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Perioperative care of the elderly oncology patient: A report from the SIOG task force on the perioperative care of older patients with cancer

Journal of Geriatric Oncology, Volume 3, Issue 2, April 2012, Pages 147 - 162

Abstract

The increasing number of older cancer patients seen in daily practice demands reflection on how to optimize their care during the perioperative period. Optimally tailored surgical management, at present the most successful cancer treatment, firmly rests on an accurate and careful anesthesiological management.

The unique peculiarities of anesthesia in older cancer patients prompted the International Society of Geriatric Oncology (SIOG) to put together a panel of international experts with the aim of reviewing the literature and drafting a consensus document. This article summarizes their views.

1. Pre-operative assessment and care

1.1. Pre-operative assessment

The pre-operative assessment of older cancer patients serves several purposes: to provide information about intra- and post-operative risk, to identify medical and nutritional problems that may be optimized before the surgical procedure, and to allow for post-operative planning. One example of post-operative planning is resource allocation to ensure that beds in intensive-care units are available, but in older adults it is also particularly important to plan for early rehabilitation and make arrangements to ensure an efficient hospital discharge. Whether age in itself is an independent risk factor for morbidity and mortality after elective surgery is unclear, but increasing age is associated with more comorbidity and disability.

The American Society of Anesthesiologists physical status classification (ASA class) is a commonly used anesthesiology tool. For elective procedures, which are common in cancer surgery, there are indications that ASA class is not sensitive enough to identify patients who are at risk of developing post-operative complications.1 and 2 In a large study of surgical risk factors and morbidity in elderly patients, including major general, general thoracic, and vascular surgical procedures, Turrentine and colleagues found that ASA class was an independent predictor of collective post-operative morbidities in the 60- to 79-year age group, but not in the 80- to 103-year age group.3 In the older group, the most frequent predictors of collective morbidities were pre-operative transfusion, emergency operation, weight loss, operative duration, and chronic obstructive pulmonary disease.

The definition of “elderly” varies in the literature, but the most commonly used cut-offs are 65 or 70 years. As aging is a highly individualized process, chronological age seems to be less important than physiologic status in determining surgical outcomes. In fact, the elderly population is characterized by a higher degree of heterogeneity than a younger population. Aging is also heterogeneous within an individual, and one cannot assume that the internal organs age at the same rate. Many elderly patients live with multiple chronic health conditions, disease-related symptoms, and disabilities. However, other groups of elderly people are fit and independent, and therefore an individualized assessment of physical status is necessary. Increasing evidence suggests that elements from a geriatric assessment, such as functional status, comorbidity, cognitive function, nutritional status, and depression, are important predictors of surgical outcomes in older patients with cancer.4, 5, and 6

1.2. An example of objective pre-operative risk stratification: The use of cardiopulmonary exercise testing (CPET)

Objective measurements of physical function have been proposed for pre-operative risk assessment. A simple measurement such as slow gait speed, defined as the time to walk 5 meters in ≥ 6 s, was able to identify a subset of vulnerable elderly patients at incrementally higher risk of mortality and major morbidity after cardiac surgery.7 An even more accurate measurement of objective fitness is obtained through cardiopulmonary exercise testing (CPET). CPET is a graded exercise challenge that provides an integrated description of cardiorespiratory reserve that mimics the surgical stresses in the perioperative period. The test identifies fitness and enables quantification of masked cardiopulmonary comorbidities in the pre-operative setting, which may be particularly significant in older patients. The estimated oxygen uptake at lactate threshold (VO2 at LT) and peak exercise measured using CPET are good predictors of cardiopulmonary mortality and morbidity after intra-abdominal surgery in patients aged 60 + or with cardiopulmonary disease.8 VO2 at LT is defined as the amount of oxygen extracted from inspired gas, per unit time, at which anaerobic high-energy phosphate production supplements aerobic high-energy phosphate production, with consequential lowering of the cellular redox state and a net increase in lactate production. A VO2 at LT < 11 ml/kg/min is associated with an increased risk of perioperative mortality and morbidity in patients undergoing major surgery.9 and 10

Peak oxygen consumption and possibly anaerobic threshold are valid predictors of perioperative morbidity and mortality in non-cardiopulmonary thoraco-abdominal surgery.11 These indicators have been proposed as a means of allocating post-operative care to appropriate patients.

Prehabilitation, defined as “the process of enhancing the functional capacity of an individual to enable him or her to withstand a stressful event,” has been shown to increase physical fitness, predominately aerobic capacity. Prehabilitation before surgery may improve physical fitness, and thereby improve surgical outcome. Hence, CPET may provide prior knowledge of increased risk, allowing intervention to modify this risk, as well as facilitating improved decision-making about post-operative care.

1.3. Nutritional assessment and care

The nutritional care of elderly patients about to undergo cancer surgery consists of the diagnosis, management and prevention of malnutrition, a state of altered nutrition which is associated with measurable adverse effects on body composition, physical function and clinical outcomes.12 Routinely used diagnostic criteria for malnutrition in elderly cancer patients (MECP) include: a) significant weight loss (≥ 5% of pre-morbid weight) and/or low body mass index (BMI < 22 kg/m2); b) hypo-albuminemia; and c) significant and sustained reduction in food intake (< 1200 kcal/day in women, < 1500 kcal/day in men or 22 and 25 kcal/kg/day, respectively). MECP can be the result of many factors (see Table 1), such as a progressive functional decline, the effects of medications, the presence of comorbidities, increased symptom burden (e.g., anorexia, dysphagia and gastrointestinal dysmotility), psycho-social determinants (e.g., depression and dementia), anticancer treatments and length of hospitalization.13 and 14 MECP can occur via three main pathophysiological mechanisms: (i) starvation, due primarily to protein-energy deficiency; (ii) sarcopenia, a reduction in muscle mass and strength independent of changes in body weight that accompany increasing age; and (iii) cachexia. The anorexia–cachexia syndrome is observed in approximately 50% of cancer patients, and is thought to be primarily the result of chronic inflammatory and metabolic stress responses to the presence of cancer which causes fat and muscle wasting, anorexia, fatigue, anemia and hypoalbuminemia.15 A variety of tools are available to screen patients at risk of MECP, as seen in Table 2. These assessments may afford the best chances to prevent MECP and its complications, such as increased post-operative mortality and morbidity, delayed recovery and wound healing, and increased length of hospital stay.12 and 13 An appropriate evaluation of patients with MECP includes the recognition of its treatable and/or aggravating factors (Table 1)16 and the identification of starvation, sarcopenia and cachexia through anthropometric, biochemical and functional measurements (Table 3). The nutritional care of older patients with cancer needs to address these pathophysiologic mechanisms through an interdisciplinary approach, which includes medical, nutritional and exercise interventions (Table 4).17 and 18 Finally, some evidence-based guidelines for the use of nutritional support therapy during cancer-related surgery, which are also applicable to the elderly are available19 (Table 5).

Table 1 Treatable causes of MECP (malnutrition in elderly cancer patients): the “meals on wheels” mnemonic. source: Adapted from Morley and Kraenzle.16

M Medication side effects
E Emotional problems (i.e., depression)
A Anorexia (nervosa, alcoholism, early satiety)
L Late-life paranoia
S Swallowing disorders
O Oral factors (e.g., poorly fitting dentures, cavities, etc)
N Nosocomial infections (tuberculosis, Helicobacter pylori, Clostridium difficile)
W Wandering and other dementia related behaviors
H Hyperthyroidism, hypothyroidism, hyperparathyroidism, hypoadrenalism
E Enteric problems (i.e., malabsorption, constipation)
E Eating problems (i.e., inability to feed oneself or to obtain preferred foods)
L Low-salt, low-cholesterol diets
S Smell and taste abnormalities (i.e., drug-induced)

Table 2 Malnutrition in elderly cancer patients (MECP) screening tools.

Instrument Advantages/limitations Included assessments
Malnutrition Universal Screening Tool (MUST) Created for adults in all health care settings BMI
Predicts increased mortality in older patients who are hospitalized Weight loss in last 3–6 months
Has low sensitivity (59%) and specificity (75%) for detecting malnutrition in cancer patients Presence of acute illness
Malnutrition Screening Tool (MST) 100% sensitivity and 81% specificity in predicting Subjective Global Assessment (SGA) categories Two questions: 1. Have you/the patient lost weight recently without trying? &
100% sensitivity and 92% specificity in predicting Patient Generated Subjective Global Assessment (PG-SGA) categories 2. Have you/the patient been eating poorly because of a decreased appetite?
Short Nutritional Assessment Questionnaire (SNAQ) Validated in mixed internal, surgical and oncological patients but not necessarily elderly patients Involuntary weight loss
Loss of appetite
Tube feeding or the use of supplemental drinks
Nutritional Risk Screening (NRS) Identifies severely ill or malnourished patients who require nutritional support BMI
Weight loss (%)
Not sensitive enough to predict weight loss in elderly patients Changes in food intake
Severity of disease
Mini Nutritional Assessment (MNA) Screening and diagnostic tool for malnutrition in geriatric patients Weight
Height
Reliably detects malnutrition in cancer patients, but lacks specificity Mid-arm circumference
Calf circumference
Weight loss over past 3 months
6 questions regarding lifestyle, medication, mobility
8 questions concerning the number of meals, food and fluid intake, autonomy of feeding
Questions regarding self-perception of health and nutrition
Nutrition risk index (NRI) Validated in elderly patients for diagnosing malnutrition It may not be accurate when low albumin is a marker of inflammation (i.e. in cancer cachexia) [(1.489 × albumin) + (41.7 × present / usual weight)]
Subjective Global Assessment (SGA) Validated tool in surgical and cancer patients Changes in weight, dietary intake or functional capacity
Reliably detects malnutrition and predicts post-operative complications Gastrointestinal symptoms that persist for > 2 weeks
Correlates with a number of objective measures of morbidity and quality of life Muscle wasting
Loss of subcutaneous fat
Ankle or sacral edema
Ascites
Patient-Generated Subjective Global Assessment (PG-SGA) Adapted from the SGA Includes additional questions regarding the presence of nutritional symptoms and short term weight loss
Specifically created/validated for oncology patients
Continuous scoring system facilitates triaging of patients
High degree of inter-rater reproducibility as well as a high sensitivity and specificity

Table 3 Nutritional-functional assessments in older patients with cancer.

Category Common measures Advantages/limitations
Anthropometry Weight Do not require sophisticated tools
Changes in weight Easy to repeat over time
BMI Do not reliably rule out MECP in the presence of normal values (i.e., the presence of sarcopenia can be missed in obese or overweight patient)
Skin-fold The technique using caliper is easy to learn. Skin compressibility in the elderly may give less reliable results
Mid-arm and mid-calf circumferences Surrogates for muscle mass
Biochemistry (routine) Serum pre-albumin and albumin Help with differentiating between starvation (low albumin, low CRP, lymphopenia, anemia) and cachexia (low albumin, high CRP, lymphocytosis, anemia)
C-reactive protein (CRP) May become a specific measure in case of infections or during chemotherapy
CBC and differential count Pre-albumin is more useful for following acute nutritional interventions or changes in nutritional status
Biochemistry (specialized) Leptin Inversely correlated with nutritional status and inflammatory reaction
Il-l receptor antagonist, 1l-6
IFN gamma, TNF alpha
Prognostic significance for post-operative survival, infection and weight-loss. TNF-alpha not very stable after freezing.
Functional Hand-grip dynanometry Quick, inexpensive, portable and reliable tool to assess muscle strength. Has reference values adjusted for age and gender. Has been successfully correlated with many clinical outcomes.
Gait speed Walking speed below 0.8m/s in the 4-m walking test is suspicious for sarcopenia
Body composition Deterioration in body composition or muscle strength can be associated with increased morbidity and mortality
More reliable in predicting post-operative outcomes in overweight individuals
Bioelectrical impedance analysis (BIA) High precision but low accuracy (i.e., cannot be a surrogate for more accurate measures such as DXA). There is a need to use specific equations, decreased accuracy in obese as well as underweight individuals can be used to monitor changes in body composition over time.
Dual X-ray absorptiometry (DXA) Gold standard for measuring fat mass and bone mineral density measures of fat-free mass are more accurate for upper and lower limbs, where it is used to diagnose sarcopenia
Fast, precise, safe (low dose radiation)
Fluctuations in total body water can affect measurements
Greater variability in fat mass and fat-free mass in obese and underweight individuals
Computed tomography (CT)/magnetic resonance imaging (MRI) Most accurate methods for evaluating body composition
CT associated with significant radiation expensive
Energy metabolism Resting energy expenditure by indirect calorimetry Important in defining basal nutritional requirements and source of energy used by the body (i.e. fat vs. carbohydrates). Identify the presence of hypermetabolic states, in some cases of the cachexia syndrome
Dynamic energy expenditure (DLW) by doubly labeled water or accelerometry Direct monitoring of energy expenditure over a 24-h period allows for a better definition of the functional status of patients before and after interventions as well as a more accurate quantification of caloric requirements. DLW requires sophisticated instrument. Tri-axial accelerometry is convenient and reliable
Food intake Decreased caloric intake is one of the major causes of malnutrition Weighed food records Different methods to evaluate the food intake, which is the principal parameter to diagnose caloric-proteic malnutrition or starvation All have limitations. Need software program to calculate amounts
Dietary history Methods are time consuming for both patients and trained health-professionals and are not for routine use
Food frequency questionnaires (FFQ) FFQ is a semi-qualitative method. Excellent for evaluating food groups
24-h food recall Probably the least demanding. A 3-d, non-consecutive recall can be as good as more traditional methods

Table 4 Nutritional management of MECP.

Pathophysiology Requirements Recommendations
Starvation Energy: 30–35 kcal/kg/day Nutritional support therapy should follow recommendations as per Table 5
Protein: 1–1.5 g/kg/day (12–15% of daily energy intake)
Fat: 35–50% of daily caloric intake
Water: 30 mL/kg/day
Sarcopenia Protein: 1–1.5 g/kg/day Multimodal therapeutic approach combining nutrition and exercise indicated
Leucine-enriched diet Anabolic therapies will increase energy needs
Creatine supplements Creatine will enhance benefit of exercises
Vit D2 or Vit D3 at 10,000 IU/week 25 (OH) vitamin D levels should be measured in all sarcopenic patients
Resistance and/or aerobic exercise for 20–30 min, 3 times/week Vit D supplementation should be given to raise levels above 75 nmol/L
Short term resistance exercise will improve strength and gait speed
Aerobic exercise improves quality of life years (QALY) and is cost effective
Cachexia Structured, interdisciplinary patient care. Combination of therapies, personalised according to pathophysiological abnormalities are required to modulate the cachectic process Treatment of reversible cause of decreased food intake (i.e., pain, nausea and vomiting, constipation, early satiety, oral mucositis, etc.)
Provision of nutritional support therapy as per Table 5
The optimum combinations of pharmacologic agents, “conventional nutrition”, nutriceuticals and exercise remains to be established Nutrients at supraphysiological levels to modulate metabolic or immune function (i.e., pharmaco-nutrition, immunonutrition, or nutraceuticals): omega-3-fatty acids, leucine arginine and glutamine (aka probiotic), creatine.
Particular therapies (i.e. appetite stimulants) need to be guided by risk benefit ratio Appetite stimulants: progestational agents (megesterol acetate and medrossiprogesterone acetate), corticosteroids (prednisolone, methylprednisolone, dexamethasone)
Anabolic drugs: steroids analogs of testosterone
Anti-cytokine and anti-inflammatory agents: thalidomide, melatonin, NSAIDS, statins, ACE- inhibitors
Additional agents: erythropoietin, beta-blocker Physical therapy/exercise

Table 5 Nutritional support guideline recommendations during anticancer treatments. source: Adapted from August and Huhmann.19

A. Nutrition support therapy during anticancer treatment Grade
1. Patients with cancer are nutritionally-at-risk and should undergo nutrition screening to identity those who require formal nutrition assessment with development of a nutrition care plan. D
2. Nutrition support therapy should not be used routinely in patients undergoing major cancer operations. A
3. Perioperative nutrition support therapy may be beneficial in moderately or severely malnourished patients if administered for 7-14 days preoperatively, but the potential benefits of nutrition support must be weighed against the potential risks of the nutrition support therapy itself and of delaying the operation. A
4. Nutrition support therapy is appropriate in patients receiving active anticancer treatment who are malnourished and who are anticipated to be unable to ingest and/or absorb adequate nutrients for a prolonged period of time. B
5. ω−3 Fatty acid supplementation may help stabilize weight in cancer patients on oral diets experiencing progressive, unintentional weight loss. B
6. Immune-enhancing enteral formulas containing mixtures of arginine, nucleic acids, and essential fatty acids may be beneficial in malnourished patients undergoing major cancer operations. A
 
Grading of guidelines
A Supported by at least two level I investigations
L Supported by one level I investigation
C Supported by at least one level II investigation
D Supported by at least one level III investigation
E Supported by level IV or V evidence
Levels of evidence
I Large randomized trials with clear-cut results: low risk of false-positive (alpha) and/or false-negative (beta) error
II Small, randomized trials with uncertain results: moderate-to-high risk of false-positive (alpha) and/or false, negative (beta) error
III Nonrandomized cohort with contemporaneous controls
IV Nonrandomized cohort with historical controls
V Case series, uncontrolled studies, and expert opinion

Reproduced from Dellinger RP, Carlet JM. Masur H. Introduction. Crit Care Med. 2004:321(11 )(suppl):S446 with permission of the publisher. Copyright 2004 Society of Critical Care Medicine.

2. Intra-operative and immediate post-operative care

2.1. Pharmacokinetics and pharmacodynamics

Pharmacokinetics in elderly patients is influenced by the physiological reduction of renal function (20–50% decrease in glomerular filtration). Moreover, an age-related increased proportion of body fat with a decreased proportion of body water implies a significant modification of volume distribution for both lipid-soluble and water-soluble drugs.

In addition, the prevalence of polypharmacy in older patients with cancer, here defined as an inappropriate use of multiple drugs for different chronic comorbidities, has been estimated to be within a range of 27–63% and some of its implications were recently reviewed elsewhere.20 Subsequently, this patient population is at an increased risk of potentially dangerous drug interactions.21 Interactions between anesthetic drugs or procedures and anticancer drugs have been poorly studied, and are summarized in Table 6.22 However, the real value of these specific interactions is limited to a quite rare setting related to unplanned emergency surgical procedures performed in patients treated with intravenous chemotherapy within hours to a few days. On the other hand, an increasing number of elderly patients with disseminated cancer are being treated with chronic, continuative delivery of oral anticancer agents, both “classic” (such as capecitabine and cyclophosphamide) or belonging to the newer family of targeted therapies (such as sorafenib, sunitinib, and everolimus) whose potential interactions with anesthetic drugs are largely unknown.

Table 6 Interactions between anesthetics and cytotoxic agents.

Cytotoxic/immunosuppressive agents Anesthetic agents Effects
c. Parvum Pentobarbitone Lethal in mice
Tribromethanol
Procarbazine Barbiturates Enhancement of CNS depressants
Sympathomimetics Hypertensive episodes
Cyclophosphamide Succinylcholine Prolonged apnea
Azathioprine Curare Reduced potency
Alkylating agents Potentiation of neuromuscular blockade
Bleomycin Oxygen Adult Respiratory Distress Syndrome

2.2. Perioperative management

The management of surgery and anesthesia is frequently different and more complex in geriatric patients than in younger cancer patients. Members of the perioperative medical team should be aware of the physiology of the aging process, the interaction of these alterations with medical conditions, particularly cancer, and the high rate of comorbidities and polypharmacy. An excellent short reference guide called “Geriatrics At Your Fingertips” has recently been updated and is available in a small pocket edition as well as on the internet (http://www.geriatricsatyourfingertips.org/).

Expectations for recovery are frequently different for the older patient with a primary focus on maintenance of function and independence. Data from Lawrence evaluating functional outcomes following abdominal surgery indicates that it takes, on average, about three months for elderly patients to reattain pre-operative levels of activities of daily living and about six months for independent activities of daily living.23

Cancer surgery is more successfully performed in an elective setting than as an emergency; despite this, waiting for the cancer surgery can be very upsetting. Hence, in most countries, surgical removal of the cancer is often offered promptly after diagnosis.

Special care should be used in handling older patients receiving a general anesthetic for cancer surgery. A layer or two of cotton padding can prevent bruising of the fragile skin on the upper arm from the blood pressure cuff. Decision regarding the use of invasive blood pressure measurement and/or frequent blood sampling is based on the same considerations as for younger patients. Age-related alterations and coexisting disease might easily persuade the experienced practitioner to institute invasive monitoring, and central venous access may be valuable for infusion of medications and fluids. Transesophageal echocardiography has been proposed as a particularly effective tool for evaluating the heart function in older patients.19 Diastolic dysfunction, which is present in a significant number of older patients, can only be detected by echocardiography. Noninvasive monitoring of physiologic variables (i.e. cardiac output) may be helpful in surgical cardiovascular management.24

Some older patients might require additional time to successfully achieve proper pre-oxygenation when being prepared for general anesthesia. Severe abdominal pain or distension can cause limited respiratory effort. A three minute period for pre-oxygenation may be utilized in elderly patients to effectively prevent hypoxemia during the induction and intubation process.25

Urinary catheters promote incontinence and urinary tract infections in the elderly. However, they do provide important information during longer surgeries. Intensive infection prevention programs, which among other things apply specific guidelines for the placement of urinary catheters according to the surgical procedure, can significantly decrease the incidence of urinary tract infections.26 The use of supra-pubic catheters should be promoted on senior men undergoing pelvic surgery.

Maintenance of normothermia is extremely important in general and for the elderly in particular, as they have an increased risk for hypothermia.27

Positioning can be an important aspect of perioperative geriatric care.28 The anesthesiologist should check the range of mobility when the patient is still awake in order to avoid limb damaging during anesthesia. Careful positioning is necessary to prevent nerve damage and avoid skin breakdown and undue stretch on contracted tendons and ligaments.

As in all aspects of fluid management, there is a lack of consensus as to the type and quantity of fluid that should be administered during elective major surgery, particularly in the elderly. In recent years, the trend seems to favor decreasing the amount of fluid administered. Prolonged mechanical ventilation results from persistent positive fluid balance in older surgical patients.29 A recent randomized study questioned the use of general guidelines, favoring goal directed therapy.30 and 31

Kehlet and colleagues have promoted a multi-modal approach to perioperative care that seeks to reduce the surgical stress response and organ dysfunction. They have shown that this approach leads to earlier recovery.32 and 33 One of the goals of this approach is to accelerate recovery and to discharge the patient as promptly as possible.

2.3. Tailored anesthesia

As elderly patients are more sensitive to drugs, the choice of anesthetic agents rests on methodical pharmacologic knowledge with emphasis on the alteration in pharmacokinetics and pharmacodynamics that occur in elderly patients.24 The consequences of these adjustments suggest the following considerations.

2.3.1. General anesthesia
2.3.1.1. Inhalation agents

The minimum alveolar concentration (MAC) of all inhalation agents sharply diminishes with increasing age to values up to 30% lower for 80-year-old patients.34 and 35 The concentration requirements are thus lower for a given depth of anesthesia.

2.3.1.2. Induction agents

Elderly patients require less induction agents. The sleep-dose requirement for thiopental decreases linearly with age. The increased sensitivity to thiopental is due to a change in pharmacokinetics (decrease in central volume of distribution) rather than pharmacodynamics.36 and 37 Older adults are more sensitive to the EEG modifications (measured with the bispectral index), sedative and hemodynamic effects of propofol.38 and 39 Pharmacokinetic changes, for example reduced central compartment and systemic clearance, are associated with delayed awakening.40 and 41 Increased sensitivity to etomidate in elderly patients is associated with pharmacokinetic changes and not related to altered brain responsiveness.42

In general, the induction dose of intravenous induction agents is lower, and the induction/awakening times are prolonged. Careful titration of the dose is mandatory in order to avoid hemodynamic instability and prolonged awakening time.

2.3.1.3. Opioids

Older patients are more sensitive to opioids; this fact is explained by both pharmacodynamic and pharmacokinetic reason.43, 44, and 45 The dosages of fentanyl, alfentanil and remifentanil required to achieve a given level of depression on the EEG decrease by 50% from 20 to 89 years of age.46 and 47 The pharmacokinetics of fentanyl and alfentanil are, however, unchanged. On the other hand, the central volume and the clearance of remifentanil decreased in elderly patients, resulting in higher plasma concentrations.47 Based on this evidence, it is recommended that remifentanil bolus doses are halved and infusion rates are decreased to one third of the adult dosage in the elderly in order to achieve the same effect. The increased sensitivity to sufentanil is probably due to pharmacodynamic changes in elderly patients.48 Elderly patients need an estimated half of the dose of opioids as compared to the younger patients to achieve the same analgesic effect.

2.3.1.4. Muscle relaxants

The required initial dose of muscle relaxants does not decline in elderly patients in parallel with the age-related decline of muscle mass.49 However, the time to recovery is prolonged because of changes in the pharmacokinetics. Dose requirements of anticholinergic drugs producing 50% antagonism of muscle relaxation (ED50) are also unaffected by age.50

2.3.1.5. Benzodiazepines

The sensitivity to the sedative effects of midazolam is greater in the elderly than in the young, reflecting pharmacodynamic changes within the g-butyric acid type receptor.51 Short-acting anxiolytics do not appear to prolong recovery or length of stay.52

2.3.2. Regional anesthesia

Both the central and the peripheral nervous system are affected by aging, resulting in a prolonged duration of neural blockade.53, 54, 55, 56, and 57 With epidural and spinal anesthesia the level of analgesia increases with increasing age. This is often accompanied by a greater hemodynamic effect instability with a greater incidence of hypotension and bradycardia.55 The differences in neural block characteristics are best explained by anatomical features and possibly pharmacodynamic changes, rather than variation in the pharmacokinetic changes in the elderly.58

It should always be kept in mind that even if age-related changes in pharmacokinetics and dynamics are true for many drugs, interindividual variability is usually large. The clinician therefore should titrate the lowest available dose against the desired effect in individual geriatric patients.

3. Post-operative care

3.1. Pharmacological management of cancer pain

Despite effective available treatment, elderly patients often are undertreated for cancer pain. Existing studies indicate a high prevalence rate and poor management of cancer pain in the elderly.59 Undertreatment can be attributed to multiple factors, including underestimation of the elderly person's sensitivity to pain and the fear of adverse effects.60 Achieving adequate pain management for the older patient may be complicated by comorbidity, increased risk of adverse drug reactions, and physician factors such as reluctance to prescribe opioid medications.

3.2. Do older persons feel less pain, or are they more sensible to analgesics?

No physiologic changes in pain perception in the elderly have been demonstrated. Possibly, the elderly may experience more pain than younger people, but they are less likely to complain of it. Pain is often considered an expected concomitant of aging. Several medical problems may prevail, other than cancer, such as depression and cognitive impairment. Both age-related pharmacokinetic and pharmacodynamic factors have been claimed to explain the presumed decrease in opioid requirements in elderly.61 However, studies dealing with the pharmacodynamic effects of opioids in elderly, report that the rate of drug delivery rather than the absolute dose over time influenced both analgesia and adverse effects.62 Tolerance may be more prominent in the young than elderly. For example, older adults demonstrated facilitation rather than inhibition during painful stimulation, suggesting decrements in endogenous analgesic response.63

3.3. Pharmacological treatment

The most common treatment of cancer pain is the use of oral analgesics. Analgesic drugs are considered in two categories: non-opioid analgesics, mainly non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; and opioids, according to the sequence of the WHO three step analgesic ladder.

3.3.1. Non-opioid analgesics

Acetaminophen is used alone or in combination with opioids. Acetaminophen has analgesic and antipyretic but no anti-inflammatory properties, probably acting centrally. It is well tolerated and its elimination is not affected by age. However, the drug is capable of causing liver or kidney damage in large doses when taken over an extended period. The maximum daily dose should not exceed 4 g a day, but lower doses should be used in older patients. NSAIDs act prevalently peripherally and vary widely in their metabolism, excretion, and adverse effects profile. Their analgesic activity is characterized by a ceiling effect, and increases in the dose will not further improve analgesia. While these drugs are effective alone or in combination with opioids and have no habit-forming properties, they have been associated with adverse effects in the elderly, and the drugs' overall safety in frail older patients has been questioned. Adverse effects from NSAIDs include gastrointestinal toxicity, including bleeding and ulceration, renal toxicity, and platelet aggregation inhibition.64

3.3.2. Opioids

When older patients have clear contraindications or manifest signs of toxicity to non-opioid analgesics, or when pain is no longer controlled with this class of drugs, opioids should be started. Opioids act on the central nervous system, and partially peripherally, to decrease the perception of pain and are the mainstay of cancer pain management. A variety of opioids are available, and they differ widely with respect to analgesic potency and adverse effects among the elderly. Recently, a better knowledge of opioid pharmacokinetics has stressed the importance of renal function.

3.3.3. Opioids for moderate pain

The step 2 opioids used for moderate cancer pain in the elderly include codeine, tramadol and propoxyphene. Their use is restricted to the treatment of moderate cancer pain because of dose-limiting side effects or because they are combined with non-opioids. Alternatively, lower doses, in the range of 15–20 mg daily, of strong opioids may be useful for moderate pain instead of second step drugs.65

Codeine is principally metabolized by the liver to codeine-6-glucuronide. Demethylation to morphine constitutes a minor pathway accounting for approximately 6–9% of the dose administered, with large interindividual differences due to genetic polymorphism, and about 10% of subjects are poor metabolizers. As most effects are derived from transformation to morphine, and since morphine is then metabolized to further substances, the clinical course may depend on the accumulation of these compounds in the presence of renal failure.

Tramadol is a centrally acting analgesic with two mechanisms of action: weak opioid agonist activity and inhibition of monoamine uptake. More than 80% of tramadol is metabolized in the liver to one active metabolite, O-demethyl tramadol, and 90% is excreted by the kidneys. In patients with impaired hepatic or renal function the elimination half-life is increased approximately two-fold, and multiple administration of tramadol requires increased dosage intervals.

Dextropropoxyphene is not recommended in the older patients with cancer because of its long half-life and the risk of accumulating the toxic metabolite norpropoxyphene.64

3.3.4. Strong opioids

Opioids used to control moderate to severe pain include morphine, oxycodone, hydromorphone, methadone and transdermal drugs. Selecting a specific drug depends on factors such as desired duration of action, preferred route of administration, side effect potential, and response to therapy. When using drugs from this class in elderly people, it is recommended to “start low and go slow”.66 Morphine's availability in multiple dose forms and its long history as an analgesic make it the gold standard in cancer pain relief. Morphine is highly extracted by the liver and is metabolized into two major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Hepatic impairment is a non-significant factor influencing pharmacokinetics of morphine. M6G accumulates in blood and penetrates the blood brain barrier, binding with strong affinity to opioid receptors and exerting a strong analgesic effect. While M6G is a potent analgesic, M3G has been shown to antagonize effects of both morphine and M6G. The parent–metabolite relationship is dramatically altered in patients with compromised renal function. In cases of renal failure or in the elderly, the ratios of M3G and M6G to morphine accumulate substantially; making opioid toxicity more likely, and kidney failure has profound effects on the behavior of the glucuronide metabolites of morphine.67 Physicians should be aware of the risks of administering morphine to patients with severe renal impairment.

Hydromorphone is more potent and soluble than morphine. It is an analog of morphine and is transformed in the liver to glucuronides which are eliminated by the kidney. Hydromorphone and its metabolites accumulate in renal failure. These substances are active and may contribute in producing opioid toxic effects.67

Oxycodone is a semi-synthetic opioid agonist that can be used as an alternative to morphine. Noroxycodone, oxymorphone and conjugated forms of oxycodone are the major metabolites. Most metabolites are eliminated by the kidneys. Clearance of the drug may be affected by hepatic and renal dysfunction. Oxycodone's pharmacokinetics are mostly independent from age, renal function and serum albumin concentration, making this opioid attractive for the elderly.67

Methadone is a low-extraction drug and is metabolized, mainly by N-methylation in the liver, to an inactive metabolite. Fecal excretion accounts for the greater part of clearance. Elimination through the kidneys is also observed. Its pharmacokinetics are highly variable. Drug interaction occurs with greater frequency with methadone than with morphine. On the other hand, methadone is not excreted by the kidneys and has no known active metabolites. However, methadone is difficult to titrate because of its long half-life and propensity for drug accumulation in older patients. Only experienced clinicians should prescribe methadone to older patients.67

Transdermal drug application has gained popularity among older patients. After establishing a subcutaneous skin depot of drug, transdermal patches deliver fentanyl or buprenorphine systemically over a 72-hour period. Transdermal fentanyl or buprenorphine are useful for patients with stable pain, those who need simplification of a medication regimen or those who cannot take medications orally. Fentanyl is metabolized in the liver to compounds that are both inactive and non-toxic, which are excreted in the urine. Fentanyl may be an alternative to morphine in patients with low renal clearance. In one study, patients were more satisfied with transdermal fentanyl than sustained-release oral forms of morphine, and the transdermal fentanyl group reported less impact from and lower frequency of adverse effects despite being significantly older than patients in the oral morphine group.68 However, transdermal fentanyl patches should be used with some caution because older patients have a decreased lean body mass to fat ratio, possibly effecting absorption, and because of its long duration of action. In fact, the effective activity may exceed 72 h in older patients. Buprenorphine is metabolized in the liver to produce inactive and weakly active metabolites, which are principally excreted via the biliary system. As pharmacokinetics of buprenorphine change little in patients with renal failure, such patients may safely receive buprenorphine.67

3.3.5. General considerations

When starting pain treatment in elderly patients, opioids should be prescribed at low doses and titrated to the patient's response and adverse effects. Although older persons are generally more sensitive to opioid-induced analgesia and adverse effects, guidelines for age-based adjustment of initial doses and incremental increases remain largely based on clinical judgment.69

Cancer patients with pain may not respond to increasing doses of opioids because they develop adverse effects before achieving an acceptable analgesia, or the analgesic response is poor, despite a rapid dose escalation. Opioid switching is an alternative approach, although data on the use of this practice are limited. The most important problem raised from the opioid switching literature is the conversion ratio among opioids. Most equianalgesic conversion data presented in reference tables are derived from older studies, including single dose studies and studies that were not designed for the detection of relative opioid potencies.60

3.3.6. Adjuvant analgesics

Adjuvant analgesics are helpful in treating certain types of chronic pain. These drugs include antidepressants, anticonvulsants, corticosteroids, bisphosphonates, and some other sedatives. Despite that anticonvulsants and antidepressants are useful agents to manage neuropathic pain in this population, the use of adjuvants has been found to be relatively uncommon in older patients with cancer.

Tricyclic antidepressants have multiple anticholinergic adverse effects that have limited their use in the elderly, including dry mouth, delirium and orthostatic hypotension. If adverse effects occur, the drug should be discontinued.64

Amitriptyline and nortriptyline are more commonly used. Nortriptyline and desipramine have the most favorable adverse effect profile. Doses used for cancer pain are much lower than the usual antidepressant starting doses. In older patients, the role of these drugs is limited by their cholinergic effects; arrhythmias, cognitive changes, and orthostatic hypotension may result in falls.70

The most commonly used anticonvulsants for the treatment of neuropathic pain include carbamazine, gabapentin, and pregabalin. Gabapentin and pregabalin have been gaining popularity for treating neuropathic pain in the elderly because they are believed to have less serious adverse effects than carbamazepine and do not require drug level monitoring. Although pharmacokinetic interactions with other drugs are minimized, their elimination is dependent on the renal function. Gabapentin is useful to manage neuropathic pain, which affects older adults as a complication of radiotherapy and chemotherapy and has the potential to enhance the analgesic effect of morphine.64 In older patients the half-life of gabapentin may be prolonged beyond 24 h. The greatest concern with antiepileptics in this population is their propensity to cause adverse effects.70

3.4. Delirium

Delirium is a common and serious complication in hospitalized older patients with cancer, with prevalence rates ranging from 28 to 48%.71, 72, 73, 74, 75, and 76 The prevalence in frail older patients may rise to 60%. Fifteen to 53% of older patients will develop post-operative delirium, and delirium rates of 70–87% are reported for older intensive care unit patients.77, 78, 79, 80, and 81

By definition, delirium is an acute disorder of attention and global cognitive function. Fluctuating symptoms and acute onset are characteristic.82 Delirium emerges in several subtypes: hyperactive, hypoactive and the mixed type. Whereas the hyperactive type is characterized by agitation, the features of the often not diagnosed hypoactive delirium are lack of movements and paucity of speech.83 The pathophysiology of delirium is still poorly understood.84 In general, delirium is considered to be a clinical syndrome caused by numerous interconnecting pathological mechanisms. Inouye and coworkers introduced the concept of predisposing and precipitating factors.82, 85, and 86 In patients with multiple preexisting conditions, relatively minor measures such as offering pre-operative fluids up to two hours before surgery, avoiding benzodiazepines for premedication, as well as intra-operative analgesia with remifentanil reduces the incidence of delirium.86 The causes of delirium are multifactorial, and most risk factors, such as advanced age and cognitive impairment are present before hospitalization.74 and 87 Other important risk factors are major surgery and severity of illness.88 and 89 Ninety percent of terminally ill cancer patients develop delirium at the end of life.71 and 72

Cognitive impairment is strongly associated with the development of delirium. Other risk factors are polypharmacy, depression and addiction.80, 90, 91, 92, and 93 Brouquet et al. showed pre-operative impaired functional status to be associated with post-operative delirium in older patients with cancer after major abdominal surgery.93 Among older patients in the intensive care unit (ICU),77 delirium is a common disorder because of their advanced age, critical illness, and multiple medical procedures and interventions.79, 94, and 95

Delirium is associated with poor outcomes, such as higher rates of functional decline,96 and 97 longer length of ICU and hospital stays,98 and 99 costlier hospitalizations99 and institutionalizations,82 and 96 and increased morbidity and mortality.74, 96, 100, and 101 Mortality rates of hospitalized patients with delirium range from 22–76%102 and mortality rates after one year vary from 35–40%.103

Despite the clinical importance, delirium often remains unrecognized by nurses and physicians.82, 94, and 104 In the ICU, delirium is frequently missed, especially when hypoactive delirium is present. Considering the preventable character of delirium, assessment of delirium with validated scales should be routinely performed, and a pre-operative assessment of cognitive function in older patients with cancer is recommended (Table 7).82, 105, 106, and 107

Table 7 Strategies to avoid delirium in older patients with cancer.

Pre-operative Avoidance of long-lasting benzodiazepines (GoR A) (108),
Administration of clear fluids up to two hours before surgery (GoR A) (87)
Intra-operative Administration of ketamine 0.5 mg/kg or s-ketamine 0.25 mg/kg (GoR B) with induction of anesthesia (109)
BIS-titrated anesthesia (BIS level 40–60) (GoR B)(110) Adequate analgesia with remifentanil or epidural anesthesia (GoR B) (87)
Maintain stable hemodynamics (+/−20% from baseline, GoR 0) (85–87), (111)
PONV prophylaxis if Apfel-Score > 2 (GoR B) (86) (112)
Post-operative Avoiding hypoxemia (GoR B) (86)
Adequate analgesia (GoR A) (86)
Avoid delirium and give neuroleptics e.g. haloperidol 0.5 to 1 mg with QTc monitoring if delirium develops [16, 35, 37(113)
Avoiding hypo- /hypervolemia and PONV (GoR B) (86)
Glasses and hearings aids (GoR B) (86)
Early mobilization (GoR A) (86)
Early enteral nutrition (GoR A) (86), (114)
Avoidance of unnecessary tubes, drains and catheters (GoR B) (86)
Follow-up Feedback from discharging department on functional and cognitive status (e.g. ADL/ PS) GoR 0 (115)
Feedback from GP after one year GoR 0 (115)

Abbreviations: GoR; grade of recommendation, BIS; bispectral index, PONV; post-operative nausea and vomiting, ADL; activities of daily living, PS; performance status, GP; general practitioner.

3.5. Intensive care issues

A decade ago, patients with hematological or metastasized solid malignancies were considered poor candidates for ICU admission.108 and 109 Since then, advances in oncological and supportive care have led to improved prognosis and longer survival in cancer patients. Patients with cancer may require ICU admission after major surgery as well as for concurrent severe illnesses. Cancer- or chemoradiation-related complications are also reasons for ICU admission. Cancer patients account for 15–20% of all ICU admissions in the western hemisphere.110 and 111 Still, admitting patients with cancer, especially elderly patients, to the ICU may be a matter of controversy.109 and 112 Groeger et al. published a mortality rate of 42% in cancer patients admitted in the ICU.113 In contrast, Taccone et al. recently reported that outcome of patients with solid cancer was comparable with that of the general ICU population, with a 27% hospital mortality rate.111

Several studies suggested age as an independent risk factor for increased morbidity and mortality,114, 115, 116, 117, 118, and 119 but studies using the APACHE scoring system have demonstrated that, when severity of illness is controlled for, age is not a predictor of ICU survival.114, 120, 121, 122, 123, and 124 Functional capacity is recognized as one of the most important variables related to the outcome of critically ill older patients.115, 125, and 126 Mortality seems to be mostly dependent on the severity of organ failures, performance status, and need for mechanical ventilation.111 and 127 However, in patients with more than three organs failing, more than 75% of those with cancer died compared with 50% of patients without cancer.111 and 115

One of the major causes of ICU admission for cancer patients is sepsis. In about 17% of medical admissions cancer is associated with sepsis, with a higher incidence in hematological cancer.128, 129, and 130 Respiratory and genitourinary infections are the main reasons for admission (52%).111, 131, 132, and 133 Age is a risk factor for the development and negative outcome of sepsis. Older patients are more likely to be infected with gram-negative organisms, with patients aged ≥ 65 accounting for 65% of the all septic cases.134 ICU teams caring for older critically ill patients must estimate the benefits of intensive care. Late ICU admission is associated with higher mortality rates when compared to early admission and cancer patients seem to benefit most from early ICU admission.111 In case of ICU admission it is mandatory that elderly patients are treated strictly in accordance with current guidelines and check-lists as this was shown to improve survival.135 and 136 Patients should be awake, cooperative and adequately pain-controlled with adequate pulmonary gas exchange and hemodynamic stability, and receive early enteral nutrition. Delirium or any other organ failure and infection should be treated as early as possible. Late ICU admission and aggressive management of severely ill cancer patients are associated with high rate of functional impairments, residual renal failure and critical illness neuromuscular syndromes with muscular weakness and prolonged weaning.

Functional status, comorbidities, quality of life, severity and acuity of illness as well as the probability of recovery and the patient's preferences toward mechanical ventilation and life sustaining measures should be considered. Age should not be the sole factor when deciding whether ICU admission is appropriate or not.

Although the majority of ICU studies have focused on mortality outcomes, when questioned, older patients are most concerned about maintaining function (especially cognitive function) and independence, and are willing to undergo burdensome treatment if it will return them to a favorable functional state (Table 8).122, 137, and 138

Table 8 ICU quality indicators: aims and measures.

Sedation Awake, cooperative Richmond Agitation Sedation Scale (RASS) 0–1 (147)
Pain control Responsive, cooperative VAS < 5(148)
Non-responsive, ventilated Behavioral Pain Scale < 6 (148)
Responsive, but not cooperative PAINAD (148, 149)
Dementia PAINAD (148, 149)
Delirium Consider hypoactive and hyperactive delirium CAM-ICU (105, 150)
ICDSC(150)
DDS (151)
NUDESC (105)
Pulmonary gas exchange Intubation criteria to be defined Blood gas analysis
paO2 in elderly patients 70–80 mm HG (152, 153)
paCO2 correct for lung structure and hemodynamics
Weaning Protocol-defined Daily check-lists (154)
Hemodynamics Maintain adequate blood pressure MAP > 60–80 mm Hg (155)
Consider positive inotropic agents ScvO2 > 70%(152)
Nutrition Early enteral nutrition Start enteral nutrition within the first 24 h after admission (114)
Gastric reflux < 800 ml/day
If increased, consider jejunal catheters
Renal support Quantitative diuresis 0.8–1.2 ml/h Rifle criteria based decision on renal support systems (156)
Use functional parameters for qualitative diuresis
Infection control Prevention control WHO-campaign on clean hands
Monitor SIRS criteria VAP bundles (157)
Start anti-infective treatment within 1 h after severe sepsis (158–160)

Abbreviations: VAS, visual analog scale; PAINAD, pain assessment in advanced dementia scale; CAM, confusion assessment method; ICDSC, intensive care delirium screening checklist; DDS, delirium detection score; NUDESC, nursing delirium screening scale; SIRS, systemic inflammatory response syndrome; VAP, ventilator-associated pneumonia.

Conflict of interest

SRK, RAA, BTHV, JS, AALV, SM, HLW, MS, AZ, SJ, MW, and MPWG report no conflicts of interest.

JHS: I receive funds from the National Institute on Aging for a large multicentered study. We also receive drug from Hospira, and monitors from Covidien and CADMed. None of these have anything to do with the paper.

CS: Reports no conflict of interest related to this manuscript.

Author contributions

Concept and design: SRK, RAA.

Data collection: All authors.

Analysis and interpretation of data: All authors.

Manuscript writing and approval: All authors.

Appendix A. Supplementary data

Download file

Supplementary Tables.

References

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Footnotes

a University of Oslo, Department of Geriatric Medicine, Oslo University Hospital, Ullevaal, 0407 Oslo, Norway

b Department of Anaesthesiology and Intensive Care, Charité-University Medicine Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany

c Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands

d Department of Anesthesiology, Mount Sinai School of Medicine, New York, NY, USA

e Department of Surgery and Geriatrics, Mount Sinai School of Medicine, New York, NY, USA

f Department of Palliative Care, Mount Sinai School of Medicine, New York, NY, USA

g McGill Nutrition and Performance Laboratory, McGill University Health Centre, Montreal, Canada

h Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, and Palliative Medicine, University of Palermo, Italy

i Musculoskeletal Biology II Research Group, Division of Aging and Chronic Disease, Clinical Sciences Centre, Aintree University Hospitals NHS Foundation Trust, Liverpool, UK

j Fondazione Poliambulanza, Medical Oncology Unit, Brescia, Italy

k Department of Anaesthesia and Critical Care, University of Southampton, Southampton, UK

l University of Liverpool, St Helens Hospital, St Helens WA9 3DA, Liverpool, UK

Corresponding author. Tel.: + 47 90787614; fax: + 47 22118701.

Reviewers/acknowledgments:

Jose A Morais MD FRCP: Associate Professor and Director, Division of Geriatric Medicine, McGill University, Montreal, Quebec, Canada; Associate Director McGill Nutrition and Performance Laboratory.

Robert D Kilgour PhD, FACSM: Professor and Chair, Department of Exercise Science, Concordia University, Montreal, Quebec, Canada; Associate Director McGill Nutrition and Performance Laboratory.

Prosanto Chaudhury MD MSc, FRCSC, FACS: Assistant Professor of Surgery and Oncology McGill University, Associate Director General Surgery McGill University Health Centre, Royal Victoria Hospital site, Montreal, Quebec, Canada; Associate Director McGill Nutrition and Performance Laboratory.


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