Mednotes

L27 RDA Iatrogenic Disease (changed 7_7)

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aliasesL27 RDA Iatrogenic Disease (changed 7_7)

19 min read

Overview

Iatrogenic disease is illness produced by the process of diagnosis or treatment. This lecture frames it in older adults: it starts from normal ageing and frailty (loss of homeostatic reserve), works through an extended case of a prescribing cascade that ends in a hip fracture and delirium, then sets out the mechanisms that make older people vulnerable (polypharmacy, adverse drug reactions, altered pharmacokinetics and pharmacodynamics, impaired compliance) and the practical measures that reduce harm (getting the “rights” correct, deprescribing, medication reconciliation, compliance aids). Hospital-acquired infections and the surgical checklist are important but not covered here.

Iatrogenic disease: definition and scope

  • Iatrogenic means “resulting from the attitude or actions of a physician”; from Greek iatros (healer or physician) and genesis (birth or origin). It is producing an illness as a result of treatment.
  • A disease caused by the process of diagnosis or treatment.
  • It need not be the action of a physician: it may be any health practitioner (allopathic or alternative), or even the patient.
  • Age alone does not define who is predisposed to iatrogenic disease and adverse effects of treatment.
  • Many drugs have not been tested in older adults, or in the drug combinations older adults actually take.

Ageing, frailty and the geriatric approach

Normal age-related changes across the body (slide diagram):

  • Head and brain: skull thickens and head size increases; brain decreases in size, with no indication this affects mental function.
  • Hair: usually greys and thins; men may go bald.
  • Face: nose and earlobes lengthen; wrinkles from facial expression and sun exposure.
  • Eyesight: lenses harden, yellow and lose transparency; near vision diminishes.
  • Skin: thinner, less elastic, fat deposits diminish, age spots develop.
  • Ears: loss of high-frequency hearing.
  • Heart: stroke volume diminishes. Lungs: vital capacity declines.
  • Urinary: kidneys filter blood more slowly; bladder capacity declines.
  • Reproductive: in men testosterone drops with erectile difficulty; in women menopause drops estrogen, with hot flashes and mood swings, reduced vaginal secretions, less elastic vaginal walls, less firm breasts.
  • Bones and joints: bones less dense; wear and tear breaks down joint cartilage.

Conditions that increase in prevalence with age:

  • Loss of homeostatic reserve and lessened resilience, that is frailty
  • Increased numbers of diseases and conditions
  • Chronicity of those diseases and conditions
  • Multiplicity of medications, the majority long-term
  • Changing psychosocial environments

Frailty trajectory: functional capacity declines through Robustness -> (stressor, recovery) -> Pre-frailty -> (stressor, recovery) -> Frailty -> (stressor, dependence) -> Disability, with recovery after each stressor diminishing as frailty increases.

Comprehensive Geriatric Assessment is the hub of older persons health, covering: functional capacity (ADL, IADL), fall risk, nutrition, cognition (MMSE, MOCA), mood (GDS, PHQ-9), social support, financial concerns, goals of care and advance care preferences, comorbidities, polypharmacy, and vision/hearing.

Case study: Mr B, aged 83 (prescribing cascade)

Baseline: living in residential care, Parkinson’s disease for 8 to 10 years treated with levodopa, difficulty mobilising to the toilet. Symptoms of overactive bladder led to oxybutynin 5 mg.

The cascade that followed:

  1. Postural blood pressure changes -> fludrocortisone (controls sodium and fluid in the body)
  2. Ankle swelling -> frusemide (diuretic)
  3. Worsened ability to stand and get to the toilet -> increased L-dopa
  4. Confusion -> lorazepam (for anxiety disorders, trouble sleeping)
  5. Several days later: pelvic X-ray showing a right hip / femoral neck fracture

Parkinson’s disease features shown: stooped posture, masked face, back rigidity, forward tilt of trunk, flexed elbows and wrists, reduced arm swing, hand tremor, leg tremors, slightly flexed hips and knees, shuffling short-stepped gait.

Problems accumulated in hospital:

  • Delirium: levodopa, oxybutynin, lorazepam, fludrocortisone, frusemide, then pain, hypoxia, an operation and opiates on top
  • Immobility: fracture, delirium
  • Constipation: Parkinson’s disease and opiates
  • Urinary retention: oxybutynin, constipation, pain, plus an indwelling urinary catheter (IDUC)
  • Marked postural instability on mobilising: L-dopa, hydration state, anaemia

Outcome: oxybutynin, fludrocortisone, frusemide and lorazepam were removed and L-dopa reduced; a low-dose antipsychotic was given for a short period; continence was managed non-pharmacologically once the IDUC was out. But deconditioning from immobility combined with poor function in the rehabilitative phase resulted in an increase in level of care.

Warning

The transcript notes the final line of this slide is cut off at the slide edge after “resulted in an increase in level of care”.

Factors that caused Mr B’s situation:

  • “Medicalisation” of conditions and polypharmacy
  • Assuming one size fits all for a type of treatment
  • Failure to explain the purpose and likely outcomes of investigations and treatments to patient and relatives/caregivers
  • Under- and over-investigation, and under- and over-enthusiastic diagnostic effort
  • Poor communication
  • Knowledge of normal values for common diagnostic tests in older age

Falls

Risk factors listed: past history of fall, lower extremity weakness, age, female sex, balance problems, psychotropic drug use, medical conditions (cognitive impairment, Parkinson’s, stroke, arthritis, vision or hearing deficit, urinary incontinence), orthostatic hypotension, dizziness, anaemia.

Model of falls (overlapping circles feeding precipitating causes):

  • Intrinsic risk factors: gait and balance impairment, peripheral neuropathy, vestibular dysfunction, muscle weakness, vision impairment, medical illness, advanced age, impaired ADL, orthostatic hypotension, dementia, drugs
  • Extrinsic risk factors: environmental hazards, poor footwear, restraints
  • Precipitating causes: trips and slips, drop attack, syncope, dizziness, acute medical illness -> FALL

Medications associated with falls (odds ratio, 95% CI; Arch Intern Med 2009):

Drug classOR95% CI
Antihypertensive agents1.241.01–1.50
Diuretics1.071.01–1.14
Beta blockers1.010.86–1.17
Sedatives and hypnotics1.471.35–1.62
Neuroleptics and antipsychotics1.591.37–1.83
Antidepressants1.681.47–1.91
Benzodiazepines1.571.43–1.72
Narcotics0.960.78–1.18

The highest odds ratios are antidepressants, neuroleptics/antipsychotics, benzodiazepines and sedatives/hypnotics; narcotics and beta blockers cross 1.

Delirium and dementia

Delirium:

  • Often caused by a medical condition, for example infection, substance intoxication or withdrawal, or a medication side effect
  • Sudden onset over hours to days, lasting days to a month, often more severe at night
  • Memory loss, disorientation, difficulty with language and speech, hallucinations, delusions
  • Change in the ability to focus, sustain or shift attention; patient often distractible, may be drowsy or lethargic
  • But can also show psychomotor agitation, sleep-wake reversal, irritability, anxiety, emotional lability, and hypersensitivity to lights and sounds

Framework for delirium: precipitating factors (drugs/toxics, medical or surgical conditions, environmental factors, CNS injury) act on the brain, while predisposing and protective factors act on patient characteristics (age, cognitive function, sensory organs, general medical and functional status). The result is delirium, characterised by impairment of consciousness, impairment of attention, global cognitive impairment, motoric hypoactivity or hyperactivity, and sleep disturbance.

Dementia:

  • Progressive decline in cognition: learning and memory, language, executive function, attention, perceptual motor and social cognition
  • Deficits become severe enough to interfere with daily function and independence, for example safety at home, finances, activities of daily living
  • Most common cause is Alzheimer’s disease
  • Subtypes as proportions: Alzheimer’s 60-80%, Lewy body dementia 5-10%, vascular dementia 5-10%, frontotemporal dementia 5-10%, others (Parkinson’s, Huntington’s); mixed dementia means dementia from more than one cause

Polypharmacy

Definition: the use of 5 or more medications in older people.

Risks attached to it:

  • Adverse drug reaction (ADR) risk increased 3-4 times; 80% of those on 6 or more medications
  • Falls risk doubled at 4 or more medications
  • Medication errors: 35% risk if 4 or more medications
  • Drug-drug interactions
  • Prescribing cascades

“Rational polypharmacy” is a challenge in older people.

Scale of the problem:

  • Europeans aged over 65 receiving home care: 51% taking 6 or more medications, 22% taking 9 or more (Fialova, JAMA 2005)
  • Christchurch 2011 in-home rehabilitation: 50% taking 6 or more medications (Geddes & Sharma)
  • In more developed countries older people use 3 times as many prescription medications as younger people and purchase 70% of non-prescription medications (Gallagher 2007)

Australian prevalence of continuous polypharmacy, aged 70 or more, 2017 (Page et al 2019): of a population of 2,593,514, 36.1% on 5+ medicines, 5.9% on 10+, 0.7% on 15+. Prevalence of 5+ rises with age from 28.2% at 70-74 to a peak of 46.0% at 85-89, then falls to 38.6% at 90-94 and 31.2% at 95+. Women 36.6% and men 35.4% on 5+, so little sex difference.

New Zealand data (HQSC NZ 2019): polypharmacy in 24.7% at 65-74 years, 41.9% at 75-84, 57.1% at 85+, 34% average overall. Antipsychotics 2.8%, benzodiazepines 11%.

An outpatient example list ran to 24 items, including etanercept, prednisone, a fentanyl patch, lorazepam, cilazapril, paracetamol, metoprolol CR, amitriptyline, nicorandil, doxazosin, omeprazole, atorvastatin, ISMN, metformin, dabigatran, fluoxetine, Incruse Ellipta, Humalog and Lantus insulins, cholecalciferol, codeine, B12 injections, a prior iron infusion and furosemide.

Adverse drug reactions

Hospitalisations from ADRs, US emergency department visits in those aged 65+ (Budnitz, NEJM 2011):

  • 38% admitted
  • Admission rate aged 85+ is 3.5 times higher than at age 65-69
  • Women make up 60%
  • More likely to be admitted: those on 5 or more medications, and unintentional overdose (two thirds of those admitted)

Four main medication types implicated in admissions:

  • Warfarin (NOACs) 33.3%
  • Insulin 13.9%
  • Oral antiplatelets 13.3%
  • Oral hypoglycaemics 10.7%

Types of ADR:

  • Type A: attributable to accentuation of the drug’s known pharmacological actions, dose-related, more predictable, relatively common.
  • Type B: idiosyncratic, unrelated to dose, often unpredictable and of unknown mechanism, governed by host factors such as genetics or allergies, less common but often more serious.

Type B example: Stevens-Johnson syndrome / toxic epidermal necrolysis due to ibuprofen, shown as serial photographs from day 1 to day 10 with blistering, crusting and erythema of the face and mucosae improving over the course of treatment.

Profile of the patient liable to an ADR:

  1. Small older female
  2. History of allergic illness
  3. Previous ADRs
  4. Multiple chronic illnesses
  5. Renal failure
  6. Polypharmacy
  7. Cognitive decline

Why older people get iatrogenic harm (numbered causes)

1. Inadequate clinical assessment and multiple disorders

  • Older people often present with non-specific symptoms: falls, confusion, incontinence
  • The doctor may not be skilled at taking a collateral history; the patient is not a “difficult historian”
  • It takes time to find the underlying cause
  • Multi-morbidity leads to more medications -> more drug interactions -> more interventions

2. Excessive prescribing and inadequate review of medication, because of:

  1. Multiple disorders (multi-morbidity)
  2. Pressure on doctors to prescribe
  3. Therapeutic enthusiasm and over-energetic treatment
  4. Inappropriate treatment then inadequate supervision of what is prescribed; know the common side effects and ask the patient

3. Altered pharmacokinetics (absorption, distribution, metabolism, excretion; Gallagher 2007)

  • Absorption: gastric atrophy impairs some absorption
  • Distribution: increased body fat relative to lean mass gives a decreased volume of distribution for hydrophilic drugs (digoxin, lithium, ethanol) and an increased Vd for lipid-soluble agents (long-acting benzodiazepines)
  • Metabolism: hepatic mass and blood flow fall with age, which matters for drugs with high first-pass metabolism, for example calcium channel blockers and propranolol. Blood liver function tests are not helpful in predicting the extent of this in an individual patient
  • Excretion (renal function with age): reduced number of functioning nephrons, decreased renal blood flow, decreased GFR with rising creatinine. Clearance is reduced but less creatinine is produced because of reduced muscle mass, so creatinine understates the loss. Many drugs are excreted by the kidney and are affected, for example digoxin

The ageing kidney is pushed by hypoxia, dietary excess, metabolic defects, infection, hypertension, inflammation, diabetes and oxidative stress, and protected by RAS inhibition, anti-fibrotic strategies (anti-TGF-beta, BMP7 agonist, AcSDKP), calorie restriction, sirtuin, Klotho, and appropriate treatment of the underlying disease.

4. Altered pharmacodynamics (the physiological effects of the drug)

  • Greater anticoagulant effect for a given dose of heparin or warfarin in older adults than in younger patients
  • Seniors tolerate CNS depressant drugs less well, for example benzodiazepines; new drugs are not specifically tested in older adults

6. Impaired compliance (see below)

Compliance

75% of seniors make mistakes with their medication; of these, 25% are potentially serious, for example a drug ADR or driving.

Patient factors: living alone and/or not coping, poor memory or confusion, tendency to judge illness by symptoms, reservations about taking medication, vision impairment, dexterity impairment.

Prescriber factors: quality of explanation and instructions, poor instructions on the prescription, inattention to the total number of drugs, excessive medication times.

Medication factors: pill size, pill packaging, delivery method (for example inhalers), side effects, interactions including with “health foods”, change in formulation/colour/shape, confusing instructions (for example bisphosphonates).

Why it matters (Wu et al, BMJ 2006): poor compliance is associated with poor outcomes, with mortality over 0 to 30 months rising as compliance falls across the 100%, 67-99%, 34-66% and 0-33% groups. Compliance can be improved with intervention: a telephone intervention group had lower mortality than control. Main message: talk to the patient.

Identifying the non-compliant patient:

  1. Lack of expected benefit
  2. Lack of knowledge of medications
  3. Unknown to pharmacy
  4. Runs out of supplies too easily
  5. Drug counts
  6. Blood or urine samples
  7. Failure to attend appointments

Do not blame the patient for non-compliance; over-prescribing is a large part of the problem.

Warning

The transcript flags that the slide’s own numbering repeats “(iii)” twice in this list (for “Unknown to pharmacy” and again for “Failure to attend appointments”), and repeats “(iv)” twice in the measures-to-improve-compliance list below.

Measures to improve compliance:

  1. Minimise types of drugs where possible
  2. Once or twice daily with meals
  3. Good explanation and simple instructions
  4. Written instructions and a drug record card
  5. Supervised “self-medicating” pre-discharge
  6. Containers: pill boxes, blister packs. These require clear labelling and do not work for all drugs
  7. Memory aids, for example calendar packs
  8. The pharmacist has a central role: inpatient, outpatient, medication management

Adherence packs are multi-coloured blister sheets, each labelled for a specific time and day dosing schedule.

Reducing adverse drug reactions

Get things RIGHT:

  • Right diagnosis
  • Right drug (or NO drug) for the diagnosis
  • Right dose
  • Right drug name (penicillin versus penicillamine)
  • Right patient (inpatient labels)
  • Right follow-up (ask about side effects and patient tolerability)

Further measures:

  • Choose non-pharmacological methods where possible
  • Address psychological factors early
  • Weigh up the benefits versus the risks
  • Always read before prescribing
  • START LOW, GO SLOW
  • Identify hazardous medications before starting them, using the revised Beers criteria or STOPP-START (AGS Updated Beers Criteria, JAGS 2012). Reference sources: New Zealand Formulary Patient Information and Lexicomp

Deprescribing:

  • Be brave enough to cease drugs, carefully, and watch for withdrawals, for example benzodiazepines (Campbell, JAGS 1999) and SSRIs
  • Expect around 75-80% to have no adverse withdrawal events
  • Watch for angina and cardiac events
  • General practice has a role in monitoring

Important

Medication reconciliation: ensure the medications someone is given are the same as those prescribed and administered. Ward and community pharmacy are pivotal. Avoid omission of prescribed medications, and ensure previously ceased medications are not restarted.

Super ageing

Counterpoints to the frailty picture: a 105-year-old French man cycled more than 14 miles round a track in an hour, having started cycling at age 68. Ida Keeling, a Caribbean American centenarian track and field athlete aged 105, holds Masters records in the 60 m and 100 m for women in the 95-99 and 100-plus age groups; in 2016, just before her 101st birthday, she set the world record for push-ups in her age bracket and broke her own 100 m record, and became a world record sprinter again at 103. Henry Tseng was still exercising on gym equipment at 111 years old.

Self-test

  1. Define iatrogenic disease and give the origin of the word.
  2. Explain why “iatrogenic” is not limited to the actions of a physician, and state what the lecture says about age as a predictor.
  3. Describe the frailty trajectory from robustness to disability and what changes with each stressor.
  4. Describe the prescribing cascade in Mr B from his initial mobility problem through to his hip fracture, naming each drug and the indication it was given for.
  5. List the factors the lecture says caused Mr B’s situation.
  6. Which four drug classes carry the highest odds ratios for falls, and roughly what are those odds ratios?
  7. Distinguish delirium from dementia in terms of onset, course and cause.
  8. List the dementia subtypes with their approximate proportions.
  9. Define polypharmacy and state the associated increases in ADR risk, falls risk and medication error risk.
  10. What are the four main medication types implicated in ADR-related hospital admissions in over-65s, with their percentages?
  11. Distinguish type A from type B adverse drug reactions, and give the lecture’s example of a type B reaction.
  12. Describe the four pharmacokinetic changes with age, giving a drug example for each.
  13. Why does serum creatinine understate the loss of renal function in an older adult?
  14. Give two examples of altered pharmacodynamics in older adults.
  15. List the profile of the patient liable to an ADR.
  16. What proportion of seniors make medication mistakes, and what proportion of those mistakes are potentially serious?
  17. Distinguish patient, prescriber and medication factors in impaired compliance, with two examples of each.
  18. List the six “rights” for reducing ADRs.
  19. What proportion of patients can be expected to have no adverse withdrawal events when drugs are ceased, and what should be watched for?
  20. What is medication reconciliation and what two things does it aim to avoid?
  21. Integrative: an 83-year-old in residential care with Parkinson’s on levodopa is started on an anticholinergic for urinary symptoms. Predict the sequence of complications and explain, using the pharmacokinetic, pharmacodynamic and polypharmacy principles from this lecture, why this population is so vulnerable and what should have been done instead.

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