1. PHARMACOKINETICS AND PHARMACODYNAMICS IN THE ELDERLY AND THEIR IMPACT ON ANESTHETIC AGENTS Samantha P. Jellinek, PharmD, BCPS, CGP Clinical Pharmacy Manager
AGS
THE AMERICAN GERIATRICS SOCIETY
Geriatrics Health Professionals.
Leading change. Improving care for older adults.
Topic

2. The problem Elderly patients require dose reductions for most agents
Become more sensitive to the therapeutic and adverse effects
Increased sensitivity results from a combination of pharmacokinetic/pharmacodynamic (PK/PD) alterations
Pathophysiology may also affect the PK/PD of anesthetic agents

3. Physiologic vS. Calendar Age
Wide variability in dose-response relationships occur with increasing age
Physiologic age and comorbidity are the primary influences on postoperative outcome
There are very healthy elderly patients who exhibit the physiology, and thus the PK and PD, of the young. On the other hand, very aged elderly patients may exhibit compromised CV and CNS systems. Thus, there is wide variability in the dose-response relationships that occur with increasing age. Recent literature indicates that physiological age and comorbidity, and not calendar age itself, are the primary influences on postoperative outcome in the elderly.

4. ObjectiveS To review the physiological changes that occur with age
To review how these changes affect the PK/PD of the agents used in anesthetic practice in the elderly

5. Changes in Body Composition: Men
Total body weight declines
Contraction of total body water and loss of lean tissue mass
Body fat fraction returns toward young adult values
By the geriatric years, total body weight in physically active older men has declined as a result of the contraction of total body water and the loss of lean tissue mass, returning the body fat fraction toward young adult values. In the elderly, muscle mass falls to about 50% of adolescent values.

6. Changes in Body Composition: Women
Little change in total body weight
More persistent trend of increasing body fat
Offsets resorption of skeletal elements and loss of total body water
Result: increment in the fat fraction of the total body weight
Older women typically experience little change in total body weight. Women have a more persistent trend of increasing body fat, which offsets resorption of skeletal elements and loss of total body water, producing an increment in the fat fraction of the total body weight.

7. ALTERED VOLUME DISTRIBUTION of Drugs (1 of 2)
A decrease in total body water causes a decrease in the central compartment (V1)
Results in higher peak drug concentrations following boluses or rapid infusions
A decrease in lean body mass causes a decrease in the rapid equilibrating compartment (V2)
Body composition changes alter the volume of distribution (Vd) of drugs. This will result in a longer duration of effect and higher peak drug concentration following boluses or rapid infusions.

8. ALTERED VOLUME DISTRIBUTION of Drugs (2 of 2)
An increase in body fat causes an increase in the slow equilibrating compartment (V3)
Results in an increase in total volume of distribution and alterations in the duration of drug effect
Computer simulations are used to interpret how these changes affect dose and time course of drug effect
Although we are aware that these changes in Vd occur, it is nearly impossible to interpret how they will affect dose and time course of drug effect without computer simulations.

9. How can we apply this to clinical practice?
Neuromuscular blocking agents given on a weight-related basis may have a more prolonged effect in the elderly
Steady-state Vd (Vdss) of thiopentone increases to 125% of the adult value, yet the initial Vd is reduced
Same is seen with soluble anesthetic vapors such as halothane
Water-soluble drugs such as cimetidine have a reduced Vdss
As muscle is the target organ for neuromuscular blocking agents, any dose given on a weight-related basis may be expected to have a more prolonged effect in the elderly. The steady-state Vd of thiopentone increases to 125% of the adult value, yet the individual Vd is reduced, increasing the apparent sensitivity of the elderly to this drug.

10. Changes in the Central Nervous System (1 of 2)
Between the ages of 20 and 80 years there is approximately a:
30% reduction in cerebral blood flow
36% reduction in cerebral oxygen consumption
30% reduction in cortical neuronal density
Neuronal activity, autoregulation, and cerebrovascular response to CO2 remain intact
Neuronal composition, cell number, and regeneration capacities in the CNS diminish
The target organ for all anesthetic agents is the CNS. Between the ages of 20 and 80 years there is approximately a 30% reduction in central blood flow, a 36% reduction in cerebral oxygen consumption, and a 30% reduction in cortical neuronal density. Neuronal activity, autoregulation, and cerebrovascular response to CO2 remain intact in the absence of disease. However, in recent years, it has been discovered that neuronal composition, neuronal cell number, and neuronal regeneration capacities in the CNS diminish with increasing age.

11. Changes in the Central Nervous System (2 of 2)
Depletion of brain neurotransmitters
Number of receptor sites and composition of receptors decrease and change
May explain why most anesthetic agents exert their effects in the elderly at lower blood and effect-site concentrations
There is a depletion of brain neurotransmitters (catecholamines, serotonin, and acetylcholine). These are associated with mood, memory, and motor function and may partly account for their loss. The number of receptor sites and the composition of these receptors that are involved in memory formation and the propagation of anesthesia, such as N-methyl-d-aspartate, also decrease and change in the elderly. These alterations may explain why most anesthetic agents exert their effects in the elderly at lower blood and effect-site concentrations.

12. Changes in the Cardiovascular System (1 of 5)
Decreased number of myocytes
Stiffening of myocardial cells
Reduced response to β-adrenergic stimulation
Large arteries dilate
Increased wall thickness and smooth muscle tone
Age-related changes in CV function explain the increased cardio-depressant effects of many anesthetics in the elderly. The decreased number of myocytes, the stiffening of myocardial cells, and the reduced response to β-adrenergic stimulation result in clinically obvious decreased contractile properties of the heart with increasing age. In parallel with these cardiac changes, the large arteries dilate, with increased wall thickness and increasing smooth muscle tone.

13. Changes in the Cardiovascular System (2 of 5)
Results in an increase in systolic BP, elevated left ventricular (LV) afterload, and LV wall thickening
Reduces LV compliance, causing impairment of diastolic function
More sensitive to the arrhythmogenic effects of anesthetics
Increased tendency to develop pulmonary edema
Clinically this results in an increase in systolic blood pressure and an elevated LV afterload, resulting in LV wall thickening. This is turn reduces LV compliance and causes impairment of diastolic function. As a consequence, the elderly are more sensitive to the arrhythmogenic effects of anesthetics, with an increased tendency to develop pulmonary edema.

14. Changes in the Cardiovascular System (3 of 5)
No age-associated decline in cardiac output in healthy older adults
Sedentary lifestyle or degenerative changes would produce a decline in cardiac output
Decreases in cardiac output with a lower tissue perfusion may lengthen the time required to transport drugs to tissues and delay the time to peak effect
Although it was previously believed that a progressive decrease in cardiac output occurs, newer longitudinal studies fail to show a significant age-associated decline in cardiac output at rest or during exercise in healthy adults between the ages of 25 and 79 years. It appears that in the elderly, a sedentary lifestyle or degenerative diseases would produce a decline in cardiac output, but an active lifestyle and good health would maintain it at relatively normal levels.

15. Changes in the Cardiovascular System (4 of 5)
Reduction in perfusion is uneven
Results in increased duration of action of anesthetic agents
Virtually all anesthetics decrease cardiac output to some degree
Dose needed for induction is reduced
Slower onset of block seen with neuromuscular blocking agents
The reduction in perfusion is uneven, with decreases in hepatic and renal blood flow and an increase of cerebral, coronary and skeletal blood flow. A reduction in perfusion of the organs responsible for drug metabolism and elimination has important PK implications for IV anesthetic agents, generally increasing their duration of action.
If we consider the effect of anesthetic drugs on cardiac output, virtually all decrease it to some degree. As a result of the decreased cardiac output, the dose of anesthetic agents needed for induction is reduced, because a relatively larger fraction of the dose is distributed to the brain. A decrease in cardiac output would also result in slower distribution of neuromuscular blocking drugs to the neuromuscular junction, explaining the slower onset of block often seen in elderly patients.

16. Changes in the Cardiovascular System (5 of 5)
Increased risk of hypotension
Decreased baroreceptor sensitivity
Decreased response to β-stimulation
Decreased response of renin/aldosterone/angiotensin system
Elderly patients are also at an increased risk of developing hypotension because of the decreased baroreceptor sensitivity, decreased response to β-stimulation, and decreased response of the renin/aldosterone/angiotensin system.

17. Changes in the Respiratory System (1 of 2)
Vital capacity, maximum voluntary ventilation, and total lung capacity decrease with increasing age
Functional residual capacity and closing volume increase
Results in collapse of small airways and air trapping
A number of striking anatomic changes occur in the respiratory system with age. Vital capacity, maximum voluntary ventilation, and total lung capacity all decrease with age, whereas functional residual capacity and closing volume (the volume about FRC at which the airways begin to close off) increase, resulting in the collapse of small airways and air trapping.

18. Changes in the Respiratory System (2 of 2)
Marked suppression of hyperventilation in response to imposed hypoxia or hypercapnia
Anesthesia, supine position, and use of narcotics worsen hypoxia
Increased risk of aspiration and postoperative pneumonia
In the elderly there is marked suppression of hyperventilation in response to imposed hypoxia or hypercapnia, putting these patients at a higher risk of respiratory failure. Anesthesia, supine position, and use of narcotics worsen hypoxia by increasing the ventilation perfusion mismatch in an age group that already has blunted ventilatory reflexes. Impaired cough and laryngeal reflexes, decreased immune response, and decreased mucociliary clearance increase the risk of aspiration and postoperative pneumonia.

19. Changes in the Hepatic System (1 of 2)
Decrease in liver volume
40% reduction in liver blood flow
Anesthesia and abdominal surgery also reduce blood flow
Reduced maintenance requirements for drugs that are rapidly cleared by the liver
Modest reduction in the rate of hepatic metabolism for drugs slowly cleared by the liver
Fall in metabolism for other anesthetics
A decrease in liver volume and a 40% reduction in liver blood flow occurs as individuals approach the end of the ninth decade. Anesthesia and abdominal surgery decrease liver blood flow themselves. These effects result in reduced maintenance dose requirements for drugs that are rapidly cleared by the liver (eg, propofol) but a modest reduction in the rate of hepatic metabolism for drugs that are cleared slowly by the liver (eg, alfentanil and vecuronium). For vecuronium, the elimination half-life is prolonged from 78 minutes in the young to 125 minutes in the elderly. There is an overall decline in metabolism of some anesthetics, such as etomidate, whose clearance falls by about 37%.

20. Changes in the Hepatic System (2 of 2)
Intrinsic hepatic capacity unchanged
No significant age-dependent difference in the activity of hepatic phase 1 and 2 drug metabolism
Hepatic cytochrome P450 activity unchanged
Production of albumin decreased
Increased free fraction of drugs that bind primarily to it, with reduced dose requirements
Alpha-1 acid glycoprotein increased
Decreased free fraction of drugs and reduced elimination
A decrease in the intrinsic hepatic capacity is not supported by recent studies that show an absence of significant age-dependent differences for the activity of hepatic phase 1 and 2 drug metabolism. Hepatic cytochrome p450 activity remains unchanged. Production of albumin by the liver is decreased, resulting in decreased plasma protein binding of drugs. A decreased albumin concentration increases the free fraction of drugs that bind primarily to it (eg, diazepam), with reduced dose requirements. An increased α-1 acid glycoprotein concentration decreases the free fraction of drugs that bind to it (eg, lidocaine) and reduce the drugs’ ability to be cleared.

21. Changes in the Renal System
Delay in the offset of renally excreted drugs
Glomerular filtration rate decreases by about 1% per year over 40 years of age
Result of decreased cardiac output and glomerular sclerosis
Elimination of drugs undergoing renal excretion is prolonged
Tubocurarine
One of the consequences of age-related changes in renal function is a delay in the offset of renally excreted drugs such as pancuronium. It would therefore be prudent to choose a different neuromuscular blocking agent for an elderly patient with signs of renal disease.
As a result of decreased cardiac output and age-related glomerular sclerosis, GFR decreases by about 1% per year over the age of 40. Elimination of drugs that undergo renal excretion may therefore be prolonged in the elderly. For example, the elimination half-life of tubocurarine is 268 minutes in the elderly but 137 minutes in younger patients.

22. Neuromuscular Blocking Agents
Onset of action is prolonged
Cisatracurium
Duration of action is prolonged
Succinylcholine, rocuronium, mivacurium, vecuronium
Atracurium and cis-atracurium not prolonged
Long-acting agents are associated with longer PACU stays and postoperative pulmonary complications
Maintenance infusion rate for adequate neuromuscular blockade is reduced
Vecuronium
Recovery from muscle relaxation is delayed
What is known about the PK/PD of neuromuscular blocking agents? First, their onset of action is prolonged secondary to reduced muscle blood flow. We also know that their duration of action is prolonged. This is seen with succinylcholine and mivacurium because of lower rates of hydrolysis caused by decreased levels of plasma cholinesterase in the elderly.
Therefore, neuromuscular blocking agents should be limited to short- acting or intermediate-acting (vecuronium and rocuronium) in all elderly patients in whom extubation is planned. Long-acting neuromuscular blocking agents are associated with long PACU stays and increased postoperative pulmonary complications.
The maintenance infusion rate for adequate neuromuscular blocking is reduced. The primary route of elimination of vecuronium is via hepatic metabolism, and the decline in hepatic blood flow with age will reduce the plasma clearance. This implies that a constant level of blockade in the elderly is reduced by about 30% and the patient will recover about 30% to 40% more slowly than a younger patient.
Finally, recovery from muscle relaxation is delayed. Elderly patients have reduced tissue distribution and clearance, which causes increased plasma drug concentrations and an increased effect.

23. Volatile Anesthetic Agents (1 of 2)
66%75% anesthetic concentration is required by an 80-year-old compared to a young adult
Rate of induction may be slowed
Dose should not be hastened to induce induction
Larger decrease in BP seen in elderly
Impairment of reflex heart rate responses to BP
Reduced myocardial contractility by inhalation anesthetics
Volume contraction
Reduction in inhalation anesthesia requirements is due to fundamental neurophysiological changes in the brain. Typically 66% to 75% anesthetic concentration is required by an 80-year-old as compared to a young adult. Rate of induction may be slowed because of reduced ventilation, but the dose of inhalation agent should not be hastened to induce induction.
There is a general perception that inhalation agents can cause a larger decrease in blood pressure at a given concentration in the elderly than in the young. Many factors account for the perceived greater hemodynamic sensitivity, but age-related impairment of reflex heart rate responses to blood pressure, decreased myocardial contractility by inhalation anesthetics, and volume contraction might enhance the decrease.

24. Volatile Anesthetic Agents (2 of 2)
Isoflurane and desflurane are metabolized less
Advantages of sevoflurane and desflurane:
More rapid control of anesthetic depth
Faster emergence from anesthesia
More rapid recovery of mental function to pre-anesthesia levels
Isoflurane and desflurane are metabolized less than other potent inhalation anesthetics; therefore, the concentration of potentially toxic metabolites (inorganic fluoride, which can cause nephrotoxicity) is lower.
The lower solubility of sevoflurane and desflurane has important advantages in the elderly, for example, more rapid control of anesthesia depth to meet varying intraoperative conditions, faster emergence from anesthesia for desflurane as compared to isoflurane, and theoretically a more rapid recovery of mental function to pre- anesthetic levels, although studies have failed to demonstrate this.

25. Intravenous Agents Must cross the blood-brain barrier
Non-ionized and protein-bound
Small changes in pH greatly alter the availability of the drug
Slow infusion rates are safer
Too slow a rate may increase the dosage requirement
To be effective, IV anesthetic drugs must cross the blood-brain barrier and be non-ionized. They are usually protein-bound, which allows some penetration of the blood-brain barrier. The degree of ionization is related to their pKa values. Changes in the degree of ionization will have profound effects on the efficiency of anesthetic drugs. Small changes in pH will greatly alter the availability of the drug. The elderly have a deterioration in renal acid-base balance control, and any such fall in pH will increase the relative potency of the drug, often to dangerous levels.
Slower infusion rates appear to be much safer. The amount of drug given at faster rates is up to 50% more than actually needed for induction. You need to take into account the circulation time or the time it takes for the drug to be delivered to the brain to induce anesthesia. The longer the circulation time, the more drug that will be infused before anesthesia occurs. Even after recognition of the onset of anesthesia, there will be more drug still to be presented to the brain. There may come a time with very slow infusion rates when either the redistribution into the lean body mass or metabolism exerts an effect on the induction dose and may increase the dose required.

26. HYPNOTICS: Propofol
Anesthetic depth synergistically increased when administered with other induction agents
Decreased maintenance requirement with increasing age
Slowly administer a reduced dose to avoid hypotensive effects
11.5 mg/kg without opioids; 0.51 mg/kg with opioids
Mask induction with sevoflurane causes less hypotension than IV propofol induction
Hypotensive response of propofol is offset by intubation response
Dose reductions for propofol are required with concurrent administration of any other induction agent, narcotics, or benzodiazepines, as anesthetic depth is synergistically increased.
Age-related decreases in clearance of propofol result in a decreased maintenance requirement with age.
The hypotensive side effects of propofol require slow administration of a reduced dose, titrated to effect, rather than a bolus of a preselected standardized dose. The dose of propofol should be 1 to 1.5 mg/kg without opioids or 0.5 to 1 mg/kg with opioids, especially when midazolam or ketamine is given. Mask induction with sevoflurane causes less hypotension in the elderly than IV propofol induction. Hypotensive response of propofol is offset by intubation response.

27. HYPNOTICS: Thiopental
Higher concentrations are seen for any given dose
Recovery can be significantly prolonged after continuous infusions or repeated bolus doses
Elderly require a 20% reduction in infusion rate
Concentration will decline nearly as rapidly when infusion is turned off
Higher concentrations are seen for any given dose of thiopental, caused by a reduction in the Vd. Recovery can be significantly prolonged after repeated boluses or continuous infusion, because metabolism becomes dependent on intrinsic hepatic enzyme activity and the degree of protein binding. Healthy elderly patients need only a modest reduction in the infusion rate, 20% or less, when compared to younger adults. If the appropriate adjustment is made, then the concentration will decrease nearly as rapidly when the infusion is turned off.

28. HYPNOTICS: Methohexital
Clearance is greater and elimination half-life is shorter than that of thiopental
Clearance largely dependent on hepatic blood flow
Elimination will be prolonged
The clearance of methohexital is greater than that of thiopental and its resultant elimination half-life is shorter. However, its clearance is largely dependent on hepatic blood flow, which declines with age, so elimination will be prolonged in comparison to that in younger individuals.

29. HYPNOTICS: Etomidate Initial volume of distribution is decreased
Requires less than half the dose to reach the same stage EEG endpoint as younger patients
The initial Vd of etomidate is reduced. An 80-year-old patient requires less than half the dose of etomidate to reach the same EEG endpoints as a 20-year-old patient.

30. Benzodiazepines: Midazolam
Increased potency
30% reduction in clearance in the elderly
Takes twice as long for concentration to fall
50%75% dose reduction required when administered as a bolus
Midazolam has increased potency in the elderly. Pharmacokinetic studies show a reduction in clearance, approximately 30% in a 80-year-old compared to a 20-year-old, and it takes nearly twice as long for the concentration to fall in an 80-year-old as in a 20-year-old. Anywhere from a 50% to 75% dose reduction is required in the elderly when midazolam is administered as a bolus.

31. Benzodiazepines: Diazepam
Desmethyldiazepam has more CNS activity than diazepam
Accumulation with long-term use can prolong its clinical effects in the elderly
The hepatic oxidative metabolism of diazepam by hydroxylation results in desmethyldiazepam, which has more CNS activity than the parent compound. With long-term use, the accumulation of the more potent metabolite can prolong its clinical effects in the elderly.

32. Benzodiazepines: Ketamine
Can exert a negative inotropic effect on ischemic myocardium
Lower induction dose for elderly critically ill patients
Decreased clearance and prolonged duration of action expected
Because ketamine can exert a negative inotropic effect on ischemic myocardium, it is prudent to lower the induction dose for critically ill elderly patients. A decreased clearance and prolonged duration of action in the elderly is expected.

33. OPIOIDS: Sufentanil Small decrease in Vd of the central compartment
Undergoes hepatic metabolism
Requires reduction in both loading and maintenance doses with increasing age
A small decrease in the volume of the central compartment is seen with sufentanil in the elderly, which would affect the dose requirements only for the first few minutes. Sufentanil undergoes hepatic metabolism, so a decreased clearance and an increased duration of action are expected, requiring a reduction in both the loading and maintenance doses.

34. OPIOIDS: Remifentanil
Has twice the intrinsic potency in elderly
Central compartment volume decreases 20%
Clearance decreases 30%
Decrease bolus and maintenance dose by 50%
Peak effect expected about 23 minutes after bolus
Remifentanil has about twice the intrinsic potency in the elderly. Pharmacokinetic studies show that the central compartment decreases 20% and the clearance decreases 30%. These changes translate into dose changes (decrease by 50% by age 65) for bolus and maintenance infusion. In addition, onset is slower in the elderly, with peak drug effect expected about 2 to 3 minutes after the bolus.

35. OPIOIDS: Fentanyl and Alfentanil
PK does not appear to be changed
Fentanyl: Increased potency of about 50%
Reduce dose by half to achieve the same effect
The pharmacokinetics of fentanyl and alfentanil in the elderly do not appear to be changed. Fentanyl does show an increased potency of approximately 50%, which would translate clinically into a reduction of dose by half to achieve the same effect.

36. OPIOIDS: Morphine Clearance decreased by 50%
Prolonged duration of action
Reductions in maintenance dosing
The clearance of morphine is decreased by 50% in the elderly, suggesting a prolonged duration of action and reductions in maintenance dosing.

37. Local Anesthetics PK/PD changes result from:
Decline in the neuron population and slowing of conduction velocity in the peripheral nerves
Deterioration in myelin sheaths and connective tissue barriers
Changes in anatomical configuration of the lumbar and thoracic spine
Progressive sclerotic closure of the intervertebral foramina
Pharmacodynamic changes in the elderly result from a decline in the neuron population within the spinal cord and slowing of conduction velocity in the peripheral nerves. Pharmacokinetic changes in local disposition with increasing age are caused by deterioration of the myelin sheaths and connective tissue barriers, changes in anatomical configuration of the lumbar and thoracic spine, and progressive sclerotic closure of the intervertebral foramina.

38. Bupivacaine Rapid initial absorption followed by a much slower phase
Epidural space
Fast: High initial concentration gradient and large vascularity
Slow: Slow uptake of local anesthetic sequestered in epidural fat
Peak plasma concentrations and peak times do not change
Terminal half-life increases
Protein binding or metabolizing hepatic enzyme activity
The absorption of bupivacaine from the epidural space shows a biphasic profile: a rapid initial phase followed by a much slower phase. The initial fast absorption phase is a reflection of the high initial concentration gradient and the large vascularity of the epidural space. The slower second phase is believed to occur from the slow uptake of local anesthetics sequestered in the epidural fat.
The peak plasma concentrations and peak times of bupivacaine do not seem to change with age. The terminal half-life increases, whereas the total plasma clearance decreases. Bupivacaine has a low hepatic extraction ratio, which means that the decline in plasma clearance is more likely due to a change in the metabolizing hepatic enzyme activity and or serum protein binding than to an alteration in liver blood flow.

39. Regional vS. General Anesthesia
There are no large prospective studies preferentially supporting the use of regional anesthesia in elderly
Outcome studies suggest no difference in mortality and major morbidity
Regional anesthesia has the advantages of:
Reduced postoperative negative nitrogen balance
Amelioration of stress response to surgery
Decreased incidence of postoperative thromboembolic complications
Decreased blood loss
Decreased postoperative mental confusion
Does the type of anesthesia administered to elderly patients influence the outcome? Is regional anesthesia preferable in this age group?
Intuitively, it makes sense that elderly patients would benefit from regional anesthesia because they remain awake during the procedures and are minimally sedated. During certain procedures, regional anesthesia has the advantages listed on the slide. However, there are no large prospective studies preferentially supporting the use of regional anesthesia in elderly patients. In fact, current outcome studies have suggested that there is no difference in mortality and major morbidity between general and regional anesthesia in most patient populations.

40. SPECIAL CONCERNS: Pre-oxygenation
Elderly patients desaturate faster
Time to peak relaxation from succinylcholine is also increased
Arteriolar, alveolar, venous, and tissue compartments are filled with oxygen
Maximum oxygen in a short period of time
8 deep breaths of 100% oxygen in 60 seconds with an oxygen flow of 10 L/min
More likely to suffer a cardiac event from desaturation
Maximum pre-oxygenation is required for elderly patients because they desaturate faster, and the time to peak relaxation from succinylcholine is also increased. Maximum pre-oxygenation is attained when along with arteriolar and alveolar compartments, venous and tissue compartments are also filled with oxygen. Maximum oxygen in a short period of time is 8 deep breaths of 100% oxygen in 60 seconds with an oxygen flow of 10 L per minute. Elderly patients are more likely to suffer a cardiac event from desaturation.

41. SPECIAL CONCERNS: Hypothermia (1 of 3)
Elderly are susceptible to effects of hypothermia:
Bleeding
Decreased immune function
Decreased wound strength
Hypothermia is more pronounced and lasts longer because of:
Low basal metabolic rate
Hypothyroidism
High ratio of surface area to body mass
Elderly patients are not immune to the adverse effects of hypothermia, which are bleeding, decreased immune function, and decreased wound strength. Hypothermia is more pronounced and lasts longer due to intrinsic factors (low basal metabolic rate, hypothyroidism, high ratio of surface to body mass).

42. SPECIAL CONCERNS: Hypothermia (2 of 3)
Core temperature must fall to 35.2 °C before:
Shivering
Cold-induced vasoconstriction
Autonomic mechanisms for thermoregulation
Oxygen consumption increases 38% over nonshivering levels
Reduction in skeletal muscle mass decreases post-op shivering
Impairment of autonomic mechanisms for thermoregulation, cold- induced vasoconstriction, and shivering in the elderly is delayed intraoperatively, until core temperature falls to lower than that in young adults. Younger patients shiver at 36.1 °C while patients older than 80 will not shiver until their core temperature decreases to 35.2 °C.
Oxygen consumption is increased 38% over non-shivering levels. Reduction in skeletal muscle mass decreases post-op shivering, thus limiting the rate at which temperature homeostasis can be reestablished.

43. SPECIAL CONCERNS: Hypothermia (3 of 3)
Inhibition of thermoregulatory responses by anesthetics is exaggerated
Prolonging clearance
Further renders the elderly susceptible to post-op hypothermia
Rewarming may precipitate sudden hypotension
Vasodilation
Hypovolemia
Inhibition of thermoregulatory responses by anesthetics is greatly exaggerated in the elderly, prolonging clearance of anesthetics, which further renders them more susceptible to post-op hypothermia. Rewarming may precipitate sudden hypotension as a result of vasodilation and hypovolemia.

44. Practice Points (1 of 4)
Induction dose in the elderly should be reduced
Administer only 50% of the induction dose of a hypnotic/opioid or neuromuscular blocking agent in an 80-year old compared to a 20-year old to ensure the same hypnotic/analgesic or neuromuscular relaxant effect
Topic

45. Practice Points (2 of 4) Onset of most agents is delayed
Wait an appropriate period of time for the maximal effect to occur in the elderly, to avoid undesired side effects
Topic

46. Practice Points (3 of 4)
Maintenance dose requirements should be reduced dramatically in the elderly
For example, remifentanil by 70%; propofol by 40%
Topic

47. Practice Points (4 of 4)
PK/PD variability appears to increase with age because of the increasing gap between the healthy and the very ill elderly
Titration to effect thus becomes increasingly important with age
Topic

48. RECOMMENDATIONS FOR DOSE ADJUSTMENT
Drug/Class
Dose Adjustment
Barbiturates
Modest reduction in bolus dose and infusion rates
Etomidate
Reduction of up to 50% in bolus dose
Propofol
Reduction of up to 30%50% in bolus dose and infusion rates
Benzodiazepines
Reduction of up to 75% in bolus dose and infusion rates
Opioids
Reduction of up to 50% in bolus dose and infusion rates
Non-depolarizing neuromuscular blocking agents
No reduction in bolus dose but generally reduced infusion rates depending on drug
Volatile agents
Reduction in inspired concentrations of 6% per decade
Local anesthetics
Small to moderate reduction in segmental dose
Topic

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