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Abstract

Surgical intervention for both emergency and elective surgeries will Increase as women live longer and maintain active lifestyles. Older women with operable conditions tolerate elective gynecologic and other nonvascular surgery with acceptable morbidity and mortality. However, increased medical comorbidities, with their associated increase in polypharmacy and perioperative risks as women age, make it important to a priori optimize perioperative medical conditions and medication management. Other considerations include assessing functional and cognitive status, since these may be impaired acutely with increased prevalence of drug use during surgical hospitalization. With aging and postmenopausal status, changes associated with aging appear to play a greater role than gender in pharmacologic responses. Surgical outcomes should be optimized to maintain and even improve women's quality of life.

Keywords

geriatrics medication management older woman outcomes perioperative pharmacotherapy surgery

General health and medical advances as well as pharmacologic interventions have contributed to an increase in American life expectancy. Over the next 25 years, the US population will evolve such that one in five people will be older than 65 years (currently ∼1/8 or 12%) [101]. The majority of this population are women, accounting for 60% of the population aged 65 years and older and 71% of the population aged 85 years and older [1]. This geriatric population, defined as persons 65 years of age and older, consumes over 30% of prescription and 40% of over-the-counter (OTC) medications, fills an average of more than 14 different prescription medications annually and takes a daily average of five prescription medications and four OTC medications [2 –4]. Of this group, older women are the greatest consumers of both prescription and nonprescription medications, with 23% taking at least five prescribed medications [2]. The average number of drugs taken among 70-year-old women increased from 2.8 to 4.0 from 1971 to 2000 [5]. With the increase in longevity, surgical interventions and prevalence of chronic conditions, drug use by this group will continue to increase, resulting in potential increase in drug-related problems (DRPs). Attention to appropriate perioperative pharmacologic management of the older woman undergoing surgery is paramount to successful surgical and functional outcomes.

A third of all surgeries take place in patients aged above 65 years [6]. Women are more likely than men to have surgery, with women accounting for 58% of all procedures performed and 59% of all hospital discharges [102]. The chance that a woman will have surgery markedly increases as she gets older, as do perioperative risks, and 75% of those surgeries performed in women over 80 years of age are for malignancy, or suspected malignancy, for which surgery is the primary treatment [7]. It has been estimated that there will be at least a 45% increased demand for pelvic floor surgery (including surgery for urinary incontinence and pelvic organ prolapse), paralleling our evolving aging demographic [8]. Surgical mortality and morbidity in older women ranges between 0–3.6% and 14–45%, respectively [7,9 –14]. Factors that may increase surgical morbidity for those over the age of 70 years have been proposed in several studies (Box 1) [9 –12,15,16]. While older patients tolerate elective surgery well, they do not tolerate surgical complications.

Since elective gynecologic and other nonvascular surgery can be safely performed in older women, surgeons should not deny or delay elective surgery for conditions where surgery is the primary treatment, particularly since emergency surgery significantly increases surgical risk. Multiple factors contribute to the complexity of operating on the older patient: multiple medication use, prevalence of concurrent medical conditions, frailty, higher incidence of impaired functional and cognitive status, age-related physiologic changes and impaired organ reserve. Surgeons should institute perioperative pharmacologic management strategies that minimize risk factors and complications and facilitate recovery from surgery. With increasing use of minimally invasive surgical techniques, such as laparoscopy and robotic-assisted approaches, morbidity and duration of hospitalization are likely to decrease [13]. While emergent surgery carries a greater risk of morbidity and mortality in the older patient, the present discussion focuses on the information available on medication management and elective or nonemergent surgery since we wish to emphasize the importance of optimization of the patient's medical condition and functional status prior to surgery, in order to decrease the risk of complications and maximize outcomes. This is less applicable to those patients requiring emergent surgery.

Box 1.

Predictors of increased surgical morbidity for those over 70 years of age.

Aspirin class III/IV

Low preoperative hematocrit or need for preoperative transfusion

Weight loss and poor nutritional status

Emergency surgery

Operative duration

Diabetes mellitus

Preoperative functional status

Clinical signs of congestive heart failure

Data taken from [9 –12,15,16].

The purpose of this article is to explore the following content areas with emphasis on the optimization of pharmacologic management in the older woman undergoing surgery. The combination of greater drug use and potential polypharmacy issues, increased risk for surgical intervention, a longer lifespan and other gender-specific issues are of significant clinical importance to warrant specifically addressing perioperative issues in the older woman. While there is a paucity of studies addressing gender differences as it pertains to perioperative care of the elderly, we illustrate them when there are available data:

Polypharmacy and DRPs;

Changes in pharmacodynamics associated with aging;

Cognitive and functional assessments – risk factors for postoperative delirium;

Anesthetic and analgesic considerations;

Clinically relevant drug–drug interactions.

Polypharmacy & drug-related problems

Hospitalization and surgical admissions uniquely expose patients to many medications for a brief but intense time period. A 2006 study by Vaurio et al. investigating 333 elderly surgical patients demonstrated an increase in the use of benzodiazepines in the pre- versus postoperative period from 11 to 23%, opioids from 23 to 100%, antidepressants from 9 to 11% and 32% of the patients received postoperative antihistamines within 48 h after surgery [17]. The most frequent iatrogenic complication in the hospital is adverse drug events or DRPs, which are defined as circumstances when drug therapy interferes with desired health outcomes. These can significantly impact surgical morbidity in the older patient. Polypharmacy is commonly defined as the concomitant use of five or more medications. Cohort studies using this definition show that ‘polypharmacy’ is a risk factor for hospitalizations, nursing home placements, decreased functional status and other DRPs, but the arbitrary cutoff of five drugs poorly differentiates or stratifies risk of perioperative morbidity and mortality [4,18,19]. Rather than using this arbitrary definition for polypharmacy as risk for DRPs, clinicians should assess whether medication use is appropriate, necessary or inadequately utilized based on current treatment guidelines.

The prevalence of DRPs vary depending on the clinical settings studied, the method for their detection and the threshold for discovery and inclusion in the studies. Up to two-thirds of patients in nursing homes and 35% of community-dwelling patients were identified as having DRPs, which account for 30% of hospital admissions in the older patient [20,21]. The Beers criteria and the Improved Prescribing in the Elderly Tool (IPET or McLeod's criteria) are the two most commonly used assessment methods in studies assessing the prevalence of inappropriate drug use [20 –22]. The 2003 update of the Beers criteria is now the most widely used criteria in studies of DRPs [21,23]. The primary differences between the Beers criteria and IPET are inclusiveness of medication categories represented and medications deemed as inappropriate. In comparison to the IPET tool, the modified Beers criteria is more sensitive for identifying inappropriate prescribing and DRPs because of its more comprehensive list of medications. Only three classes of medications are shared between the Beers criteria and the IPET tool: long-acting benzodiazepines, NSAIDs in peptic ulcer disease, and β-blockers use in chronic obstructive pulmonary disease [24]. Since almost half of the drugs on these two lists are not approved for use in other countries, ranging from 29% in Italy to 68% in Norway, the use of the Beers and IPET criteria by studies in non-North American countries would result in an underestimation of the prevalence of inappropriate medication use [23]. Studies using these two criteria have established that potentially inappropriate prescribing is highly prevalent, but there are no data describing how the use of these tools directly affects patient outcomes and clinical practice.

Changes in pharmacokinetics associated with aging

The combination of drug–drug interactions, drug–disease interactions, altered pharmacokinetics, altered pharmacodynamics and age-related changes in body composition and physiology make prescribing medications more complex in the older patient and increases the potential for DRPs. A decrease in gastrointestinal (GI) tract blood flow, gastric motility and gastric acidity can reduce the absorption of medications requiring active transport and acidic milieu. Once absorbed, factors that affect the volume of distribution include the medication's degree of protein binding and solubility in lipids versus water. Gender differences attributed to the effects of sex hormones are not observed in older postmenopausal women. With aging, the relative decreases in lean body mass and body water, increases in body fat and decreases in protein binding can decrease the volume of distribution for hydrophilic drugs (i.e., lithium, ethanol, digoxin and atenolol) and increase it for lipid-soluble drugs (i.e., benzodiazepines and haloperidol) and highly protein-bound drugs (i.e., phenytoin, theophylline, warfarin and digoxin). This can all increase the potential for DRPs (either toxicity or lower efficacy) in the older patient. Total serum drug levels to assess therapeutic plasma concentration is less useful in the elderly and must be interpreted based on albumin level, degree of protein binding and competitive binding to albumin by other drugs. Seemingly, subtherapeutic levels of phenytoin, which is 90% bound to albumin, in the setting of low albumin may actually be therapeutic [25].

Functional reserve of the various organ systems and the ability to compensate for physiologic stress may be greatly reduced in the older patient without notable gender differences [26]. The three critical systems that affect perioperative DRPs are cardiovascular, hepatorenal and the brain. The general guidelines for the perioperative management of medications in the older patient is to continue the medication, if needed, in order to control a disease process that would otherwise adversely affect the patient during the perioperative period. In general, most chronic medications and cardiovascular agents will need to be continued in the perioperative period. Warfarin, antiplatelet agents, aspirin and other non-steroidals, hypoglycemic agents, herbal and other over-the-counter agents should generally be discontinued prior to surgery (Table 1).

Table 1.

Recommendations for the perioperative management of medications in the elderly.

Medication	Potential risks in elderly	Perioperative recommendations	Ref.
ACE inhibitors and ARBs	Hypotensive episodes due to blunting of renin–angiotensin system compensatory action with general anesthesia	Consider stopping these agents 12–24 h prior to surgery and using β-blockers for blood pressure and heart rate control on day of surgery	[104,105]
α2 agonists	↓ Stress response to general anesthesia/surgery vs rebound hypertension if stopped	Continue on day of surgery owing to potential benefits and consequences of acute withdrawal
Alzheimers drugs	Cholinesterase inhibitors have cholinergic side effects, mildest with donepezil. Memantine has fewer side effects and is disease modifying	No clear recommendation perioperatively. Stopping the cholinesterase inhibitors for 6 weeks appears to erase cognitive benefits, suggesting that this class of medications do not alter the disease process	[106]
Anticoagulants	Lower dose in elderly to achieve equivalent effect, ↑ bleeding risk (baseline 1.6%, but respiratory rate of 3.0 with INR = 2.5)	If low risk for thrombosis, stop 2–5 days prior to surgery. If high risk of bleeding, keep INR <1.5. If high risk for thrombosis, change over to heparin	[77,104,107]
Antidepressants (SSRIs)	May ↑ bleeding owing to effect on platelet aggregation (OR: 3.71 for risk of transfusion), idiosyncratic ↑ hyponatremia risk	Recommendation for SSRI is that consequences of bleeding vs severity of psychologic disorder must be balanced. SSRI wash-out period is up to 3 weeks, which could exacerbate mood disorders	[69,70,104]
Anti-Parkinson agents	Hemodynamic and arrhythmogenic effects with use vs acute withdrawal and neuroleptic malignant syndrome	No clear recommendations – slow taper to lowest effective dose several weeks before surgery	[104,106]
Antipsychotics	Sedative properties	Consider haloperidol and atypical neuroleptics (ie., risperidone) if at risk for psychosis. Safer owing to fewer active metabolites, lower extrapyramidal and anticholinergic effects	[6,104,108]
Benzodiazepines	Impaired cognition and memory, sedation, confusion and unsteadiness	Use short-acting agents at 50% of dose if medical necessity outweighs risks (including discontinuation syndrome)	[31,78]
β-blockers	↓ Myocardial oxygen demands and ↓, perioperative ischemic events	Continue on day of surgery owing to benefits of ↓ postoperative cardiovascular events and consequences of acute withdrawal	[79,104]
Digoxin	↑ Toxicity with renal disease, verapamil, amiodarone, quinidine, ↓ K, ↓ Mg and ↑ Ca	Toxicity occurs more frequently in elderly and is more difficult to recognize. Digoxin levels alone do not reliably reflect level of drug activity in the elderly, but ECG is a better test	[31]
Dipyridamole	↑ Bleeding complications owing to antiplatelet and vasodilatory effects	Stop at least 2 days prior. If warranted, weigh consequences of perioperative hemorrhage vs thrombotic events	[104]
Diuretics	Hypovolemia and systemic vasodilation can predispose to hypotension with general anesthesia and hypokalemia risk	No consensus	[31,44]
Estrogen (systemic)	Dose-dependent risk of venous thromboembolism of 2.1–6.9	Insufficient evidence to initiate or stop systemic enzyme-replacement therapy perioperatively. British National Formulary and International Consensus recommend stopping 4–6 weeks prior to surgery	[80,81]
Herbal therapy	↓ Ability to metabolize active components, proper dosing unclear and many potential drug interactions	All herbal agents should be stopped at least 1 week prior to surgery and probably permanently. No evidence that herbal medications improve surgical outcomes exists and some studies suggest they may increase perioperative morbidity	[82,104]
Hypoglycemics	Cognitive deficits due to neuroglucopenia with hypoglycemia vs hyperglycemic risks	Avoid hypoglycemia and severe hyperglycemia, but optimal perioperative glucose range unknown. Hold oral hypoglycemic agents on morning of surgery	[83]
Hypolipidemics	Small risk of myopathy and rhabdomyolysis but statins may ↓, risk of perioperative vascular events	Discontinuation of all hypolipidemic agents at least 24 h prior to surgery (except statins).	[28,29,104]
Proton-pump inhibitors and H₂ antagonists	Decrease gastric pH and volume – avoid cimetidine owing to drug interactions	Continuation of proton-pump inhibitors owing to increase risk of gastric mucosal injury during the perioperative period	[104]
Thiazide diuretics	Hypokalemia and hyponatremia can cause delirium in the elderly, in addition to hyperuricemia	Best used in low doses (12.5 mg/day). Loses diuretic effect if CrCl < 20ml/min	[31]
Traditional NSAIDs and acetylsalicylic acid	↑ Bleeding (surgical and gastric). Chronic renal insufficiency + NSAID + hypovolemia = ↑ risk of acute renal failure	Optimal management uncertain – weigh consequences of perioperative hemorrhage vs thrombotic events. Stop 3–5 days prior, if warranted	[104]

ACE: Angiotensin-converting enzyme; ARB: Angiotensin-receptor blocker; CrCl: Creatinine clearance; INR: International normalized ratio

SSRI: Selective serotonin-reuptake inhibitor.

Cardiovascular system: physiologic changes & pharmacologic optimization

Cardiovascular medications are the single most common group of drugs prescribed in the geriatric patient and are used by 76% of patients admitted to the hospital [24]. In a group of 367 octagenerians admitted for surgery, 50% had hypertension, 30% had coronary artery disease, 15% had congestive heart failure and 17% had arrhythmias [27]. This reflects the high prevalence of cardiovascular disease in the older patient. In addition, cardiovascular changes associated with aging, such as increased peripheral vascular resistance, decreased ventricular compliance, dependence on diastolic filling and limited ability to increase heart rate, all increase the older patient's susceptibility to systolic hypertension and heart failure as well as their inability to compensate for hypotension. Therefore, it is important to determine which medications provide perioperative survival benefits and which ones might exacerbate hypertension, heart failure and hypotension, either directly or via drug–drug or drug–disease interactions.

Hypolipidemic agents, with the exception of statins, should be discontinued at least 24 h prior to surgery as risks of myopathy and rhabdomyolysis associated with these agents increase with surgery. While these risks are also associated with statin therapy, perioperative benefits, such as reduction in cardiovascular events in the early postoperative period after vascular surgery in patients with coronary disease or coronary equivalents, have been suggested from mostly large observational studies [28 –30]. Studies do not provide a clear guidance on timing of the initiation of statins prior to surgery; however, a reasonable recommendation is to begin at least 1 month prior to planned surgery in order to assess for potential adverse effects and to reach target low-density lipoprotein-cholesterol levels as recommended for patients with coronary disease or coronary equivalents.

Digoxin toxicity occurs more frequently in the older patient owing to decreased renal function and decreased volume of distribution of water-soluble drugs. ECG changes, such as evidence of heart block, prolonged PR, and depressed ST segment, better reflect the level of digoxin activity in the older patient than plasma digoxin levels or symptoms [31]. Dosing in the older woman should be adjusted based on lean bodyweight and creatinine clearance, rather than using serum creatinine as an assessment of renal function.

Antihypertensive agents, with the exception of β-blockers, should be stopped 24 h prior to planned surgery unless necessary for blood pressure control. Angiotensin-converting enzyme inhibitors and Ang II-receptor blockers have the potential to cause severe and prolonged intraoperative hypotension in the elderly, particularly with induction of anesthesia. Careful volume and potassium replacement is important in patients on chronic diuretics in order to minimize the risk of cardiac arrhythmias [30]. Calcium-channel blockers have been associated with an increased incidence of postoperative bleeding as a result of inhibited platelet aggregation, but should be continued if necessary to treat the patient's underlying chronic medical condition [32].

β-blockers are the most commonly prescribed antihypertensives in the elderly [24]. This class of drugs has potential perioperative benefits and unique adverse effects. Perioperative use of β-blockers have been shown to decrease postoperative cardiovascular mortality in patients with risk factors for coronary heart disease by decreasing myocardial oxygen demand, which may result from surgical stress and catecholamine release [33 –35]. Patients with three or more risk factors for coronary heart disease treated with preoperative β-blockers have a decrease in perioperative cardiovascular mortality from 9 to 3%, with the largest benefit in the highest risk patients [33,36,37].

The Perioperative Ischemic Evaluation (POISE) trial, a randomized, placebo-controlled trial of metoprolol use, suggests potential harm with an increase in stroke (relative risk [RR]: 2.17) and total mortality (RR: 1.33) [38]. Other adverse outcomes associated with the use of β-blockers include perioperative hypotension in 15% of the patients, bradycardia requiring atropine in over 20% of the patients, exacerbation of underlying reactive airways, diabetes and heart failure [24]. In addition, propranolol, a lipid-soluble nonselective β-blocker, should be avoided as it is associated with adverse CNS effects (i.e., vivid dreams and depression), fatigue and adverse pulmonary effects in patients with reactive airways disease and obstructive pulmonary disease [31,33,34,36,39].

Based on the POISE results and 2007 American College of Cardiology/American Heart Association guidelines, patients who have risk factors for cardiovascular disease and are scheduled to undergo noncardiac surgery should be considered for the β-1 cardioselective β-blockers therapy (i.e., atenolol, metoprolol and bisoprolol) [38,40]. In order to minimize the risk of perioperative hypotension and maximize benefits, β-blockers should be initiated days to weeks before planned surgery, titrated to a resting heart rate between 60 and 65 beats/min, and continued indefinitely postoperative to treat underlying cardiac condition [36]. No studies support the use of prophylactic preoperative β-blockers therapy.

Withdrawal syndromes have been described with β-blockers and centrally acting sympatholytic drugs, such as clonidine and methyldopa. These agents should not be stopped abruptly as a result of an increase in risk of adverse perioperative events, such as rebound hypertension. The sudden cessation of β-blockers can cause angina, myocardial infarction and sudden death in patients with underlying coronary artery disease [40].

Hepatic & renal systems: effects of physiologic changes on drug metabolism and elimination

Aging often impairs drug elimination owing to a decrease in hepatic and renal function. Hepatic metabolism is dependent on hepatic blood flow, which can be decreased up to 46% with aging, extractability of the medication on ‘first pass’, and hepatic enzymatic activity [41]. This results in potentiation of β-blockers, tricyclic antidepressants and antipsychotic agents due to impaired drug metabolism [25], but a decrease in the efficacy of enalapril and codeine due to impaired hepatic conversion to the active drug form [42].

A decrease in renal mass and renal blood flow can compromise renal function and drug elimination. The aged kidney's ability to concentrate and excrete can be measured in the decline in creatinine clearance of approximately 1 ml/min/year after 40 years of age due to decreased protein catabolism in the older patient [25]. Therefore, serum creatinine is not an adequate marker for renal function in the elderly. Creatinine clearance can be estimated using the Cockrift–Gault formula: (0.85 adjustment for women) × (140 - age) (weight in kg)/72 (creatinine in mg/dl) or simplified to [(140 - age) × bodyweight in kg × 0.012]/creatinine, or measured in a 24 h urine sample [43,103]. Drugs that are excreted through the kidney, such as many antibiotics, lithium, NSAIDs and digoxin, require renal dosing (decrease in dose or increase in dosing intervals) to avoid toxicity. In addition, renal elimination of active metabolites of glyburide, morphine and meperidine can be impaired, resulting in toxicities such as hypoglycemia, respiratory depression/sedation and seizures, respectively.

Functional reserve of the kidneys may also be reduced in the older woman. Renal blood flow is decreased by approximately 50%, resulting in a concomitant decrease in glomerular filtration rate. This decrease in renal blood flow increases the kidney's susceptibility to injury in the setting of low cardiac output, hypotension and hypovolemia. Systemic vasodilatation induced by anesthetic agents may cause hypotension in patients who are intravascularly depleted from diuretics, potentially resulting in renal damage. The combination of decreased organ functional reserve and increased susceptibility to derangements in potassium, fluid and acid–base status in the elderly results in the poor tolerance of medical complications. Perioperative use of diuretics, especially thiazides, can predispose the older patient to hypovolemia, hypokalemia and hyponatremia [44], which can be further exacerbated by postoperative ileus, nasogastric suction, emesis or diarrhea. For patients who require diuretics perioperatively, physicians should pay close attention to volume and electrolyte abnormalities.

Cognitive & functional assessments & postoperative delirium

There is a wide variation in both cognitive and functional status in patients over the age of 65 years. Cognitive function should be assessed preoperatively as indicated in order to provide a baseline and to identify any impairments that may impact informed consent, postoperative care, postoperative quality of life and extent of surgery. The presence of underlying cognitive impairment as well as exposure to general anesthesia, medication use and alterations in fluid and electrolyte homeostasis can all contribute to increased confusion and other postoperative morbidity such as delirium, falls and functional dependence [31].

CNS agents, the second most commonly prescribed class of drugs in the older patients, are one of the most common reasons for hospitalizations for drug–drug interactions [24,45]. These include benzodiazepines (∼25%), antidepressants (∼20%) and those with anticholinergic side effects – all of which can adversely affect the elderly by worsening memory problems, increasing the risk of falls and resulting in DRPs due to drug–drug interactions [24]. Perioperative use of benzodiazepines can cause cognitive and memory impairment, confusion, daytime somnolence, falls, depression and physiologic dependence with long-term use (correlates with dose and duration of treatment) [46]. Therefore, it is recommended that acute benzodiazepine use should be minimized in the older patient and shorter-acting agents, such as lorazepam and oxazepam, should be used if needed for short courses at 50% the usual dose. They are not recommended for the treatment of postoperative delirium unless related to alcohol withdrawal. Of all drugs, those with anticholinergic effects are the most common cause of adverse drug events, drug side effects and worsening co-existing illness in the older patient.

Postoperative cognitive dysfunction (POCD) and delirium are common complications after surgery in the older woman and the causes are poorly understood. POCD is defined as a sub-clinical decline in cognitive performance diagnosed by formal neuropsychological testing as compared with delirium, which is clinically diagnosed but can be confirmed using formal instruments, such as the Clinical Assessment of Confusion. In the early weeks after major noncardiac surgery, a significant proportion of people demonstrate POCD (26–33 vs 7% in those undergoing minor surgery), with the older patient being more at risk [47]. However, at 3 months after surgery, there was no difference between those who underwent major surgery and the control group [47]. Mechanisms for the early temporary cognitive changes after surgery are still unclear.

Postoperative delirium has been reported in 10–70% of older surgical patients, with a 10–65% mortality in hospitalized patients [48]. In addition to significant mortality, delirium is associated with a decline in functional status after hospital discharge, and a substantial socioeconomic impact, in turn, associated with prolonged hospitalization and posthospitalization rehabilitation and home care [49]. Delirium typically has a multifactorial etiology; however, is preventable in 30–40% of the cases. Box 2 describes factors associated with the development of postoperative delirium in older surgical patients [17,47 –50]. Prior studies have attempted to identify and quantify risk factors for postoperative delirium and potential causal relationships with limited success due to the inability to control for confounding factors.

The initial management of the symptoms of delirium should include correction of suspected causes, use of nonpharmacologic therapy, and avoiding psychotropic or sedative medications when possible. The medication list should be carefully reviewed to exclude DRPs as a cause. However, owing to many possible factors and interactions that occur during hospitalization, effective evidence-based strategies for prevention and intervention are still not known.

Anesthetic & analgesic consideration

There is debate regarding the ideal anesthetic approach and analgesic strategy in the older patient. Neither regional nor general anesthesia have demonstrated superiority of outcome in the older woman and should be individualized by patient and type of surgical procedure. Despite earlier reports of a greater incidence of POCD in patients who received general anesthesia, a recent systematic review of this issue provides little evidence that anesthetic techniques are responsible for any changes in cognition observed after surgery [47,51]. Leung and colleagues report of 544 consecutive patients over the age of 70 years undergoing noncardiac surgery, demonstrated that the type of anesthesia (regional vs general), duration of anesthesia, blood loss and type of noncardiac surgery were not significant, independent predictors of adverse postoperative outcomes in the geriatric surgical patient [51].

Regional anesthesia is often used in older patients undergoing surgery because of its dual use in postoperative pain control and the need for minimal sedation during the surgery. If sedatives are necessary for regional anesthesia, they should be short acting and have a high safety margin, such as midazolam, lorazepam, ketamine, propofol and low-dose opioids [52]. Changes in pharmacokinetics and pharmacodynamics associated with aging, decrease in neural population and conduction velocity, and underlying impaired liver function can lead to an increased sensitivity, decreased dose requirement and a change in the onset and duration of action of local anesthetics in the elderly [52]. Epinephrine should be used cautiously to prolong the duration of peripheral blocks since it can cause ischemic neurotoxicity in peripheral nerves [52]. Bupivacaine has greater potential for drug–drug interactions and increased toxicity with β-blockers, tricyclic antidepressants and phenothiazines as compared with lidocaine [53]. The key to minimizing adverse anesthetic outcomes is not the route of administration, but careful management with individualization based on the type of surgery and underlying medical comorbidities.

Box 2.

Perioperative factors associated with the development of postoperative delirium.

Age >70 years (OR: 2.50)

Female gender

Presence of other comorbid medical conditions

Pre-existing functional and cognitive impairments

Depression

Alcohol intake

Surgical duration

Preoperative moderate–severe chronic pain at rest (OR: 2.19–3.72)

Postoperative pain management and use of patient-controlled analgesia

Postoperative use of benzodiazepines

Data taken from [17,47 –50].

Pain is one of the most prevalent concerns among the elderly, with 86% reporting pain in the past year [53]. Acute postoperative pain is often undertreated owing to agism, resulting in sympathoadrenal stress, impaired ambulation and respiratory effort, increased postoperative pulmonary complications and increased risk of chronic pain development [53,54]. Since the effects of pain are widespread (e.g., sympathoadrenal stress, impaired ambulation, increased postoperative pulmonary complications and development of chronic pain, depression, decreased socialization and sleep disturbances), the efficient evaluation and management of pain are essential to the quality of life for the older patient [53 –56].

Several recent excellent reviews of animal and observational human studies explore the genetic, hormonal, pharmacodynamic and social basis for sex, gender and age differences in pain responses and treatment (Boxes 3 & 4); however, the underlying mechanisms for the differences continue to be complex and unclear [56 –59]. Women appear to be more susceptible than men to adverse side effects of opioid analgesia, such as increase in nausea, vomiting and reduced responsiveness to CO₂ with associated respiratory depression; however, this may be due to reporting bias, polypharmacy and more frequent surgery [60,61]. These sex differences in postoperative opioids response were not observed in older subjects, suggesting that analgesic efficacy may be modulated by female sex hormones and that menopause may mark the equalizing point between sexes [62]. It is important to recognize that while the adage ‘start low, go slow’ is prudent in the elderly, rapid titration with full-dose narcotics must occur in order to alleviate immediate postoperative pain. The best predictor of PCA morphine requirement in the first 24 h postsurgery, after the initial loading dose was the patient's age: average first 24 h morphine requirement (mg) = 100 - age [63]. However, studies suggest that doses for long-term treatment of chronic pain are likely to be reduced, owing to altered pharmacokinetics and cumulative effects of the drugs [53,56].

Opioids may be safer in the long-term than chronic NSAID use in the older patient, in terms of the effect on baseline renal insufficiency and gastric mucosal bleeding. However, several pain medications should be avoided in the elderly: propoxyphene hydrochloride (Darvon®, Eli Lilly, IN, USA) owing to less efficacy and more adverse side effects than its opioid counterpart [56]; meperidine hydrochloride (Demerol®, Hospira, IL, USA) since it is the least potent opioid analgesic (50%) with the narrowest therapeutic index of all opioids, need for frequent dosing, serious drug–drug interaction potential with monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin-reuptake inhibitors (SSRIs) and CNS excitation effect [64]. Demerol has been noted to be only as effective as an NSAID for pain relief, but has excessive opioid side effects [56]. Additional consideration should be given to tramadol use as it has equivalent efficacy as codeine with less respiratory depression.

The safe and effective management of acute postoperative pain involves preoperative assessment of pain potential of the surgical procedure in the context of other factors, such as current medications, comorbidities, and baseline cognitive and functional status. General pain management principles in the older woman should include a combination of drugs with different but complementary mechanisms of action to provide the greatest pain relief while minimizing effects on respiration, ambulation and drug–drug interactions. The use of NSAIDs or acetaminophen as an adjuvant to opiate therapy allows for opioid dose reduction [53,65 –67]. The addition of proton-pump inhibitors in those at risk for GI bleeding and peptic ulcer disease should also be considered.

Clinically relevant drug-drug interactions

Drug–drug interactions are described as two or more drugs interacting in such a way that effectiveness or toxicity of the drug(s) is altered, either beneficially or adversely. Prevention of DRPs in the older patient with existing impaired organ reserve and pre-existing medical conditions require the ability of the clinician to identify the potential for adverse interactions. These include drug combinations causing similar adverse effects that may be additive, those interfering with the absorption, distribution, metabolism, elimination of other drugs, those with narrow therapeutic indexes, and drugs that induce or inhibit cytochrome P450 enzymes. Some common antiepileptic medications (e.g., phenobarbital, phenytoin and carbamazepine), antituberculosis medications (e.g., rifampin and isoniazid), alcohol, grapefruit juice, and St John's wort are inducers of the cytochrome P450 enzymes and decrease the efficacy of other drugs. However, SSRIs (e.g., fluoxetine, paroxetine and sertraline), erythromycin and azole antifungals (fluconazole and ketoconazole) are inhibitors of this hepatic enzyme system and can result in toxicity of drugs requiring hepatic metabolism, particularly those with a narrow therapeutic index, such as codeine, tramadol, methadone, warfarin, tricyclic antidepressants and loratadine (Table 2) [41].

Table 2.

Drug-drug interactions that may be of concern for older women in the perioperative setting.

Affected drug	Precipitant drug	Adverse effects	Ref.
ASA	Garlic and ginger	Risk of bleeding as a result of combined antiplatelet effect	[73]
ASA	β-blocker and ACE inhibitor	ASA decreases efficacy of antihypertensive effect owing to inhibition of renal prostaglandin/blood flow	[73]
NSAID-ASA	NSAID	Increases risk of gastrointestinal bleeding and renal impairment	[73]
NSAID	Ginkgo	Increases risk of bleeding owing to a decrease in platelet aggregation	[73]
NSAID	Corticosteroids	Increases risk of gastrointestinal toxicity and bleeding
NSAID	SSRI	Increases risk for gastrointestinal bleed (12.2-fold with paroxetine) since SSRIs inhibit serotonin uptake by platelets and augments antiplatelet effect of NSAIDs	[73]
NSAID	Furosemide	Decrease antihypertensive activity and increase renal insufficiecy owing to a decrease in renal blood flow	[73]
Methadone	Rifampin, phenytoin, carbamazepine and phenobarbital	Diminishes analgesia and opioid withdrawal symptoms	[42]
Opioid	Benzodiazepine and metoclopramide	Additive sedation, hypnosis and respiratory depression	[42]
Opioid	Long-term ethanol use	Tolerance to analgesia from opioid	[42]
Opioid	St John's wort	Increases sedative effect of opioids; stop 2–3 weeks prior to surgical procedure	[73]
Amlodipine, albuterol, estrogen and progesterone	St John's wort	Lowers efficacy by increasing metabolism of calcium-channel blockers, HRT/oral contraceptive pills and albuterol	[73]
ACE inhibitor	NSAID	Hyperkalemia and reduced renal function	[42]
Diuretics that cause hypokalemia and aminoglycosides	Nondepolarizing neuromuscular-blocking drugs	Prolongs neuromuscular blockade	[42]
Warfarin	Garlic, ginger and ginkgo	Increases risk of bleeding owing to the effect on platelet aggregation	[73]
SSRI	Meperidine	Serotonin syndrome	[42]
MAOI	Meperidine	Cardiovascular instability, hyperpyrexia, seizures, coma and possibly death	[42]
MAOI	Dopamine, norepinephrine, epinephrine, ephedrine and phenylephrine	Risk of hypertensive crisis	[42]
Sedative hypnotics	Alcohol	Excessive sedation	[42]
Benzodiazepine	Ketoconazole, fluconazole and erythromycin	Excessive sedation	[42]
TCA	Phenylephrine, pancuronium and ketamine	Hypertensive response	[42]
TCA	Phenobarbital, carbamazepine and phenytoin	Reduces antidepressant effect	[42]
TCA	Cimetidine, fluoxetine, diltiazem and MAIO	Increases antidepressant toxicity	[42]
Drugs	Calcium	Delays gastric emptying and may reduce absorption of β-blockers, iron, levothyroxine and alendronate – recommend administration of calcium several hours after administration of medication	[73]

ACE: Angiotensin-converting enzyme; ASA: Aspirin; MAOI: Monoamine oxidase inhibitor; SSRI: Selective serotonin-reuptake inhibitor; TCA: Tricyclic antidepressant.

Box 3.

Observed gender differences in pain response.

In response to laboratory-based noxious visceral and somatic stimuli, healthy women experience greater pain than men

Women appear to have higher baseline pain measurements and a lower pain threshold

Men are less likely to report pain from noxious stimuli compared with female peers and reluctance to report is proportional to the attractiveness of the tester

When reporting bias that is minimized with use of patient-controlled analgesia, men used more morphine/kg than women during the first 3 postoperative days

Data taken from [57 –59,74 –76].

Box 4.

Observed gender and age differences in pain treatment.

Hormonal influences may explain gender differences in NSAID-induced hepatotoxicity and nephrotoxicity, dopaminergic side effects of medications and recruitment of opioid receptor; however, these gender differences are minimized after menopause

In the postoperative setting, females recover faster from anesthesia than men; however, the onset of opioid analgesia (i.e., intravenous morphine) takes longer in females than in males

Female body composition may play a role in changes in transdermal pharmacokinetics such as delayed distribution in transdermal fentanyl in women

Greater analgesic effect of ibuprofen and aspirin is observed in men; however, greater analgesic effect of ketorolac, nalbuphine hydrochloride (Nubain®, Endo Laboratories, PA, USA) and κ-opioids is observed in women

Data taken from [57 –59].

While it is important to treat depression, the use of antidepressants can carry significant and unique perioperative risks in the older patient. Currently, SSRIs are the preferred treatment for anxiety and depression in older women owing to their efficacy and minimal anticholinergic effects [68]. Perioperative use of SSRIs has been associated with an increase risk of falls, hyponatremia, perioperative hemorrhage and life-threatening serotonin syndrome. The incidence of hyponatremia (8/1000) is highest in women over the age of 70 years who are receiving fluoxetine during the first couple of weeks of treatment concurrently with diuretic or psychotropic therapy [69]. This is believed to be an idiosyncratic reaction that is likely to recur with the use of a different SSRI. Symptoms generally respond quickly and completely to discontinuation of the causative agent (SSRIs). However, fluid restriction and use of hypertonic saline may also be needed, but hyponatremia should be corrected slowly to prevent brain demyelination [69]. SSRI use may also increase perioperative hemorrhage owing to the effect on platelet aggregation (OR = 3.71 for risk of transfusion) and the effect is worsened with concomitant use of garlic [70].

One of the most life-threatening risks of SSRI therapy is the development of serotonin syndrome, which often occurs hours after concurrent use of meperidine or St John's Wort [64,71]. It is characterized by excitatory symptoms, such as agitation, hyperthermia and fever, diaphoresis, tachycardia and hemodynamic instability, and neuromuscular disturbances such as rigidity and seizures, as well as by depressive symptoms, such as respiratory depression, hypotension and coma. The depressive symptoms of serotonin syndrome can be confused with opioid overdose but is not correctable with naloxone hydrochloride (Narcan®, Endo Laboratories, PA, USA) administration. Management should include re-evaluation of all patient medications and stopping the causative agent(s). This is yet another reason why meperidine should not be used as a first-line agent for the management of acute postoperative pain in the older postoperative woman. Owing to the potential 3-week washout period with SSRIs, if the above perioperative risks outweigh the risk of exacerbation of mood disorders, the SSRI dose should be tapered down and gradually discontinued preoperatively over several weeks [67,68].

Herbals & other nonpresciption drug interactions

Herbal therapy is used by 50–60 million people [72]. Approximately 50% of older patients taking herbal remedies do not report the use to their primary-care providers and approximately 20% use herbal agents concurrently with prescription medications [73]. In a study of community-dwelling geriatric women, 41% reported the use of at least one herbal product in addition to prescribed medication, 80% reported taking five or more medications and 74% took drugs that had identifiable moderate- or high-risk drug–drug interactions using a web-based pharmacology program [73]. Of the drug–drug interactions, 52% were between drugs and herbals, and 63% of these involved NSAIDs. More than 70% of the NSAID drug–drug interactions occurred with the use of nonpresciption NSAIDs [73]. There is no evidence that herbal medications improve surgical outcomes and some evidence suggests that they may increase perioperative morbidity. Therefore, it is recommended that all herbal agents should be stopped at least 1–2 weeks prior to surgery and, possibly, permanently.

NSAIDs should be avoided in the older woman with a history of chronic renal insufficiency or those with peptic ulcer disease owing to increased risk of worsening renal failure or gastric bleed. Older patients treated with NSAIDs had a three- to four-fold increase risk for developing GI bleeding compared with their younger peers (3–4 vs 1%, respectively) [51]. Even those taking the low-dose aspirin (81 mg) for cardiovascular protection have an increased risk of GI bleeding when taken with another NSAID and this DRP accounts for 10–15% of all admissions to the hospital for upper GI bleed [73].

Conclusion

Surgery in the older woman should be performed with an appreciation and understanding of the unique factors that contribute to the complexity of perioperative care of these patients, as a result of aging more so than sex or gender. In the geriatric population disease status, medications, cognitive status, psychological status and functional dependence are all important potential risk factors that increase the geriatric patient's susceptibility to unsatisfactory perioperative outcomes. Improving the quality of geriatric surgical care requires careful preoperative evaluation of risk assessment and correcting modifiable risks, understanding the effect of aging on the drug pharmacokinetics and functional reserve in order to allow for optimization of medication therapy and comorbidities, consideration of intraoperative issues, such as anesthetic selection, use of minimally invasive approaches when appropriate, limiting blood loss and duration of surgery, and careful postoperative care such as pain-management strategies. One should review medications being prescribed compared with those actually received by the patient during the hospital before treating new symptoms with additional medications. Ideally, preoperative assessment of more complex patients should allow for sufficient time to perform necessary diagnostic testing, correct modifiable risks, optimize medications and obtain multidisciplinary assistance such as consultation with their primary-care physician, anesthesiologist, geriatrician and others.

Future perspective

Older women are a heterogenous population with respect to the presence of medical comorbidities and functional and cognitive considerations. In response to the demands and future needs of the aging woman undergoing surgery, there is an increased awareness of the importance of ‘proactive’ efforts to optimize their care, however, there is little current research addressing the relative impact of gender versus aging in perioperative risk prediction. To identify perioperative risks that are unique to older women and initiate preventative strategies through optimization of perioperative medication management, it will require a collaborative multidisciplinary effort and the performance of meaningful intervention trials using validated relevant outcome measures and quality indicators. Areas identified for future research include:

Determining the relative impact of female gender versus female sex differences versus aging on perioperative risks;

Expert national consensus is needed regarding perioperative medication use in the older woman; these recommendations should be based on clinical relevance, prevalence of specific adverse drug events in the older person undergoing surgery, gender and racial differences;

The current use of claims data and International Classification of Diseases (ICD) coding groups in studies may not accurately identify adverse outcomes or provide relevant clinical information regarding these events. Therefore, studies that depend on these data may not facilitate the optimal development of preventative strategies;

The impact of perioperative medication management on surgical health outcomes needs to be re-examined and national measures of quality derived for the prevention of DRPs in line with increasing national hospital patient safety efforts;

As the chance of having surgery increases with increasing age, developing new and validating existing tools in order to assess inappropriate medication prescribing and their impact on surgical outcomes;

The need for randomized trials to delineate the precise role of postoperative pain strategies and the prevention of postoperative delirium in the older woman undergoing surgery.

Executive summary

Introduction

The geriatric population, particularly women over 70 years of age, will represent a significant proportion of our surgical practice.

Elective nonvascular surgery can be safely performed in women aged above 70 years by minimizing factors that increase surgical morbidity.

Minimally invasive surgical techniques are likely to decrease hospitalization and morbidity.

While multiple factors contribute to the complexity of operating on the older patient, elderly women should not be denied elective surgery for conditions where surgery is the primary treatment.

Polypharmacy & drug-related problems

Drug-related problems are the most common iatrogenic events in hospitalized patients.

Arbitrary use of five drugs or more to define polypharmacy poorly stratifies risks, but has been described as a risk factor for hospitalizations, nursing home placements, decreased functional status and other drug-related problems.

Drug utilization review tools, such as the Beers' and McLeod's criteria, are useful in examining inappropriate prescribing prevalence and trends in North America, however they are not accurate for use in other countries with different drug formularies nor in predicting patient outcomes.

Changes in pharmacodynamics associated with aging

Perioperatively, continue the medication if it is needed to control a disease process that would otherwise adversely affect the patient during the perioperative period.

Only β-blockers and statins have been shown to reduce surgical risks with perioperative use before noncardiac surgery.

Age-related decreases in hepatic and renal function can impair drug elimination or conversion to active metabolite, resulting in toxicities or decreased efficacy.

Cognitive & functional assessments & postoperative delirium

Preoperative establishment of baseline cognitive function and functional status is key to informed consent, determining extent of surgery and optimal postoperative care.

The presence of underlying cognitive impairment, general anesthesia, medication use and alterations in fluid and electrolyte homeostasis increases postoperative morbidity, such as delirium, falls and functional dependence.

Anticholinergics and benzodiazepines should be avoided in the elderly.

Severe chronic pain and postoperative pain management techniques may influence the risk of postoperative delirium more than other predictors (functional/cognitive impairments, alcohol intake, CNS medications, anesthesia technique and depression).

Anesthetic & analgesic considerations

Women are more likely to report pain, adverse effects of medications and use more analgesia than men.

Patient-controlled analgesia and regional anesthesia are important options to enable elderly patients, particularly males, to access adequate analgesia given their lower likelihood to request.

Sex differences in postoperative opioids response were not observed in elderly patients suggesting that menopause may mark the equalizing point between sexes.

Gender differences owing to reporting bias, sex hormones and body composition influence efficacy and adverse effects of analgesics.

Footnotes

Holly E Richter is partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK 068389). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Pharmacologic Management of the Older Woman Undergoing Surgery

Abstract

Keywords

Polypharmacy & drug-related problems

Changes in pharmacokinetics associated with aging

Cardiovascular system: physiologic changes & pharmacologic optimization

Hepatic & renal systems: effects of physiologic changes on drug metabolism and elimination

Cognitive & functional assessments & postoperative delirium

Anesthetic & analgesic consideration

Clinically relevant drug-drug interactions

Herbals & other nonpresciption drug interactions

Conclusion

Future perspective

Footnotes

References