. Pfeifer MA, Weinberg CR, Cook D, et al. Differential changes of autonomic nervous system function with age in man. Am J Med 1983; 75: 249–58.[ISI][Medline]
  5. Lakatta EG, Mitchel HJ, Pomerance A, Rowe GG. Human aging: changes in structure and function. J Am Coll Cardiol 1987; 10 (2 Suppl A): 42A–7.
  6. Schnider TW, Minto CF, Shafer SL, et al. The influence of age on propofol pharmacodynamics. Anesthesiology 1999; 90: 1502–16.[ISI][Medline]
  7. Schnider TW, Minto CF, Gambus PL, et al. The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology 1998; 88: 1170–82.[ISI][Medline]
  8. Aeschbacher G, Webb AI. Propofol in rabbits. 1. Determination of an induction dose. Lab Anim Sci 1993; 43: 324–7.[ISI][Medline]
  9. Poller U, Nedelka G, Radke J, et al. Age-dependent changes in cardiac muscarinic receptor function in healthy volunteers. J Am Coll Cardiol 1997; 29: 187–93.[Abstract]
  10. Shimada K, Kitazumi T, Sadakane N, et al. Age-related changes of baroreflex function, plasma norepinephrine, and blood pressure. Hypertension 1985; 7: 113–7.[Abstract/Free Full Text]
  11. Tanabe S, Bunag RD. Aging escalates baroreceptor reflex suppression by the posterior hypothalamus in rats. Hypertension 1991; 17: 80–90.[Abstract/Free Full Text]
  12. Coetzee A, Fourie P, Coetzee J, et al. Effect of various propofol plasma concentrations on regional myocardial contractility and left ventricular afterload. Anesth Analg 1989; 69: 473–83.[Abstract/Free Full Text]
  13. Brussel T, Theissen JL, Vigfusson G, et al. Hemodynamic and cardiodynamic effects of propofol and etomidate: negative inotropic properties of propofol. Anesth Analg 1989; 69: 35–40.[Abstract/Free Full Text]
  14. Hamilton DL, Boyett MR, Harrison SM, et al. The concentration-dependent effects of propofol on rat ventricular myocytes. Anesth Analg 2000; 91: 276–82.[Abstract/Free Full Text]
  15. Li YC, Ridefelt P, Wiklund L, Bjerneroth G. Propofol induces a lowering of free cytosolic calcium in myocardial cells. Acta Anaesthesiol Scand 1997; 41: 633–8.[ISI][Medline]
  16. Robinson BJ, Ebert TJ, O’Brien TJ, et al. Mechanism whereby propofol mediates peripheral vasodilatation in humans: sympathoinhibition or direct vascular relaxation? Anesthesiology 1997; 86: 64–72.[ISI][Medline]
  17. Hoka S, Yamaura K, Takenaka T, Takahashi S. Propofol-induced increase in vascular capacitance is due to inhibition of sympathetic vasoconstrictive activity. Anesthesiology 1998; 89: 1495–1500.[ISI][Medline]
  18. Kamijo Y, Goto H, Nakazawa K, et al. Arterial baroreflex attenuation during and after continuous propofol infusion. Can J Anaesth 1992; 39: 987–91.[Abstract/Free Full Text]
  19. Rocchiccioli C, Saad MA, Elghozi JL. Attenuation of baroreceptor reflex by propofol anesthesia in the rat. J Cardiovasc Pharmacol 1989; 14: 631–5.[ISI][Medline]
  20. Przyklenk K, Li G, Whittaker P. No loss in the in vivo efficacy of ischemic preconditioning in middle-age and older rabbits. J Am Coll Cardiol 2001; 38: 1741–7.[Abstract/Free Full Text]
  21. Abete P, DeSantis D, Condorelli M, et al. A four-year-old rabbit cannot be considered the right model for investigating cardiac senescence. J Am Coll Cardiol 2002; 39: 1701–2.[Free Full Text]
  22. Abdel-Rahman AR. Inadequate blockade by hexamethonium of baroreceptor heart rate response in anesthetized and conscious rats. Arch Int Pharmacodyn Ther 1989; 297: 68–85.[ISI][Medline]
  23. Collister JP, Osborn JW. The chronic infusion of hexamethonium and phenylephrine to effectively clamp sympathetic vasomotor tone: a novel approach. J Pharmacol Toxicol Methods 1999; 42: 135–47.[ISI][Medline]
Accepted for publication July 9, 2004.




This article has been cited by other articles:


Home page
 Anesth. Analg.Home page
K. K. Tremper
Anesthesia Information Systems: Developing the Physiologic Phenotype Database
Anesth. Analg., September 1, 2005; 101(3): 620 - 621.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Memtsoudis, S. G.
Right arrow Articles by Heerdt, P. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Memtsoudis, S. G.
Right arrow Articles by Heerdt, P. M.
Related Collections
Right arrow Cardiovascular
Right arrow Pharmacology

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press