CHRONICITY
PAIN PATHWAYS
PAIN NEUROTRANSMITTERS
 Glutamate
o NMDA: influx of Ca2+
o AMPA: influx of Na+
 Substance P
o NK-1: intracellular signaling  activation
of arachidonic acid pathways, NO
synthesis, activation of NMDA receptors
 PKC removes Mg that blocks
NMDA receptors  allows
glutamate to attach
 CGRP
o CGRP-R: altered neuronal activity 
central sensitization (lowered threshold for  Self-management: life skills programs, personal
evoking action potentials)
ENDOGENOUS OPIOIDS
 Types: enkephalins, dynorphins, endorphins
 Receptors: mu, delta, kappa
o 7-transmembrane spanning proteins
coupled to inhibitory G-proteins
o All in high concentrations in dorsal horn
o Differ in cellular distribution, relative
affinity for ligands, and effects
 Effects
o Closing of voltage-gated Ca2+ channels on
presynaptic channels  decreased release
of all pain neurotransmitters
o Opening of K+ channels on postsynaptic
channels  hyperpolarization
ASCENDING
 For transmitting pain signal to brain
 Injury  activated immune and skin cells release
cytokines, importantly prostaglandins  activate
nociceptors of 1st order neuron  substantia
gelatinosa of dorsal horn  2nd-order crosses 
spinothalamic tract  thalamus  3rd-order neuron
 somatosensory cortex
 Aβ fibers: mechanical stimulus
o Largest and fastest conduction velocity
 Aδ fibers: mechanical pain and temperature
 C fibers: mechanical and chemical pain,
temperature
o Smallest and slowest conduction velocity
DESCENDING
 For controlling and inhibiting ascending pathway
 Periaqueductal gray matter (midbrain)  synapse at
nucleus raphe magnus (medulla)  5HT/NA
neuron goes to substantia gelatinosa
o 1) bind to receptors of 1st-order and inhibit
release of substance P
o 2) stimulate interneuron  release
enkephalin (endogenous opioid)
BIOPSYCHOSOCIAL MODEL OF PAIN
 Biological: genetic predispositions, drug effects,
physical health, nervous system
Psychological: cognitions, emotions, behaviors,
motivation, attention, memory, learning, trauma
 Social: culture, relationships, environmental,
legal/insurance
 Pain is a psychophysiological behavior pattern, all
of the above factors perpetuate pain
TEAM MEMBERS
 Physiotherapist, pharmacist, psychologist, NP,
occupational therapist, social worker
NON-MEDICAL THERAPIES
 Physical rehabilitation: exercise, movement, graded
activity participation
 Psychological interventions: individual and group
psychotherapy, education sessions, mindfulness-
based interventions, support groups
practices such as breathing, pain education
ORANGE FLAGS
 Psychiatric symptoms: clinical depression,
personality disorder
YELLOW FLAGS
 Beliefs, appraisals, judgments: unhelpful beliefs
about pain, expectations of poor treatment outcome
 Emotional responses: distress, worry, fears not
meeting criteria for mental disorder
 Pain behavior: avoidance of activities due to
expectations of pain, over-reliance on passive
treatments (e.g. cold packs, analgesics)
ACUTE VS. CHRONIC PAIN
 Acute treatment:
o Usually due to trauma, surgery, acute
illness
o Short-term, curative treatment
 Chronic:
o Has persisted for >3 months
o High mental comorbidity
o Goal-oriented, non-curative treatment
 A, B, C’s
o Assess pain at regular intervals
o Believe the patient
o Choose the appropriate therapies
o Deliver in a logical, coordinated fashion
o Empower and educate patients to control
pain
LADDER
 Multimodal approach exploits effectiveness of
different agents to maximize efficacy and minimize
side effects
1. Mild postoperative pain
a. Nonopioid analgesic + local anesthetic
infiltration
2. Moderate postoperative pain
a. Step 1 + intermittent doses of opioid
3. Severe postoperative pain
a. Step 1 and 2 + local anesthetic peripheral
neural blockade + sustained release opioid
analgesics
NOCICEPTIVE PAIN

 Due to chemical, mechanical, or thermal (noxious)
stimuli  somatic (MSK, localized and sharp) or
visceral (dull and diffuse)
DRUGS
 Acetaminophen
o Mild potency
o Inhibits COX not through active site in
CNS  inhibit synthesis of prostaglandins
 analgesic and antipyretic effects
o Not for liver failure or active hepatic
disease
 NSAIDs
o Mild potency: ibuprofen, naproxen
o Moderate potency: celecoxib, diclofenac,
meloxicam
o Inhibits COX  no conversion of
arachidonic acid to thromboxanes (platelet
adhesion), prostaglandins (vasodilation,
temperature set-point, anti-nociception),
prostacyclins
 COX-1 for gastric mucosal
integrity
 COX-2 for inflammation (selective
= celecoxib)
o Not for heart disease, renal disease,
anticoagulation therapy, history of ulcers
OPIOIDS
 Majority are agonists of mu-opioid receptors
 Naturally-derived can only reach certain potency
 Synthetic are refined to be more powerful
o Methadone
o Meperidine
o Oxycodone, oxymorphone
o Hydrocodone, hydromorphone
o Fentanyl
 Increasing potency: codeine, morphine,
oxycodone, hydromorphone, fentanyl (mainly in
chronic pain)
 Methadone also NMDA antagonist and SNRI
SIDE EFFECTS
 Nausea, from direct stimulation of chemoreceptor
trigger zone in medulla
 Dose-dependent respiratory depression, from
decreasing brain stem respiratory centre
responsiveness to carbon dioxide, and depressed
respiratory centres in pons and medulla
 Antitussive effect, repress cough centre in medulla
 Suppression of immune system
 Morphine and meperidine may produce histamine
o If injection, dilation of cutaneous blood
vessels and flushing
 Meperidine produces tachycardia, from structural
similarity to atropine
 Other opioids produce dose-dependent bradycardia,
from increased centrally mediated vagal stimulation
 Itching, from pruritoceptive neural circuits
 Constipation, from decreased gastric motility
 Antidiuretic, from depressed renal function
 Urinary retention, from increased sphincter tone
ADDICTION
 GABA-inhibitory interneurons of VTA release
GABA  inhibit release of dopamine from
dopaminergic neurons onto nucleus accumbens
(pleasure and reward)
 Mu receptors on interneurons decreases GABA
release  more dopamine
 Chronic use causes desensitization of receptor
signaling and down-regulation of receptors
o If stopped, lack of receptor activity
manifests as withdrawal symptoms,
opposite to pharmacologic effects
o Diarrhea, elevated BP
o Feelings of dysphoria and anxiety
BUPRENORPHINE
 Partial mu receptor agonist
 Antagonist at delta and kappa receptors
 Maximal effects much smaller
 Lower risk of side effects, abuse, addiction
NALOXONE
 Antagonist at opioid receptors in brain (affinity
stronger and prevent from binding again)
CANADIAN GUIDELINES
 Opioid agonist therapy: a synthesis of Canadian
guidelines for treating opioid use disorder
 https://www.camh.ca/-/media/files/professionals/
canadian-opioid-use-disorder-guideline2021-
pdf.pdf
 Engaging patients and initiating OAT;
pharmacological options; guidance,
recommendations, and considerations to optimize
outcomes in special contexts; recommendations if
co-occurring disorders; guidance on discontinuing
OAT
OTHER
 Benzodiazepines: diazepam, midazolam
 Nerve blocks: neuraxial (epidural, spinal),
peripheral, truncal
 Alpha2 agonists: dexmedetomidine, clonidine
STEPPED APPROACH FOR NOCICEPTIVE OR MIXED
 Non-opioid analgesics
o NSAIDS and/or acetaminophen
 Weak opioids
o Codeine, tramadol, tapentadol,
buprenorphine
 Strong opioids
o Morphine, oxycodone, hydromorphone,
fentanyl, methadone
 Interventions
o Nerve blocks, epidurals, PCA pump,
neurolytic block therapy, spinal stimulators
NEUROPATHIC PAIN
 Abnormal activity secondary to injury, disease, or
dysfunction of nervous system  central (CNS) or
peripheral (PNS)
ETIOLOGY
 Stroke
 Phantom pain
 Cancer, chemotherapy
 Infection or inflammation
o Shingles, post-herpetic neuralgia
 Peripheral neuropathy
 o Diabetes, alcohol, HIV, vitamin B  Activated pain neurons release neurogenic
deficiencies inflammatory chemicals: substance P, CGRP,
 Nerve trapping or trauma cytokines, chemokines  positive feedback
CLINICAL FEATURES  Ceases once heals
 Constant or paroxysmal CENTRAL (CNS) SENSITIZATION
 Burning, stabbing, shooting, lancinating, numbness,  1st-order releases glutamate, substance P, CGRP,
tingling, electrical cytokines/chemokines  depolarization
 Anesthesia dolorosa (skin not sensitive to touch but  Glial cells detect inflammation and release
still have pain) cytokines  positive feedback
 Allodynia (very light touch stimulates pain)
PHARMACOLOGIC TREATMENT CHRONIC PAIN
 Treat underlying cause
 4-6 week trials ETIOLOGY
 1st and 2nd line:  Neuropathic (see above)
o Amitriptyline (tricyclic) or duloxetine  Nociceptive due to tissue injuries such as burns,
(SNRI) bruises, sprains
 Increase NE and serotonin in  MSK pain: back, myofascial
synapses preferentially of analgesic  Inflammatory pain: autoimmune, infection
pathway  Psychogenic pain: somatic symptoms caused by
o Gabapentin or pregabalin (anticonvulsants) emotional, psychological, or behavioral factors
 Inhibits voltage-gated calcium  Mechanical pain: expanding malignancy
channels, esp. a2-d1  inhibit EVALUATION
release of excitatory  Verbal numeric rating scale
neurotransmitters  Significance of impact on pain
o Carbamezapine (anticonvulsant)  Screen for psychological conditions
 Block voltage-gated Na and Ca o MDD and GAD are most common
channels comorbid conditions
 3rd line: cannabinoids TOOLS
o THC, CBD  Brief Pain Inventory: assess beliefs on pain and
 Tramadol for rescue short-term (neurotransmitter impact on lives
and opioid)  McGill Pain Questionnaire: drawing for location
NON-PHARMACOLOGIC of pain, questionnaire regarding previous pain
 Physiotherapy medication and past experiences with pain
 Acupuncture  Neuropathic Pain Scale
 Percutaneous (through) or transcutaneous (along)
electrical nerve stimulation
 Counselling, CBT
 Reduce stress, anxiety, depression

TRANSITION FROM ACUTE TO CHRONIC PAIN

Other senses: desensitization from chronic stimulus

Pain: sensitization to make you avoid action
o Increased neuronal sensitivity to noxious
stimuli: hyperalgesia
o Reduced threshold to otherwise normal
stimuli: allodynia
 Major role in generation and persistence of chronic
and neuropathic pain
PERIPHERAL (SITE) SENSITIZATION
 Injury of vascularized tissue  inflammation
(redness, heat, pain, swelling)  activate mast
cells, macrophages, neutrophils, T cells
o 1) H+, ATP, serotonin, substance P POLYPHARMACY
 Directly bind receptors on
nociceptors and open Ca, Na  Prescription of multiple medications, threshold
channels ranging from 5-9 simultaneous drugs
o 2) bradykinin, histamine, prostaglandins,  Major challenge in geriatric population
nerve growth factor (NGF) o Rising prevalence of multi-morbidity
 Upregulates ion channels in o Several condition-specific guidelines
nociceptors  lower threshold for o Proliferation of medications
depolarization (sensitization) o Patient demand from available information
COMPLICATIONS
  Increases risks associated with
o Age-related changes in pharmacology
o Averse drug events
 Examples of ADEs
o Most commonly from warfarin and other
antiplatelet agents, insulin and other
hypoglycemic agents
o CVD  electrolyte and volume
disturbances, hypotension, falls, syncope
o CNS  altered mental status and falls
o Antimicrobials  allergic reactions,
diarrhea, and other ADEs
EVALUATION
 Careful medication reconciliation at each visit and
especially at time of care transitions
o Unclear diagnosis or indication
o Uncertain dose or route of administration
o Stop date and hold parameters
o Lab tests for monitoring
o Duplication
o Drug-drug and drug-disease interactions
 Also assess for ADEs, adherence, and effectiveness
MANAGEMENT
RECOMMENDATIONS FOR GERIATRIC
PRESCRIBING
 Evaluate thoroughly to identify all conditions that
could (a) benefit from drug; (b) adversely affected
by drug; (c) influence efficacy of drug
 Consider how clinical status (e.g. renal function) of
each patient could influence pharmacology
 From drugs or active metabolites eliminated
predominantly by kidney, use formula to
approximate age-related changes in renal function DEPRESCRIBING IN CANADA
and adjust dosages accordingly; Cockcroft-Gault
underestimates
 Manage without drugs as often as possible
 Start with smaller doses and increase gradually until
effective or intolerable side effects
 Avoid adverse drug-drug interactions
 Monitor older patients frequently for adherence,
drug effectiveness, adverse effects, and adjust
accordingly
o Drug blood concentrations helpful in
potentially toxic drugs
ADHERENCE
 Make drug regimens and instructions very simple
 Use same dosage schedule whenever feasible
 Time doses in conjunction with daily routine
(meals)
 Use aids (e.g. pillboxes or drug calendars)
 Careful education
o Account for impaired cognitive function,
hearing, and poor vision when instructing
patients and labelling prescriptions
o Make sure patient can afford prescriptions
and can open container
o Engage relatives and caregivers
 Enlist other health professionals (e.g. pharmacists,
home health aides) to ensure compliance
 Keep updated medication records
 Review knowledge of and adherence with drug
regimens regularly
DESCRIBING
 Consider the following:
1) Diuretics and hypotensive agents
a. Systolic hypotension or postural
hypotension that can precipitate near-
syncope and falls
2) Antianxiety and hypnotic, esp. benzodiazepines
3) Psychotropic and other drugs with anticholinergic
activity
a. Dry mouth, constipation, and long-term risk
of cognitive impairment
4) PPIs with unclear indications
5) Cholinesterase inhibitors and memantine in patients
with severe cognitive impairment
6) Hypoglycemic agents in multi-morbidity who
should not have tightly controlled blood sugar
7) Statins in patients with severe chronic illness near
end of life
 General principles:
1) Ascertain all drugs and reasons
2) Consider overall risk of drug-induced harm to
inform deprescribing intervention
3) Assess drug to current or future potential benefit vs.
harm/burden
4) Prioritize drugs for discontinuation with lowest
benefit-harm ratio and lowest likelihood of adverse
withdrawal reactions
5) Implement discontinuation regimen based on
pharmacology of drug being discontinued and
monitor closely for outcomes and adverse effects
 https://deprescribing.org/resources/
deprescribing-guidelines-algorithms/
 For antihyperglycemic:
https://deprescribing.org/wp-content/uploads/20
18/08/ppi-deprescribing-algorithm_2018_En.pdf
 PPI, antihyperglycemic, antipsychotic,
benzodiazepine receptor agonist, and cholinesterase
inhibitors and mermantine

EFFECTS OF DISEASE ON DRUG RESPONSE
RENAL DISEASE
 Renal excretion of parent drug and metabolites
o Glomerular filtration
o Specific drug transporters
 If primarily excreted through kidneys, dosages must SUMMATIVE
be reduced in patients with renal dysfunction
 In non-end-stage, changes in renal drug clearance
generally proportional to creatinine clearance
LIVER DISEASE
 Standard tests of liver function not useful in
adjusting doses (hepatitis, cirrhosis) unlike kidney
 Hepatocyte dysfunction, altered liver architecture,
portacaval shunts  first-pass metabolism may
decrease  increased oral bioavailability
For high first-pass drugs (e.g. morphine, nifedipine)
oral dose should be reduced
HEART FAILURE AND SHOCK
 Decreased tissue perfusion  redistribute cardiac
output to heart and brain >> other tissues 
additionally impaired drug clearance by
liver/kidney and gut absorption  higher plasma
drug concentrations, CNS or cardiac effects
ELDERLY
 Aging changes in organs involved in clearance
o Renal 35-50%
o Decrease in size of and blood flow to liver,
decreased activity of metabolizing enzymes
 Not detected readily
 Altered drug sensitivity
o Analgesic effects of opioids, increased
sedation from benzo and other CNS
depressants, increased risk of bleeding from
anticoagulation therapies, increased
response to CVD drugs because impaired
homeostasis
 Altered pharmacokinetics/dynamics +
polypharmacy + concomitant disease = increased
ADEs elderly
PRACTICALLY
 Published recommended adjustments
 Low initial doses and increase slowly, adjust based
on creatinine clearance
 Follow with plasma concentration data and clinical
observation
DRUG-DRUG INTERACTIONS
 Increase drug action or side effects
 Decrease drug action
MECHANISMS OF DECREASING DRUG EFFECTS
 Decreased gastrointestinal absorption
 Altered gastric pH  decreased solubility and
absorption
 Increased genetic expression of CYPs and/or P-
glycoprotein (metabolic enzymes)
o Stopping inducer can cause major toxicity
as clearance drops to baseline
 Inhibit bioactivation of prodrugs
 Inhibit drug delivery to intracellular sites of action
MECHANISMS OF INCREASING DRUG EFFECTS
 Inhibit drug elimination
 Inhibit CYP (since multiple substrates can compete
for active site), P-glycoprotein
 Inhibit xanthine oxidase
 Inhibit renal tubular transport
EFFECTS
 Separate components of common process  greater
effect than either alone
 Antiplatelets (glycoprotein IIb/IIa inhibitors,
aspirin, clopidogrel) and anticoagulants (warfarin,
heparins, dabigatran, apixaban, rivaraxaban,
edoxaban)  increased risk of bleeding
 Anticoagulants and NSAIDs  upper GI bleeding
due to ulcer risk
 NSAIDs (indomethacin, piroxicam) antagonize
antihypertensive effects of B-adrenergic receptor
 blockers, diuretics, ACE inhibitors  elevated
BP
 Sildenafil and nitroglycerin/related nitrates 
profound hypotension
o Sildenafil: inhibition of PDE type 5 isoform
that inactivates cyclic GMP
o Nitroglycerin: vasodilation by elevating
cyclic GMP
 Diuretics + QT-prolonging antiarrhythmics
(quinidine, sotalol, dofetilide)  torsades de
pointes ventricular tachycardia
o Hypokalemia prolongs QT and potentiates
drug block of ion channels that result in QT
prolongation
WARFARIN
 Inhibits vitamin K-dependent clotting factors and
metabolized by CYP450 isoenzymes
 Antimicrobials: inhibit CYP450, alter protein
binding, diminish absorption of vitamin K by gut
flora  increase bleeding and INR
o Most likely: TMP/SMZ, metronidazole,
fluconazole
 NSAIDs: affect gastric mucosal integrity 
gastrointestinal ulcers  increase bleeding except
for celecoxib
 Amiodarone: inhibit CYP2C9, 1A2, 3A4 enzymes
 increased warfarin effects
 Statins: inhibit CYP2C9  increased warfarin
effects
DIRECT ORAL ANTICOAGULANT MEDICATIONS
 Inhibit factor Xa (rivaroxaban, apixaban) or
thrombin (dabigatran)
 Ketoconazole, ritonavir, fluconazole,
amiodarone: inhibit CYP3A4 and P-glycoprotein
 increase DOAC effects
STATINS
 Amiodarone: inhibits CYP3A4  increase risk of
statin-related muscle toxicity
o Fluvastatin and pravastatin metabolized
through alternative pathways
 Azole antifungals: inhibits CYP3A4 and CYP2C9
 increase risk of statin-related muscle toxicity
o Rosuvastatin and pravastatin alternatives
 Calcium channel blockers: may inhibit CYP3A4
PDE-5
 Nitrates: both exert effects gy potentiating
vasodilatory effects of cyclic GMP
CLONIDINE
 Beta-blocker: In presence of beta2-receptor
blockade, vasoconstrictor properties of
catecholamines unopposed  exaggerated
hypertension after discontinuation of clonidine
DRUGS WITH CHELATION RISK
 Multivalent cations (aluminum, magnesium,
calcium, iron) and tetracycline drugs,
fluoroquinolone antibiotics, or thyroid drugs:
insoluble complexes formed in gut  reduced
absorption of drugs
POTASSIUM SUPPLEMENTS
 ACE inhibitors, A-II receptor blockers, direct
renin inhibitors, or K-sparing diuretics:
hyperkalemia
DRUGS THAT PROLONG QTc INTERVAL
 QT prolongation increases risk of torsades de
pointes; most likely when two more drugs and
already high risk
 High risk: age >65, bradycardia, female,
hypokalemia, hypomagnesemia, underlying heart
disease
 High-risk drugs: antiarrhythmics (amiodarone,
dofetilide, quinidine, sotalol), antidepressants
(citalopram, escitalopram, fluoxetine), and
psychotropics (paliperidone, quetiapine,
ziprasidone)
 Lower-risk drugs: analgesics, antiemetics
(chlorpromazine), antimicrobials (antimalarials,
antiretrovirals, fluoroquinolones), serotonin
agonists (sumatriptan, zolmitriptan)
DRUGS THAT DEPRESS CNS
 Antipsychotics, barbiturates, benzodiazepines,
hypnotics (eszopiclone, zaleplon), muscle relaxants,
opioid analgesics
ATRIAL FIBRILLATION
 Atrial rate so fast (350-600/min) that distinct P
waves not discernible on ECG
 Average ventricular rate in untreated is 140-160
RISK FACTORS
 General CVD: age, HTN, DM, obesity, smoking,
sleep apnea
 CVD: CAD, CHF, valvular heart disease (esp.
mitral valve), preexcitation tachycardia,
cardiomyopathies, pericarditis
 Noncardiac: pulmonary disease (COPD, pulmonary
embolism, pneumonia), hyperthyroidism or other
sources of increased sympathetic activity (e.g.
stress, cocaine), hypomagnesemia and
hypokalemia, excessive alcohol consumption
(holiday heart syndrome)
PATHOPHYSIOLOGY
 Likely multiple wandering atrial reentrant circuits
 Paroxysmal (sudden, unpredictable): initiated by
rapid firing of foci in sleeves of atrial muscle that
extend into pulmonary veins or in fibrotic atrial
tissue
 Sustained: minimum number of reentrant circuits
needed, facilitated by enlarged atrium or diseased
tissue
o Diseases that increase atrial pressure
include heart failure, HTN, CAD,
pulmonary disease
o Thyrotoxicosis and alcohol consumption
 Remodeling: electrophysiological changes with few
hours; fibrosis and dilation within few months;
electrical and structural remodeling increases
susceptibility to AF
 Contract rapidly and ineffectively  blood stasis 
increased risk of thrombus formation in left atrial
appendage  embolize e.g. stroke
 Atrial impulses encounter refractory tissue at AV
node, allowing some depolarizations to be
conducted to ventricle  irregularly irregular
rhythm
CLINICAL FEATURES
 When ventricular <100bmp, may be asymptomatic
  When faster,
o Palpitations
o Decreased CO  hypotension, dizziness,
syncope, and dyspnea
 Complications
o Acute left heart failure: pulmonary edema
(esp. in those with ‘stiff’ LV)
o Thromboembolic: stroke/TIA, renal infarct,
splenic infarct, intestinal ischemia, acute
limb ischemia
o Life-threatening ventricular tachycardia
DIAGNOSIS
 ECG
o P waves indiscernible, narrow QRS
complexes, tachycardia, irregularly
irregular RR intervals
 Lab studies
o CBC for infection
o Serum electrolytes
o TSH
o Kidney and liver tests
 Transthoracic echocardiogram
o Assess cardiac function and rule out
underlying structural disease (e.g. mitral
valve stenosis)
 CXR
o Signs of heart failure and pulmonary edema
o PE, pneumonia, COPD
TREATMENT
 Ventricular rate control, anticoagulation to prevent
thromboembolism, and restore sinus rhythm
 1) antiarrhythmic drugs
o First-line
 Beta blockers (metoprolol,
atenolol, propranolol)
 Avoid in COPD
 Nondihydropyridine Ca2+ channel
blockers (diltiazem, verapamil)
 Avoid in decompensated
HF (low EF)
o Second-line
 Digoxin
o Third-line
 Amiodarone; if all other options
have failed
o **Except for preexcitation syndromes (e.g.
WPW, inhibit AV nodal conduction 
increased conduction in aberrant pathway
 risk of VTach and VFib)
o Continued after restore sinus rhythm to
prevent recurrence
 2) anticoagulation therapy
o AF < 48 hours, only low risk (CHA2DS2-
VASc score 0 men, 1 women) can consider
anticoagulation and long-term not required
o AF > 48 hours or unknown duration
predisposes to thrombus formation 
indicates anticoagulation for at least 3
weeks prior to cardioversion
o Alternatively, transesophageal echo to
evaluate presence of thrombus; visualizes
atria and left atrial appendage (hotspots)
 If none and little thromboembolic
risk, then proceed directly with
cardioversion followed by
anticoagulation as it may take time
to return to normal contraction
 If there is, then receive >=3 weeks
of anticoagulation and repeat TEE
before procedure
 3) restore sinus rhythm
o Chemical cardioversion by administration
of class IC, IA, or III antiarrhythmic drugs
 Dofetilide, ibutilide, flecainide,
propafenone
o Electric cardioversion: gradually increasing
strength of direct current shock until sinus
rhythm is restored
o Contraindications: long-standing persistent
Afib, reversible causes, high-risk of
thromboembolic events
 If asymptomatic, then appropriate to control
ventricular rate and continue anticoagulation
 Long-term anticoagulation if underlying valvular
disease, hypertrophic cardiomyopathy, and/or
CHA2DS2-VASc score >=2 men and >=3 women
o Valvular Afib or nonvalvular with severe
hepatic disease/CKD: vitamin K
antagonists
o Nonvalvular Afib: DOACs, alternatively
heparin
SURGICAL
 Surgical maze procedure: multiple incisions in left
and right atria to prevent formation of reentry
circuits
o Sometimes in cardiac surgery for coronary
artery or valve disease with AF
 Percutaneous catheter ablation: areas of LA
around pulmonary veins cauterized to interrupt
reentry circuits and foci that initiate AF
o Extensive catheter manipulation and
ablation in LA
o Risk of stroke and cardiac perforation that
can cause pericardial tamponade
o Usually reserved refractory to
pharmacologic
 Catheter ablation of AV node: complete heart
block to permanently slow ventricular rate,
ventricular pacemaker required
o For recurrent or refractory Afib, or do not
tolerate pharmacology
 Left atrial appendage ligation or occlusion:
excludes LAA from circulation, removing it as
source of thrombi
CEREBRAL PALSY
 Heterogeneous group of disorders affecting muscle
tone and development of movement/posture
 Non-progressive damage to brain in utero or during
infantile development up to age of 3 years
 If damage to cortex/pyramidal tract: spastic
o Spastic paresis in one or more limbs, 75%
 If damage to extrapyramidal tracts (e.g. basal
ganglia, cerebellum): non-spastic
 o Dyskinetic: abnormal involuntary
movements
o Ataxic: intention tremor, lack of balance
and coordination
EPIDEMIOLOGY
 Most common motor disability in children
 2/1,000 live births in developed countries
ETIOLOGY
 Most commonly idiopathic
 Risk factors:
o Preterm birth and low birth weight, most
important
o TORCH infection
o Perinatal asphyxia
o Postnatal infection (e.g. meningitis,
encephalitis)
o Intracranial hemorrhage
o Kernicterus/chronic bilirubin
encephalopathy – deposit unconjugated
bilirubin in basal ganglia and/or brain stem
nuclei
CLINICAL FEATURES
 All types
o Do not reach certain milestones
o Intellectual disability (50%)
o Seizure disorder (35-50%)
o Joint contractures
 Spastic type
o Initially hypotonia, then increased muscle
tone after 6-12 months
o Increased deep tendon reflexes and
persistence of primitive reflexes
o Toe walking or equinus deformity
o Muscle weakness and/or atrophy
o Scissor gait due to spastic paraplegia of hip
adductors
o Hearing or vision impairment
 Non-spastic type
o Involuntary movements that worsen with
stress and disappear with sleep:
 Chorea, athetosis, dystonia, ataxia
o Dysarthria and dysphagia (pseudobulbar
involvement)
DIAGNOSIS
 Mainly clinical
 Cranial U/S in early neonatal period: e.g.
intracereberal hemorrhage and/or hypoxic-ischemic
injury, structural abnormalities
 MRI in older infants: detect causative lesion (e.g.
periventricular leukomalacia, congenital
malformation, intracranial hemorrhage)
TREATMENT
NONPHARMACOLOGICAL
 Physical therapy: prevent muscle contractures
 Occupational therapy: motor skill development
 Speech therapy: communication skills
 Orthotic devices (e.g. braces, splints, casts) and
assistive devices (walkers, wheelchairs)
 Educational, nutritional, social, and psychological
support
PHARMACOLOGICAL
 Antispasmodics: botulinum toxin, baclofen,
benzodiazepines
 Anticholinergics: rigidity and sialorrhea
 Anticonvulsants
SURGERY
 Orthopedic to treat scoliosis, relieve contractures
 Neurosurgical management of spasms
ADVANCE CARE PLANNING
 Advance care planning and goals of care
discussions
 Use of ACP information materials
o Visual aid during conversation
o Resource to take home and remind them
o Guide can assist to talk to loved ones
 1. Introduce ACP
o I want to provide you with the best care
possible and the care you want. We can
plan your care together through something
called advance care planning. Helps to
understand what healthcare options are best
for you. Together we can decide how you
want to be cared for. I would like to discuss
it more; would that be OK?
 2. Explain ACP
o Process that helps people think and talk
about goals for future healthcare should
they be unable to speak for themselves
o Helps people create plans for what type of
care they want
o Gift to loved ones; less stress/anxiety if
HCPs know what to do in case something
happens
o Advanced care planning is voluntary. I am
here to give information/answer
questions/help with process
o ACP is fluid. Can review on regular basis
on change over time
 3. Explore patient’s current health condition
o What concerns do you have about health?
o What do you know about your
illness?/Please tell me about your illness
 Identify knowledge gaps, offer
further information, discuss
treatments/expectations/outcomes
o Where do you see things going with your
illness?
 4. Explore patient’s values, goals, and beliefs
o Please tell me what gives your life purpose
or meaning?
o What are your biggest fears or worries?
o What beliefs are most important to you?
o Who or what helps you get through your
difficult times in life?
 5. Explore patient’s past health experiences
o Do you know of anyone who has gone
through something similar?
o Have you ever thought about what kinds of
treatment you would want or not want if
you were unable to speak for yourself?
o Are there situations where you would not
want life prolonging treatments?
 6. Clarify goals for life-sustaining preferences
 o What do you understand of life support, life
prolonging treatments, and the ICU?
(replaces or supports critical bodily
functions; keep patients alive, not cure)
o Discuss benefits and burdens
o Discuss potential health outcomes (e.g.
cognitive impairment, coma) and relate ack
to values and goals
 7. Identify substitute decision-maker
o Most knowledge of patient’s healthcare
wishes and who understands values/goals
o Provincial/territorial legislation
 8. Encourage patient to communicate with SDM
and other loved ones
o Stress that important to inform SDM and
communicate wishes with them and loved
ones on an ongoing basis
 9. Defining goals of care
o Medical care: curing or managing illness
but without use of resuscitative or life
support measures. Acute care or non-
hospital location
o Comfort care: optimal symptom control
and QOL when cure or control is no longer
possible. Includes terminal care.
o Resuscitative care: curing or managing the
patient’s condition. ICU care, attempted
resuscitation, and intubation
o Goals of care designation form (if SDM not
with you), complements personal directive BASIC PROCESSES
(SDM)
 10. Give green sleeve
o Document holder for patients
o GCD order, advance care planning tracking
record goals of care discussions, personal
directive, guardianship order
TIPS
 Focus on open-ended questions
o “What is important to you in your life right
now?”
o “How have you been feeling since the last
time we met?”
 Explore the meaning of ambiguous words and
phrases
o “What does __ look like to you”
o “What do you mean by __”
 “Some” is positive polarity item and will usually
encourage someone to answer ‘yes’ and elaborate
o Negative polarity will answer ‘no’: any,
ever, at all, never
 Friendly and comforting tone, with pauses to allow
patient to reflect and ask questions
 Empathetic statements to validate
 Acknowledge and support hopes whenever
possible; promise not outcomes but that HCPs will
always be there to support and help
 Minimize use of medical jargon and ask if they
understand
 If goes off topic, allow to complete thought,
acknowledge contribution, then gently redirect
conversation
 Frequently paraphrase/summarize at end to assess
and reinforce mutual understanding
 Focus more on what can be done to meet goals for
care and to make life worth living rather than on
what you cannot do for them
 Praise them for steps they have taken toward
completing components of ACP
 Non-verbal
o Try to look relaxed and unharried with
open and relaxed posture
o Remove obstacles such as tables
o When appropriate, gently touch hand, arm,
or shoulder to demonstrate you care
ANATOMY
 Two groups of organs:
 GI or alimentary tract
o Oral cavity  pharynx  esophagus 
stomach  duodenum, jejunum, ileum 
cecum, ascending colon, transverse colon,
descending colon, sigmoid colon  rectum
 anal canal  anus
o State of tonus (sustained contraction)  5-
7m in living, 7-9m in cadaver
 Accessory digestive organs
o Teeth in physical breakdown
o Tongue in chewing and swallowing
o Salivary glands (parotid, sublingual,
submandibular), liver, gallbladder, and
pancreas produce or store secretions for
chemical digestion
 Ingestion: taking foods and liquids into mouth
 Secretion: release of water, acid, buffers, and
enzymes into lumen of GI tract
 Motility: alternating contractions and relaxations of
smooth muscles of tract mix food and secretions
and propel them toward anus
 Digestion: process of breaking down ingested food
into small molecules that can be used by cells
o Mechanical: teeth grinds, stomach and
small intestines churn
 Food dissolved, mixed with
enzymes
o Chemical: carbs, lipids, proteins, nucleic
acids split into smaller molecules by
hydrolysis
 Absorption: movement of products of digestion
from lumen of GI tract in blood or lymph
o Substances not requiring digestion:
vitamins, ions, cholesterol, water
 Defecation: wastes, indigestible or unabsorbed
substances, bacteria, cells sloughed from tract lining
leave anus as feces/stool
LAYERS OF THE GI TRACT
 GI tract has same 4-layered arrangement starting
from lower esophagus
 Deep to superficial: mucosa, submucosa,
muscularis, serosa/adventitia
MUCOSA
 Composed of epithelium, lamina propria, and
muscularis mucosae
 Epithelium: simple columnar for secretion and
absorption in stomach and intestines,
nonkeratinized stratified squamous everywhere else
 o Between epithelial are exocrine cells that
secrete mucus and fluid, and
enteroendocrine that secrete hormones
 Lamina propria: areolar connective containing
blood and lymphatic vessels
o Contains majority of mucosa-associated
lymphatic tissue (MALT)
 Muscularis mucosae: ensures all absorptive cells
exposed to contents of lumen
SUBMUCOSA
 Areolar connective containing blood and lymphatic
vessels and submucosal plexus
MUSCULARIS
 Skeletal muscle in:
o Mouth, pharynx, superior and middle
esophagus for voluntary swallowing
o External anal sphincter for voluntary
defecation
 Smooth muscle everywhere else
o Inner sheet circular fibers
o Outer sheet longitudinal fibers
 Between muscle layers is myenteric plexus
SEROSA/VISCERAL PERITONEUM
 Specific to parts in the abdominal cavity
 Simple squamous (mesothelium) and serous
membrane of areolar connective underneath
 Named adventitia in esophagus
PLEXI
 Myenteric plexus between serosa and muscularis
 Submucosal plexus between muscularis and
submucosa
PERITONEUM
 Parietal peritoneum lines wall, visceral lines organs,
peritoneal cavity in between
 Retroperitoneal organs only has peritoneum on
anterior surfaces
 Unlike pericardium and pleurae, peritoneum has
large folds weaving between viscera that 1) binds
and 2) blood vessels, lymphatic, nerve supply
o Greater and lesser omentum, falciform
ligament, falciform ligament, mesentery,
mesocolon
MOUTH OR ORAL/BUCCAL CAVITY
 Cheeks:
o Mucous membrane consisting of
nonkeratinized stratified squamous
o Buccinator muscles and connective tissue
between skin and mucous membranes
 Lips:
o Similar layers as cheeks but has orbicularis
oris muscle
o Muscles together keep food between teeth
while chewing and assist in speech
 Palate:
o Hard palate in anterior, soft palate in
posterior roof of mouth
o Possible to eat and breathe simultaneously
 Tongue:
o Skeletal muscle covered by mucosa
 Extrinsic muscles (attach to bones)
move tongue side to side and in and
out for chewing, moving food
 Intrinsic muscles (insert to
tongue’s connective tissue) alter
shape and size of tongue for speech
and swallowing
o Median septum extending entire length
o Upper and lateral surfaces covered with
papillae, projections of lamina propria
covered by stratified squamous
 Main contain taste buds
 Some lack but have
mechanoreceptors
SALIVARY GLANDS
 Three major pairs: parotid (parotid duct),
submandibular (submandibular duct), and
sublingual (lesser sublingual ducts)
 Minor: labial (lips), buccal (cheeks), palatal
(palate), lingual (tongue) glands
 Acinus is ‘grape’ at end of branching duct system
 Acinar cells produce initial saliva
 Passes through intercalated duct then striated duct
 Ductal cells in striated which alter concentrations
of various electrolytes into final saliva
 Myoepithelial cells in acini and intercalated
contract to eject saliva into mouth
PHARYNX
 Skeletal muscle encased by mucosa
 Nasopharynx only in respiration
 Both oropharynx and laryngopharynx also have
digestive functions  propel food into esophagus
ESOPHAGUS
 Inferior end of laryngopharynx  mediastinum
anterior to vertebrae  pierces diaphragm through
esophageal hiatus
 Superior third skeletal, intermediate skeletal and
smooth, inferior third smooth
 Upper esophageal sphincter skeletal and controls
food from pharynx to esophagus, prevents air
 Lower esophageal sphincter smooth and controls
food from esophagus into stomach, prevents acid
STOMACH
 Lesser curvature = concave medial border; greater
curvature = convex lateral border
 Cardia surrounds opening of esophagus into
stomach
 Fundus superior and to left of body
 Body inferior of fundus, central portion
 Pyloric antrum connects to body, pyloric canal
leads to pylorus, which connects to duodenum via
the smooth muscle pyloric sphincter
 Differences in motility:
o Orad proximal and thin walled
o Caudad distal and thick walled to generate
stronger contractions
GASTRIC GLANDS
 Gastric pit  epithelial cells extend into lamina
propria  gastric glands  muscularis mucosae
 Three kinds of exocrine gland cells:
o Mucous neck cells secrete mucous, HCO3-
o Parietal cells produce intrinsic factor (for
vit B12 absorption) and HCl
o Chief cells secrete pepsinogen and gastric
lipase
PYLORIC GLANDS
  Similar configuration but deeper pits, in antrum
 Mucous neck cells secrete mucous, HCO3-
 Enteroendocrine cell G cell secretes gastrin not into
pyloric ducts but circulation
PANCREAS
 Head near curve of duodenum, central body, tail
 Pancreatic duct combines with common bile duct
 hepatopancreatic ampulla surrounded by
sphincter of hepatopancreatic ampulla  major
duodenal papilla
 Accessory duct directly into duodenum superior to
hepatopancreatic ampulla
EXOCRINE GLANDS (99%)
 Organized similar to salivary glands
 Unique that ductal cells extend into acinus as
centroacinar cells
o Both secrete HCO3-
ENDOCRINE GLANDS (1%)
 Islets of Langerhans
LIVER
 Divided into right and left lobe by falciform
ligament, fold of mesentery
 Left and right coronary ligaments are extensions
of parietal peritoneum suspending liver from
diaphragm
 Ligamentum teres (round ligament) remnant of
umbilical vein in free border of falciform
HISTOLOGY
 Hepatocytes: specialized epithelial with 5-12 sides
 Hepatic laminae: plates of hepatocytes one cell
thick, highly branched and irregular
 Hepatic sinusoids: endothelial-lined vascular
spaces that border hepatic laminae
o Contains fixed phagocytes, stellate
reticuloendothelial cells, which destroy
WBC and RBCs, bacteria, other foreign
 Bile canaliculi: small ducts in the grooves between
adjacent hepatocytes
o  bile ductule  bile duct  right and left
hepatic ducts  common hepatic duct +
cystic duct  common bile duct
 Portal triad: bile duct, branch of hepatic artery,
branch of portal vein
ORGANIZATION
 Hepatic lobule: centre is central vein, sinusoids
radiate outwards, three corners portal triad
o Difficult to see in human liver
 Portal lobule: portal triad is centre, triangle
connecting three central veins
 Hepatic acinus: preferred functional/structural unit
o Short axis by portal triad of hepatic lobule
o Long axis by curves between central veins
o Divided into zones with no sharp
boundaries:
 Zone 1 closest to portal triad (first
to receive nutrients, first to take up
glucose or break down glycogen,
first to show morphological
changes to obstruction or toxin, last
to die, first to regenerate)
 Zone 2 middle (intermediate)
 Zone 3 farthest (last to show
impaired circulation, first to show
fat accumulation)
BLOOD SUPPLY
 Receives blood from 1) oxygenated hepatic artery
and 2) deoxygenated hepatic portal vein with
newly absorbed nutrients, drugs, toxins
o 2) comes from spleen, stomach, pancreas,
small intestine, and colon
 1) and 2) drain into sinusoids  central vein 
hepatic vein  IVC
GALLBLADDER
 Pear-shaped sac in depression of posterior liver
 Consists, from inferior to superior: fundus, body,
neck
 Mucosa is simple columnar epithelium arranged in
rugae resembling stomach
 Contraction of smooth muscle fibers in muscular
coating ejects contents into cystic duct
 Innervated by phrenic so get radiation to shoulder
SMALL INTESTINE
 Epithelial layer:
o Absorptive cells contain enzymes that
digest and microvilli that absorb
o Goblet cells secrete mucous
 Intestinal glands: deep crevices of epithelium
o Paneth cells secrete lysozyme
(bactericidal) and can phagocytose
o Enteroendocrine cells (S, I, K)
 Secrete secretin, cholecystokinin,
and GIP respectively
 Lamina propria:
o MALT
o Solitary lymphatic nodules, groups called
aggregated lymphatic follicles, abundant in
ileum
 Submucosa:
o Duodenal glands secrete alkaline mucous
ORGANIZATION
 Circular folds are folds of mucosa and submucosa
that end in midportion ileum
o Increases SA for absorption
o Causes chyme to spiral
 Villi are fingerlike projections of mucosa
o Embedded within are arteriole, venule, and
blood capillary network, and lacteal
 Microvilli on absorptive by 20-30 actin filaments
o Create fuzzy line brush border on
microscope
LARGE INTESTINE
 Attached to posterior abdominal wall by
mesocolon, double layer of peritoneum
 Joins small intestine at smooth muscle sphincter
ileocecal sphincter  cecum (attached is
appendix)  colon  rectum  anal canal with
internal (involuntary) and external anal sphincter
(voluntary)
 Ascending colon  right colic (hepatic) flexure 
transverse colon  left colic (splenic flexure) 
descending colon  sigmoid colon
o Ascending/descending are retroperitoneal;
transverse/sigmoid not
 Anal canal mucosa arranged in anal columns
  Epithelium:
o Long tubular crypts of Lieberkuhn contain
absorptive (water) and goblet cells
(mucous)
o Absorptive cells have microvilli
 Lamina propria:
o Solitary lymphatic nodules
 Muscularis
o Unique to large intestine, portions of
longitudinal muscles are thickened, forming
three bands called teniae coli
 Separated by less or no longitudinal
muscle
o Attached to teniae coli are pouches of
visceral peritoneum filled with fat, omental
(fatty) appendices
o Tonic contractions of teniae coli gather
colon into pouches called haustra
IMMUNITY
 Lipopolysaccharide from bacteria and Th2
cytokines are goblet cell stimulants
 Mucous is physical barrier to motility and feeding
of pathogens
 IgA in mucous can trap invading bacteria
 Defensins, both a- and B-, kills wide spectrum of
pathogens in vitro
 Tissue-resident macrophages, eosinophils, mast
cells can phagocytose, release toxic + inflammatory
mediators such as N radicals and histamine
 Pathogen recognition receptors normally
expressed on basal side of epithelium or
intracellularly to avoid activation by normal flora
o TLR and NOD families
o Initiates powerful inflammatory response
MOTILITY
 Contraction and relaxation of walls and sphincters
o Grinds, mixes, and moves food
 All contractile tissue in GI tract except pharynx,
upper third of esophagus, and external anal
sphincter, which are striated, is smooth
o Unitary smooth muscle  electrically
coupled via gap junctions
 Circular smooth muscle decreases diameter
 Longitudinal smooth muscle decreases length
 Plastic contractions: periodic contractions
followed by relaxation (action potentials)
o Esophagus, gastric antrum, and small
intestine
 Tonic contractions: constant level of tone without
regular periods of relaxation (subthreshold slow
waves produce weak contraction)
o Upper region of stomach, lower
esophageal, ileocecal, and internal anal
sphincters
SLOW WAVES
 Not action potentials
 Oscillating depolarization and repolarization of
membrane potential of smooth muscle cells
o Depolarize: Ca channels inward
o Repolarize: K channels outward
 If at peak the membrane potential depolarized to
threshold, group of action potentials generated
 Frequency changes based on part, stomach lowest
(3/min) and duodenum highest (12/min)
 Interstitial cells of Cajal are pacemakers
CHEWING
 1) Mixes food with saliva to lubricate
 2) Reduces size of food to facilitate swallowing
 3) Mixes carbohydrates with salivary amylase
 Both voluntary and involuntary components
SWALLOWING
 Initiated voluntarily but thereafter involuntary
 Somatosensory receptors in pharynx  vagus and
glossopharyngeal nerves  medullary swallowing
centre  striated muscle in pharynx/upper
esophagus
 A. Oral phase
o Tongue forces bolus of food toward
pharynx
 B. Pharyngeal phase
o Soft palate upward, epiglottis closes, upper
esophageal sphincter relaxes
o Peristaltic wave of contraction propels food
into esophagus
 C. Esophageal phase
o Swallowing reflex closes sphincter and
sends another peristaltic wave down
esophagus
o If primary wave does not clear food,
secondary peristaltic wave initiated by
continued distention of esophagus (enteric)
ESOPHAGEAL MOTILITY
 Sequential contractions create area of high pressure
behind bolus, pushing it continuously
 At lower esophageal sphincter:
o Peptidergic fibers in vagus nerve release
VIP which produces relaxation of sphincter
and receptive relaxation of stomach
GASTRIC MOTILITY
 1) relaxation of orad region to receive bolus
 2) contractions reduce size of bolus and mix with
gastric secretions
o Wave of contraction begin in middle of
body and move distally along caudad
 3) gastric emptying propels chyme into duodenum
o Retropulsion: but most propelled
backward because contraction closes the
pylorus
 Contracts 3-5 times per minute because 3-5 slow
waves per minute:
o Parasympathetic by gastrin and motilin
increase frequency  stronger contractions
o Sympathetic by secretin and GIP decrease
frequency  weaker contractions
 Migrating myoelectric complexes are 90min
interval gastric contractions mediated by motilin
during fasting that clears stomach of residue
GASTRIC EMPTYING
 Rate closely regulated for neutralization of gastric
H+ in duodenum and digestion and absorption
 Inhibited by:
o Fat in duodenum causes secretion of CCK
o H+ in duodenum via enteric nervous
system
SMALL INTESTINE
  ~12 slow waves/min in duodenum, ~9 in ileum
o Parasympathetic by vagus increases
contraction (ACh, peptidergic: VIP,
enkephalins, motilin)
o Sympathetic by fibers from celiac and
superior mesenteric ganglia decreases
 Migrating myoelectric complex clears residual
chyme
 Two types of contractions coordinated by enteric
NS
SEGMENTATION CONTRACTIONS
 Mix chyme and expose to mucosa for absorption
 Section of small intestine contracts, splitting chyme
 Then relaxes, merging bolus back together
PERISTALTIC CONTRACTIONS
 Propel chyme toward large intestine
 Simultaneously contraction at point orad to (behind)
chyme and relaxation at point caudad to (in front
of)
 Circular and longitudinal reciprocally innervated
o Orad: circular contracts, longitudinal
relaxes
o Caudad: circular relaxes, longitudinal
contracts
 Peristalsis: bolus sensed by ECL cells of intestinal
mucosa  release 5-HT  5-HT binds to receptors
in primary afferent neurons  initiate peristaltic
reflex in that segment  orad excitatory
transmitters (ACh, substance P, neuropeptide Y)
released in circular muscle, inhibited in longitudinal
muscle, caudad inhibitory pathways (VIP, NO)
activated in circular but excitatory in longitudinal
VOMITING
 Vomiting centre in medulla receives input from
vestibular system, back of throat, GI tract, and
chemoreceptor trigger zone in fourth ventricle
LARGE INTESTINE
GASTROILEAL REFLEX
 Immediately after meal intensifies peristalsis in
ileum and forces chyme into cecum
 Gastrin also relaxes sphincter
MOVEMENTS
 Segmentation contractions/haustral churning:
o In cecum and proximal colon
o Haustra remain relaxed  become
distended  once threshold, contract and
squeeze into next haustrum
 Mostly churning, less advancement
 Peristalsis:
o 3-12 contractions per minute
 Mass movements:
o Strong peristaltic wave that begins in
middle of transverse colon and quickly
drives contents of colon into rectum, where
stored until defecation
o 1-3 times/day
o Water absorption in distal colon makes
fecal contents of large intestine semisolid
and difficult to move
GASTROCOLIC REFLEX
 Distention of stomach  parasympathetic nervous
system  CCK and gastrin release  increased
motility of colon (increased frequency of mass
movements)
DEFECATION
 Rectum fills and distended  sensory nerve
impulses to sacral spinal cord  motor impulses
along parasympathetic to desc/sigmoid colon,
rectum, anus  contraction of longitudinal rectal
muscles shortens rectum and increases pressure
inside  pressure, contractions of abdominal
muscles, and parasympathetic opens internal anal
sphincter
o Rectosphincteric reflex
 If external anal sphincter not relaxed  feces back
up into sigmoid colon until next mass peristalsis
 Urge to defecate when rectum 25% filled
 Intra-abdominal pressure created for defecation can
be increased by Valsalva maneuver (expiring
against a closed glottis)
SECRETION
 Addition of fluids, enzymes, and mucous to lumen
by salivary glands, gastric mucosa, pancreas, liver
SALIVARY SECRETION
 Composition of saliva:
o Initial approximately same electrolyte
composition as plasma and isotonic
o Ductal cells have Na-H, Cl-HCO3, and H-K
transporters on luminal  net absorption
of Na, Cl and excretion of K, HCO3- but
impermeable to water
o Final is hypotonic, composed of -amylase,
lingual lipase, kallikrein, mucous, mucin
glycoproteins, IgA, and electrolytes
o At higher flow rates, less time in contact
with ductal cells, most like plasma
 Functions:
o 1) Initial digestion of starches and lipids
o 2) Dilution and buffering of ingested foods
o 3) Lubrication to aid movement
 Kallikrein cleaves HMW kininogen
to bradykinin  local vasodilation
 high blood flow
 Regulation:
o Exclusively neural without hormonal
control
o Both sympathetic and parasympathetic
stimulates saliva production and secretion
GASTRIC SECRETION
 Composition of gastric juice:
o HCl, pepsinogen, intrinsic factor, mucous
 Functions:
o 1) initiate process of protein digestion
o 2) absorption of vit B12 in ileum
o 3) protect from corrosive HCl and lubricate
gastric contents
HCl SECRETION MECHANISM
 Apical: H-K ATPase and Cl- channels
 Basolateral: Na-K ATPase and Cl-HCO3
exchangers
 1. Intracellular CO2 from aerobic metabolism
combines with H2O to form H2CO3 which
dissociates into H+ and HCO3-
 2. Apical, H+ secreted into lumen against
electrochemical gradient and Cl- diffuses
  3. Basolateral, HCO3- exits into blood and Cl- enters
SUBSTANCES THAT ALTER HCl SECRETION
 Histamine:
o Released from ECL cells in gastric mucosa
o Binds to H2 receptors on parietal cells  Gs
 AC  cAMP  PKA  secretion of
H+
o Cimetidine blocks H2 receptors
 ACh:
o Released from vagus nerves
o Binds to muscarinic (M3) receptors on
parietal cells  Gq  phospholipase C 
diacylglycerol, IP3 from membrane
phospholipids  diacylglycerol and Ca2+
from intracellular stores activate protein
kinases  secretion of H+
 Also stimulates ECL cells (indirect)
o Atropine blocks muscarinic receptors
 Gastrin:
o Released by G cells (endocrine mechanism
instead of paracrine like histamine)
o Binds to cholecystokinin B (CCKB)
receptors on parietal cells  IP3/Ca2+
system
 Also stimulates ECL cells (indirect)
o Gastrin release triggered by distention of
stomach, presence of small peptides and
amino acids, and stimulation of vagus
nerves
 Potentiation because of relationships between
substances  consequences for drugs except
omeprazole, which counteracts H-K ATPase
 Vagal stimulation both ACh on parietal and GRP
on G cells  atropine will block direct effect but
not indirect gastrin-mediated effect
STIMULATION OF H+ SECRETION
 Three phases:
 Cephalic phase: ~30% total HCl
o Stimuli: smelling, tasting, chewing,
swallowing, and conditioned reflexes in
anticipation of food
o Mechanisms: direct (ACh) and indirect
(GRP) stimulation by vagus nerve
 Gastric phase: ~60% total HCl
o Stimuli: distention of stomach, presence of
breakdown products of protein (amino
acids and small peptides)
o Mechanisms: distention  vagus effects |
distention of antrum  local reflex 
gastrin release | protein products stimulate
G cells
 Intestinal phase: ~10%
o Mediated by protein products
INHIBITION OF H+ SECRETION
 When food moves to small intestine  less
buffering  lower pH  inhibits gastrin secretion
 Somatostatin is major inhibitory mechanism:
o Released by D cells
o Direct: receptors on parietal cells and Gi
protein to counteract histamine
o Indirect: inhibit histamine and gastrin
release
 Prostaglandins inhibit via Gi on parietal cells
PANCREATIC SECRETION
 ~1L into duodenum per day
 Aqueous component high in HCO3- (neutralize) and
enzymatic component (digestion of macro)
 Formation of enzymatic:
o Acinar cells: synthesized on RER  Golgi
complex  condensing vacuoles 
zymogen granules until stimulus triggers
secretion  apical membrane via
cytoskeletal network  fusion and release
o Amylases and lipases secreted as active
forms, proteases in inactive
 Formation of aqueous:
o Initial secretion by ductal and centroacinar
followed by modification in ductal
 Cl-HCO3- exchanger in apical
 Na-H exchanger in basolateral
 Net: secretion of HCO3, absorption
of H, so pancreatic venous acidic
o Isotonic containing Na, Cl, K, HCO3-
 Only Cl and HCO3- vary with flow
rate due to exchanger
 Higher = more HCO3-, less Cl-
 Regulation:
o Sympathetic by postganglionic from celiac
and superior mesenteric plexuses
o Parasympathetic by vagus which synapse in
enteric NS and postanganglionic on
pancreas
o Sympathetic decreases, parasympthateic
increases secretion
STIMULATION OF PANCREATIC SECRETION
 Cephalic phase:
o Same stimuli and mediated by vagus nerve
o Mainly enzymatic secretion
 Gastric phase:
o Distention of stomach and vagus nerve
o Mainly enzymatic secretion
 Intestinal phase: ~80%
o Both enzymatic and aqueous secretions
stimulated
o Acinar cells (enzymatic): CCKA and
muscarinic (ACh) receptors
 Amino acids, small peptides, FAs
 I cells secrete CCK  CCK on
acinar via IP3/Ca  enzymes
 ACh stimulates potentiates
o Ductal (aqueous): CCK, ACh, and secretin
receptors
 H+  S cells secrete secretin 
secretin on ductal via cAMP 
aqueous secretion
 ACh, CCK potentiates
INHIBITION OF PANCREATIC SECRETION
 Presence of fat in distal small intestine signals
intestinal phase concluding
 Inhibitors peptide YY secreted by endocrine of
ileum and somatostatin
LIVER AND GALLBLADDER PHYSIOLOGY
LIVER
 1) processing of absorbed substances
 2) synthesis and secretion of bile acids
 3) bilirubin production and excretion
 o Hemoglobin degraded by RES  biliverdin
byproduct (green)  bilirubin (yellow) 
bound to albumin in circulation  taken up
by hepatocytes  conjugated with
glucuronic acid by UDP-glucuronyl
transferase in hepatic microsomes 
now water soluble  excreted in urine and
secreted into bile
o Conjugated bilirubin in bile  terminal
ileum and colon  deconjugated by
bacterial enzymes  metabolized to
urobilinogen
 Some absorbed by enterohepatic
circulation and delivered to liver,
some to systemic and kidney
 Remainder converted to urobilin
(urine) and stercobilin (feces)
o Jaundice: yellow discoloration of skin or
sclera due to accumulation of free or
conjugated bilirubin
 Increased destruction of RBCs,
obstruction of bile ducts, liver
disease
 Conjugated bilirubin, if cannot go
into bile (clay stool), goes into
urine (dark) and blood (jaundice)
 4) metabolism of key nutrients
o Carbohydrates: GNG, converts to
glycogen and triglycerides, releases stored
glucose when needed, convert certain aa,
lactic acid, and other monosaccharides to
glucose
o Proteins: synthesizes nonessential aa,
deaminates aa so can be used for ATP
production or converted to carbohydrates or
fats, converts ammonia (byproduct of
catabolism) to urea in urine
o Lipids: FA oxidation, synthesizes
lipoproteins (transport FAs, TGs, and
cholesterol to and from body cells), store
some TGs, synthesize cholesterol, use
cholesterol to make bile salts
 5) synthesize proteins
o Synthesize almost all plasma proteins
including albumin, clotting factors
 6) storage
o Primary storage site for certain vitamins (A,
B12, D, E, K) and minerals (iron and
copper)
 7) activation of vitamin D
o Involved in synthesis of active vitamin D
 8) detoxification and excretion of waste products
o ‘First pass metabolism’ so little substances
make into systemic circulation
o Eg) bacteria phagocytized by hepatic
Kupffer cells (in addition to aged RBCs and
WBCs)
o Eg) enzymes modify endogenous and
exogenous toxins to render water soluble
and capable of being excreted in bile or
urine
o Phase I reactions: catalyzed by
cytochrome P450
o Phase II: conjugate with glucuronide,
sulfate, amino acids, or glutathione
BILIARY SYSTEM
 1. Hepatocytes continuously synthesize and secrete
constituents of bile
 2. Flows through cystic duct and
stored/concentrated in gallbladder
 3. Contraction of gallbladder secretes bile through
hepatopancreatic ampulla
 4. Bile salts emulsify lipids and solubilize products
of lipid digestion in micelles
 5. Bile salts recirculated to liver via enterohepatic
circulation
o Na-bile salt cotransporters
o Mostly at ileum so high bile salt
concentrations throughout small intestine
 6. Bile salts extracted from portal vein by
hepatocytes to bile salt/acid pool
o Liver must replace only the small
percentage of bile salt excreted in feces
 Fecal loss is about 600mg/day out
of total bile salt pool of 2.5g
o Negative feedback mechanism with bile
salts inhibiting RLS cholesterol 7a-
hydroxylase
 7. Choleretic effect: recirculation of bile salts to
liver stimulates biliary secretion
BILE SALTS (50%)
 Hepatocytes: cholesterol  7a-hydroxylase 
cholic and chenodeoxycholic acid (primary bile
acids)
 Intestinal bacteria: cholic and chenodeoxycholic 
7a-dehydroxylase  deoxycholic and lithocholic
acid (secondary bile acids)
 Hepatocytes: conjugates bile acids w/ aa glycine or
taurine  eight bile salts (e.g. glycocholic acid)
o Primary bile salts have more hydroxyl
groups and better at solubilizing lipids
 Solubility:
o Bile acids pKa~7, bile salts pKa~1-4
o At duodenal pH 3-5, bile acids HA while
bile salts ionized A-  more soluble
 Amphipathic:
o Bile salts have hydrophilic and
hydrophobic
 Functions:
o Emulsify lipids: negatively charged bile
lipids surround lipids but repel each other,
causing droplets to disperse rather than
coalesce
o Micelles: inner products of lipid digestion
are dissolved in aqueous intestinal lumen
PHOSPHOLIPIDS AND CHOLESTEROL (40% AND
4%)
 Phospholipids are amphipathic and line micelles
 Cholesterol included in micelles
BILIRUBIN (2%)
 Major bile pigment
 Liver conjugates to bilirubin glucuronide, secreted
into bile and gives yellow colour
IONS AND WATER
 Secreted by epithelial cells lining bile ducts
  Secretory mechanisms same as pancreatic ductal,
and also stimulated by secretin
GALLBLADDER
 1) Storing bile
o Smooth muscle relaxes and sphincter of
Oddi is closed
 2) Concentrating bile
o Epithelial cells of gallbladder absorb ions
and water in isosmotic fashion similar to
PCT
 3) Ejecting bile into small intestine
o Begins within 30 minutes of ingestion
o Major stimulus is CCK, 1) contracts
gallbladder and 2) relaxes sphincter of Oddi
o Pulsatile spurts because rhythmic
contractions of duodenum (when relaxed,
duodenal pressure is lower)
DIGESTION & ABSORPTION OF MACRONUTRIENTS
CARBOHYDRATES
DIGESTION:
 Only monosaccharides are absorbed so must digest
carbs to glucose, galactose, and fructose
 -amylase (salivary and pancreatic) hydrolyze 1,4-
glycosidic bonds
o Starch  maltose, maltotriose, -limit
dextrins
 Maltase, -dextrinase, and sucrase (intestinal
brush border) then hydrolyze oligosaccharides 
glucose
 Lactase, trehalase, sucrase hydrolyze
disaccharides  monosaccharides
o Lactose  lactase  glucose and galactose
o Sucrose  sucrase  glucose and fructose
o Trehalose  trehalase  glucose
ABSORPTION:
 Glucose and galactose
o Na-dependent cotransport (SGLT1) in
intestinal luminal membrane
 Sugar uphill, Na downhill
 Na gradient maintained by Na-K
pump in basolateral membrane
o Then facilitated diffusion (GLUT2) into
blood
 Fructose
o Transported exclusively by facilitated
diffusion, so cannot be absorbed against
concentration gradient
PROTEINS
DIGESTION:
 Can absorb amino acids, dipeptides, and tripeptides
 Endopeptidases hydrolyze interior peptide bonds
 Exopeptidases hydrolyze one aa at a time from C-
terminus of peptides
 Pepsin (endo):
o Secreted as pepsinogen by chief cells of
stomach and activated by H+ from parietal
o Optimal pH 1-3, denatured when >5
o HCO3- in pancreatic fluids of duodenum
inactivates pepsin
 Pancreatic proteases:
o Secreted in inactive forms and activated in
sequence in small intestine
o Trypsinogen activated to trypsin by brush
border enzyme, enterokinase
o Trypsin converts more trypsinogen,
chymotrypsinogen, proelastase,
procarboxypeptidase A and B to active
o Pancreatic proteases degrade each other and
absorbed with dietary proteins
ABSORPTION:
 Free amino acids:
o Na-dependent luminal cotransport followed
by facilitated diffusion into blood
(analogous)
o Four separate carriers for neutral, acidic,
basic, and imino amino acids
 Dipeptides and tripeptides:
o H-dependent luminal cotransport, faster
than amino acids
o Cytoplasmic peptidases hydrolyze to amino
acids then facilitated diffusion into blood
LIPIDS
DIGESTION:
 Stomach:
o Mixing breaks lipids into droplets to
increase SA for pancreatic enzymes
o Lingual lipases digest minority of TG to
monoglycerides and FAs
o CCK slows gastric emptying  adequate
time for digestion/absorption in intestine
 Small intestine:
o Bile acids emulsify lipids to increase SA
AND solubilize hydrophobic products of
digestion into micelles
o Pancreatic lipases hydrolyze lipids to FAs,
monoglycerides, cholesterol, lysolecithin
 Pancreatic lipase, cholesterol ester
hydrolase, phospholipase A2
ABSORPTION:
 1. Micelles bring products into contact with
intestinal surface
 2. FAs, monoglycerides, cholesterol diffuse into
cell
o Glycerol is hydrophilic, not in micelles
 3. Products of lipid digestion reesterified to TGs,
cholesterol ester, and phospholipids
 4. Form chylomicrons with apoproteins
 5. Chylomicrons transported out of intestinal cells
by exocytosis
 6. Enter lacteal because too big for capillaries 
lymph vessels  thoracic duct  blood
ENERGY METABOLISM
 Energy required for maintenance of ionic and
osmotic gradients, cell transport, nerve conduction,
intermediary metabolism, biosynthesis, heat
generation, and performance of mechanical work
 Supply largely from mitochondrial production of
high-energy phosphate bonds generated by
oxidation of fat, carbohydrate, and protein
 1. Hydrolysis of carbohydrates  simple sugars,
fats  fatty acids and glycerol, proteins  amino
acids
 2. Used immediately or stored endogenously
o Largest source of endogenous energy is TG
in adipose tissue  high energy density
 o Glycogen, the other largest source, in liver
and muscle tissue as a gel  less dense
 3. Most of these small molecules converted to
acetyl unit of acetyl-CoA
o Many amino acids enter citric acid cycle as
α-ketoglutarate or oxaloacetate instead
 4. Citric acid cycle and oxidative phosphorylation
o As acetyl-CoA oxidized, reduced NADH
and FADH2 transfer electrons to respiratory
chain in inner mitochondrial membrane
o Transfer of electrons down electron
transport chain coupled to generation of
ATP
MEASURING ENERGY
 Portion of energy produced is dissipated as heat
 One kcal, or 4.184 kilojoules, is amount of heat
required to raise temperature of 1kg of water by 1C
 Direct calorimetry: transfer of heat from body to
water in chambers or suits
 Indirect calorimetry: measure CO2 production and
O2 consumption
PROTEINS
 Definition: amino acids joined by peptide bonds
 Essential amino acids: histidine, isoleucine, leucine,
lysine, methionine, phenylalanine, threonine,
tryptophan, valine, possibly arginine
 Metabolism: >75% of aa from protein breakdown
reused for synthesis of new proteins (also glucose,
ketone bodies, FAs), remaining oxidized
 Liver is main site of catabolism for essential amino
acids with exception of branched-chain aa
 Branched-chain aa leucine, isoleucine, valine taken
up by skeletal muscle, undergo transamination,
yielding alanine, glutamine, branched-chain keto
acids
o Keto acids used as fuel
o Alanine and glutamine go to liver and
intestine, respectively
LIPIDS
 Definition: soluble in organic solvents, include TG,
sterols, glycolipids, phospholipids, vitamins
o In diet mostly TGs, saturated and
unsaturated long-chain FAs
 Essential fatty acids: those with n-3 double bond
and n-6 double bond, e.g. linoleic and oleic acid
 Metabolism: hormone-sensitive lipase in adipocytes
hydrolyzes adipose tissue TG, lipoprotein lipase at
capillary endothelium hydrolyzes plasma TG
o Former releases free FAs into bloodstream,
latter releases free FAs for local tissue
uptake
 In mitochondria, FAs degraded by β-oxidation to
acetyl-CoA
 Ketone bodies produced by partial oxidation of FAs
in liver increases with rate of FA production >>>
rate of FA oxidation, e.g. starvation or DM
o Ketone bodies cross BBB and spares
glucose for other tissues
 FA production by fatty acid synthase
o Acetyl-CoA carboxylase regulates rate-
limiting step, formation of malonyl-CoA
o Stimulated by citrate, abundant when ATP
and acetyl-CoA abundant
o Antagonized by palmitoyl-CoA, end
product
CARBOHYDRATES
 Definition: contain carbon, hydrogen, oxygen atoms
 Metabolism: undergo hydrolysis to yield glucose,
other simple sugars, and short-chain FAs
o Some cells, such as RBCs, WBCs, renal
medulla, eye tissues, peripheral nerve
tissue, cannot perform citric acid cycle so
requires glucose for anaerobic glycolysis
 Glucose can be stored as glycogen or fat, glycogen
in skeletal muscle for itself, in liver for rest of body
 Glycolysis is conversion of glucose to pyruvate that
generates ATP but does not require oxygen
o Only 2 ATPs /glucose vs. 36 ATPs in
Krebs
 Hepatic glycogenolysis most endogenous glucose
production, hepatic gluconeogenesis from lactate,
glycerol, and most amino acids (principally alanine)
ABSORPTION OF NON-MACRONUTRIENTS
VITAMINS
 Coenzymes or cofactors not synthesized in body
FAT-SOLUBLE (A, D, E, K)
 Processed same as lipids
 Micelles  diffuse across apical membranes 
incorporated into chylomicrons  lymph
WATER-SOLUBLE
 In most cases Na-dependent cotransport
 Exception is vitamin B12
o Released from foods by pepsin in stomach
 binds to R proteins from salivary juices
 proteases degrade R proteins in
duodenum, so B12 transferred to intrinsic
factor  complex resistant to degradative
actions and travels to ileum for absorption
CALCIUM
 Dietary vitamin D3 or cholecalciferol is inactive
o Converted to another inactive form in liver,
which is primary circulating form
o Activated by 1-hydroxylase in kidney
PCT
 Induces synthesis of vitamin D-dependent Ca 2+-
binding protein (calbindin D-28K) in intestinal
epithelial cells  promotes absorption of Ca2+
IRON
 Absorbed either as free iron (Fe2+) or heme iron
(iron bound to hemoglobin or myoglobin) in
duodenum
o Heme iron digested by lysosomal enzymes
in absorptive cells to release free iron
 Most non-heme iron bound to transferrin in plasma
o Transferrin transfers iron from enterocytes
and storage pools (macrophages of RES
and hepatocytes) to RBC precursors in BM
 Hepcidin is hormone produced by hepatocytes
o Binds to iron exporter ferroportin on
duodenal enterocytes and RES cells 
induces degradation  diminished
absorption of iron and trapping in RES 
less in serum
o Increased in states of iron overload and
inflammation (anemia of chronic inflamm.)
 o Decreased in states where erythropoiesis
increased (e.g. hemolysis) or O2 tension
low
 Storage
o Ferritin: ferric iron complexed to
apoferritin (liver, spleen, bone marrow
main ferritin storage sites)
 Also an acute phase reactant
o Hemosiderin: aggregates or crystals of
ferritin with apoferritin partially removed
(macrophage-monocyte system main
storage)
 Anemia would show low serum iron, low serum
ferritin, high total iron binding capacity (indirect
measure of total amount of transferrin in blood)
COLON
 Bacteria:
o Ferment remaining carbohydrates 
release H, CO2, methane gases
o Convert proteins  aa  indole, skatole,
HS, fatty acids
o Produce some B vitamins and vitamin K
 Some indole and skatole eliminated in feces, some SEIZURE
absorbed and transported to liver where converted
to less toxic and excreted in urine
INTESTINAL FLUID AND ELECTROLYTE
TRANSPORT
 Small and large absorb ~9L of fluid daily
 Composed of ~2L diet and ~7L salivary, gastric,
pancreatic, biliary, and intestinal secretions
 100-200mL not absorbed excreted in feces
 Permeability of tight junctions determines
whether fluid and electrolytes move para- or
transcellularly
o Tight junctions in small are leaky and
permit paracellular, but in large are tight
ABSORPTION
 By cells lining villi
 Absorbate always isosmotic, solute and water
absorption occur in proportion
JEJUNUM
 Identical to kidney PCT
 Apical:
o Na-monosaccharide and Na-amino acid
cotransporters
o Na-H exchanger, H comes from carbonic
anhydrase in cell
 Basolateral:
o Na-K ATPase
o HCO3- channel from carbonic anhydrase
ILEUM
 Same as jejunum but additional Cl-HCO3- exchange
in apical AND Cl instead of HCO3 transporter in
- -
basolateral
 Net absorption of NaCl instead of NaHCO3 -
COLON
 90% of water absorbed in small intestine
 Similar to principal cells of late DCT and collecting
 Apical:
o Na channel absorption
o K channel secretion
o Aldosterone increases synthesis of Na
channels and secondarily K secretion (more
K enters via Na-K ATPase and more
secreted)
 Basolateral:
o Na-K ATPase
 Other ions (e.g. chloride)
SECRETION
 By cells lining intestinal crypts
 Apical:
o Cl- channel
 Basolateral:
o Na-K-2Cl- cotransporter bringing all into
the cells
o Na-K ATPase
 **Na+ follows Cl- passively paracellular, and water
follows NaCl
 Normally Cl- channels closed
o Open to substances such as ACh and VIP
via cAMP
o Normally excreted electrolytes and water
absorbed by intestinal villi, but when
maximally stimulated  diarrhea
 Seizure: abnormal, unregulated electrical activity of
cortical neurons that results in transient changes in
behavior
o Provoked = non-epileptic
o Unprovoked = epileptic
 Epilepsy: chronic neurologic disorder with
following:
o 2 or more unprovoked seizures separated by
more than 24 hours
o One unprovoked seizure with underlying
predisposition to seizures (recurrence risk
over 10 years similar to after 2 unprovoked)
ETIOLOGY
 Provoked seizure
o Metabolic/electrolyte: hypo and
hyperglycemia, hypo and hypernatremia,
hypocalcemia, uremia, thyroid storm,
hyperthermia
o Mass: brain tumors and metastases
o Withdrawal: ABBA (alcohol most common
adults, barbiturates, antiseizure drugs)
o Intoxication:
 Cocaine, ecstasy, CO poisoning
 Amitriptyline, penicillin, lithium,
antipsychotics
o Infections: encephalitis, meningitis, abscess
o Ischemia: stroke, perinatal injuries, TBI
o Increased ICP and cerebral edema:
eclampsia, hypertensive encephalopathy
o Fever in infants and children
 Causes of provoked by age group
o TBI in all
o Neonates: congenital, perinatal injury
o Infants and children: fever, idiopathic,
infections, metabolic
o Adolescents: illicit substance abuse
o Younger adults: alcohol withdrawal, illicit
substance abuse
 o Older adults (>35): alcohol withdrawal,
stroke or TIA, metabolic disorders, vascular
encephalopathies
 Epilepsy
o General increase in neuronal
hyperexcitability
o Genetic mutations of ion channels or
transmitter receptors
o Cryptogenic (idiopathic)
o Structural/metabolic: preexisting chronic
cerebral lesion of CNS abnormality
(hypoxic-ischemic injury, PKU, tuberous
sclerosis)
o Triggers: excessive physical exertion,
sleep deprivation, strobe light flashing, loud
music
CLASSIFICATION
 Anatomical origin
 Focal: one area
o Aura: neurological symptoms that precede TREATMENT
migraine or seizure
o Clonic, involuntary, repetitive movements
of contralateral limbs
o Visual (hallucinations), somatic
(paraesthesia), position (vertigo), hearing
(complex sounds), olfactory (unusual or
intense smells)
o With or without impaired consciousness
 Generalized: both hemispheres
o Classic tonic-clonic/grand-mal: LOC,
tonic phase (generalized muscle
contractions), clonic phase (rhythmic
muscle twitching)
o Clonic seizures: LOC, rhythmic jerking
motor movements
o Tonic seizures: LOC, muscle contractions
o Myoclonic: brief LOC, sudden jerky
muscle twitching of muscles or group of
muscles
o Atonic seizures: brief LOC, sudden loss of
muscle tone (~2 seconds)
o Absence (non-motor seizure): common in
childhood. Brief LOC; blank stare,
unresponsiveness can happen several
hundred times in day but 5-20 seconds
 Status epilepticus: continuous seizure lasting ≥ 5
min, or ≥ 2 repetitive, separate seizures with
consciousness not fully regained in the interictal
period
CLINICAL FEATURES
 Ictal phase: sudden onset, rapid progression of
symptoms, 1-3 minutes
 Postictal phase: residual neurologic symptoms,
varying degree of confusion and impaired alertness,
minutes to hours
DIAGNOSIS
 1. Confirm seizure
 History identifies aura or provocative factors
 EEG
o Ictal (during)
 Epileptiform discharges (spikes,
sharp waves, spike waves,
hypsarrhythmia)
 If no discharges, consider
pseudoseizures
o Interictal (between)
 Normal findings, possibly show
epileptiform activity
 2. Exclude underlying condition
 ECG in ever patient with LOC to exclude
cardiogenic causes (e.g. arrhythmia  cerebral
hypoxia)
 CT/MRI (with and without contrast) to rule out
structural lesions after first seizure
o Always for focal, less concerned for
general tonic-clonic
o Don’t have to do for absence
 Lab tests
o Glucose, electrolytes, toxicology screen,
renal and liver function tests, antiepileptic
drug levels
 Lumbar puncture: if CNS infection suspected
 Acute
o Cardiopulmonary resuscitation (ABC)
 Airway management
 Prevention of aspiration
o Avoid hazards
 Remove sharp objects within
patient’s reach
 First seizure
o Long-term not required unless status
epilepticus or abnormalities on EEG or
MRI
o Remove cause or provoking factors
 Recurrent seizures with cause that cannot be
eliminated OR neuroimaging or EEG shows
findings after first seizure
o Antiepileptic drugs raising lowered
threshold  decreased neuronal excitability
o Focal first line: lamotrigine, levetiracetam,
phenytoin, phenobarbital (children)
o Tonic/clonic first line: lamotrigine,
valproate, phenobarbital
o Typical absence: ethosuximide (blocks
thalamic T-type Ca2+ channels), valproate
o Atypical absence, myoclonic, atonic:
valproate, lamotrigine, topiramate
 Combination therapy
o Monotherapy should be maintained and
increased dosage before initiating
combination
o Combination should be different classes
and/or different modes of action
 Nonpharmacologic if pharmacoresistance
o Surgery: resection of pathological lesion,
disconnection of neuronal circuits
o Stimulation techniques: vagus nerve
stimulation, deep brain stimulation
ANTICONVULSANT DRUGS
 First-generation
o Valproate: inhibits GABA transaminase 
increased GABA  decreased neuronal
excitability
o Carbamezapine: Inactivates Na channels
 o Ethosuximide: inhibits voltage-gated Ca
channels (T-type) in thalamic neurons
o Phenytoin: inactivates Na channels
o Phenobarbital: GABA agonist  increased
GABA inhibitory action
o Benzodiazepine: indirect GABA agonist 
increased GABA inhibitory action
 Second-generation
o Lamotrigine: inhibition of voltage-gated Na
channels  decreased glutamate release
o Levetiracetam: blockage of SV2A receptor
 GABA and/or glutamate release
modulation and inhibition of voltage-gated
Ca channels
o Gabapentin, pregabalin: inhibition of
presynaptic Ca channels  decreased
intracellular Ca flow
o Topiramate: blockage of voltage-gated Na
channels, increased GABA
 Preventing seizures
o Na channel inactivators
 Phenytoin, carbamazepine,
lamotrigine, valproic acid
o GABA activators
 Phenobarbital, tiagabine,
vigabatrin, valproic acid
o Other mechanisms
 Gabapentin, topiramate,
ethosuximide
TREATMENT OF STATUS EPILEPTICUS
 First-line: benzodiazepines (lorazepam)
o Bind to GABA-receptor (chloride channel
 hyperpolarization  less firing)
o Enhances inhibitory effect of GABA by
increasing frequency of opening of channel
 Second-line: phenytoin
o Inactivates Na channels
o Many side effects: gingival hyperplasia,
hair growth, rash
 Third-line: phenobarbital (barbituates)
o Binds to GABA-receptor (chloride channel)
o Enhances inhibitory effect of GABA by
increasing duration channel is open
 Then general anesthesia and intubate
DIABETES MELLITUS
 Chronic disorder of elevated blood glucose level
 Due to insufficient insulin, response to insulin, both
TERMINOLOGY
 Mellitus = sweet (urine was sweet)
 Insipidus = lacking flavor (urine lacks flavor)
o Rare disorder of low ADH activity
 Different mechanisms but both polyuria, polydipsia
CLINICAL PRESENTATION
 Often asymptomatic, esp. in early stages
o “Silent killer”  basis for screening
o Often no symptoms until complications
 Classic hyperglycemia symptoms
o Polyuria (osmotic diuresis from glucose)
o Polydipsia
 Acanthosis nigricans
o Hyperpigmented plaques on skin
o Intertriginous sites (folds) classically back
of neck and axillae
o Associated with insulin resistance
 Often seen in obesity, diabetes
o Rarely associated with malignancy: gastric
adenocarcinoma most common
DIAGNOSIS
 1) Asymptomatic
o Fasting blood glucose level (no food for 8
hours because will elevate after meal)
 <100mg/dL = normal
 100-125 is prediabetes
 >=126 is diabetes
 2) Symptoms plus glucose >200mg/dL = diabetes
 3) Glucose tolerance test
o Oral glucose load administered
o Plasma glucose measured 1-3 hours later
o High glucose indicates DM
o Often used to screen for gestational DM
 Some insulin resistance normal in
pregnancy, so study response
 4) Hemoglobin A1c
o Small fraction of Hb is glycated
 Glucose combines with a/b chains
o Subfraction HbA1c used in DM
 Non-enzymatic glycation of b-
chains at amino-terminal valines
 Higher glucose = higher glycation
o Reflects average glucose over past 3
months (RBCs survive around 3 months)
 Normal <5.7%
 Prediabetes 5.7-6.4%
 Diabetes >=6.5%
o Sometimes diagnosis but important for
monitoring therapy
 Higher value = worse control and
need to adjust medication
TYPE 1 DIABETES MELLITUS
 Autoimmune, type IV hypersensitivity disorder
 Etiology:
o Associated with HLA-DR3 and HLA-DR4
o Mostly a childhood disorder
 Bimodal distribution
 Peaks at 4-6 and 10-14 years
 Pathophysiology:
o T-cell mediated destruction of beta cells
 Inflammation of islets
 Lymphocytes on biopsy
(“insulitis”)
 Clinical presentation:
o Often with symptomatic hyperglycemia
(polyuria, polydipsia, glucosuria)
o Commonly presents as DKA
o Autoantibodies may be present
 Islet-cell and insulin antibodies
 Lifelong insulin treatment
TYPE 2 DIABETES
 Insulin resistance in muscle, adipose, liver
 Pancreas responds with increased insulin but
eventually pancreas can fail
o Insulin can be high or low depends on stage
 Epidemiology:
 o Much more common than T1DM
o Common in adults and becoming more
common in children
 Risk factors:
o Obesity is major risk factor
 Central or abdominal obesity
carries greater risk
o Intra-abdominal (visceral fat) greater risk
than subcutaneous fat
 Visceral fat breakdown less
inhibited by insulin  more
lipolysis if lots of visceral fat 
more free FAs to be used as fuel 
decreased glucose transport into
cells  worse DM
o “Apple” shape (more visceral fat) worse
than “pear” shape (more subcutaneous fat)
o Weight loss improves glucose levels
o Family history
 Strong genetic component, stronger
than T1DM
 Any first degree relative w/T2DM:
2-3x increased risk
 Histology:
o Amylin peptide normally made by beta
cells  packaged and secreted with insulin
 accumulates in islets in T2DM
o Amyloid in pancreatic islets
 Pathophysiology:
o Reason is unknown
o Data suggest insulin receptor
abnormalities
o FAs my activate serine-threonine kinases
 phosphorylate aa on beta chain of
insulin receptors  inhibit tyrosine
phosphorylation
o Increased TNF-a may be synthesized by
adipocytes  activate S-T kinases
COMMON COMPLICATIONS
 Chronic hyperglycemia  cardiac disease, renal
failure, neuropathy, blindness
 Two key mechanisms:
o A) Non-enzymatic glycation: glucose
added to aa groups on proteins (high
glucose drives)
 Crosslinked proteins  ‘advanced
glycosylation end products’
(AGEs)
o B) Sorbital accumulation: polyol pathway
is glucose  aldose reductase  sorbitol
 sorbitol dehydrogenase  fructose
 Little activity at physiologic
glucose
 Chronic hyperglycemia 
increased sorbitol  osmotic
damage
A) ATHEROSCLEROSIS
 Example of diabetic macroangiopathy
 AGEs trap mLDL in large vessels and also glucose
increases formation of mLDL  atherosclerosis
o Strokes/TIA
o CAD: angina, MI
o Peripheral vascular disease: claudication,
arterial ulcers, poor wound healing,
gangrene
A) DIABETIC KIDNEY DISEASE
 Example of diabetic microangiopathy
 AGEs damage to glomerulus and arterioles 
ESKD
o Afferent arteriole: decreased renal blood
flow and ischemia
o Efferent arteriole: hyperfiltration and
albuminuria
o BM: glomerulosclerosis
 Decreased RBF, hyperfiltration
contribute to glomerulosclerosis
o All  renal failure
 Renal arterioles:
o Possible AGEs  crosslink collagen 
hyaline arteriosclerosis (also seen in HTN)
 Thickening of arterioles
o Efferent rarely seen except DM
 Proteinuria in diabetics:
o Annual screening for albuminuria because
early indicator of kidney disease
o Proteinuria is indication of ACE-I
 Possible dilation of efferent
arteriole  reduction in
hyperfiltration  reduce
progression to ESRD
 Glomerular BMs:
o Visible on EM
o AGEs  diffuse BM thickening  can
mesangial (cells in matrix that surround
capillaries) proliferation 
fibrosis/scarring
 Diffuse glomerulosclerosis:
o Deposits of proteins (collagen IV) diffuse
on BMs of glomerular capillary loops
o Also occurs with aging and hypertension
o Severe  nephrotic syndrome
 Nodular glomerulosclerosis:
o Nodules form in periphery of glomerulus in
mesangium
o Rarely occurs outside of DM
o Kimmelstiel-Wilson nodules hallmark
 Clinical presentation:
o Often asymptomatic, foamy urine
o Initially microalbuminura 
macroproteinuria and nephrotic syndrome
 Treatment:
o Antihypertensive: ACE inhibitors or ARBs
o Second-line can be added including
diuretics or calcium channel blockers
B) CATARACTS
 Sorbitol accumulates in lens  increased
osmolarity  fluid into lens  opacification
B) DIABETIC NEUROPATHY
 Sorbitol accumulates in Schwann cells (myelinating
cells of peripheral nerves)  osmotic damage
 Metformin also decreases absorption of vitamin
B12 at terminal ileum
 Clinical presentation:
o Classically ‘stocking-glove’ sensory loss
 Longest axons affected most
  Often feet/legs
 Worse distally; better proximally
o 1) loss of vibration sense, proprioception
o 2) impairment of pain, light touch, temp.
o Motor symptoms usually less significant
o Autonomic neuropathy:
 Erectile dysfunction, urinary
retention or incomplete emptying
 Postural hypotension
 Delayed gastric emptying
(gastroparesis), nausea, abdominal
bloating, loss of appetite
 Pupillary dysfunction
 Treatment:
o Pain management with anticonvulsants
(pregabalin, gabapentin, valproate) or
antidepressants (TCA, SNRI)
AB) DIABETIC FOOT DISEASE
 Peripheral vascular disease (ischemia) + neuropathy
can  ulcers, infection, amputation
o Cannot feel small cuts and poor blood flow
does not allow wounds to heal
o Maul perforans: painless ulcers over
pressure points, heel or head of metatarsals
 Secondary infection may lead to
cellulitis and osteomyelitis
o Charcot foot: deformation of joints and
bones, tarsus and tarsometatarsal common
 Acute inflammation
 Chronic painless bone deformities,
midfoot collapse, osteolysis
 Ulcer treatment:
o Surgical debridement
o Wound management with wound dressing
o Mechanical offloading
o Antibiotics if become infected
o Interventional or surgical revascularization
in patients with PAD
o Amputation if all else fails or severe life-
threatening complications
AB) DIABETIC RETINOPATHY
 Can cause blindness
 Pathophysiology:
o Capillary BM thickening (AGEs)
o Hyaline arteriosclerosis
o Pericyte degeneration from osmotic
damage due to sorbitol accumulation
 Cells that wrap capillaries
 Microaneurysms  rupture 
hemorrhage
o Retinal ischemia  neovascularization
 Ophthalmological findings:
o Microaneurysms, hemorrhages
o Exudates
 Leakage proteins, lipids
o Cotton-wool spots
 Nerve infarctions
 Occlusion of precapillary arterioles
o Vessel proliferation (proliferative
retinopathy)
 Retinal ischemia  new vessel
growth  damage retina
 “Neovascularization”
o Macular edema
 Symptoms:
o Asymptomatic until very late stages
o Visual impairment and progression to
blindness
 Treatment:
o Nonproliferative: focal photocoagulation
(corrects ischemic hypoxia), anti-VEGF
o Proliferative and severe nonproliferative:
panretinal photocoagulation over numerous
appointments, vitrectomy if traction RD
and vitreal hemorrhage
o Macular edema: same as nonproliferative
DIFFERENTIAL COMPLICATIONS
DIABETIC KETOACIDOSIS
 Life-threatening more common in T1DM
 Often precipitated by infection/trauma
 Pathophysiology:
o Requires low insulin (more common in T1)
o Low insulin leads to high glucagon
o In trauma and infection, high EN
o Low insulin + high glucagon + high EN
 increased glucose and lipolysis 
increased ketone bodies  urine ketones
and glucose
 Increased glucose:
o Polyuria  dehydration (low BP) and/or
hypophosphatemia
 Ketone bodies:
o Acetyl-CoA from FAs can normally
combine with oxaloacetate to become
citrate
 1) In low insulin/high EN,
oxaloacetate driven toward glucose
 2) FAs  NADH  favors
conversion of oxaloacetate to
malate
 TCA stalls  increased acetyl-
CoA  ketone production
o One is acetone  fruity breath
o Some ketone bodies acids  acidosis 
hyperkalemia and hypophosphatemia
 Acidosis shifts phosphate to
extracellular fluid  phosphaturia
caused by osmotic diuresis
 High EN and acidosis  slowed GI motility 
abdominal pain, nausea, vomiting
 Clinical presentation:
o Abdominal pain, nausea, vomiting
o Dehydration, fruity smell
o Hyperglycemia, hyperkalemia
o Elevated plasma/urine ketones, glucosuria
o AG metabolic acidosis  Kussmaul
breathing
 Hyperventilating to blow off CO2
 Complications:
o If phosphate becomes too low  loss of
ATP  muscle weakness (resp. failure)
and heart failure (decreased contractility)
o Hyperkalemia  arrhythmias
o Cerebral edema (mechanism poorly
understood but common cause of death)
o Mucormycosis
  Caused by Rhizopus sp., Mucor sp.
 Starts in sinuses and spreads to
adjacent structures
 Thrives in high glucose,
ketoacidosis
 Patient with DKA in recovery
phase develops fever, headache,
eye pain
 Treatment:
o Insulin lowers glucose and shifts K into
cells
o IV fluids treats dehydration
o Careful monitor glucose
 Continue insulin until acidosis
resolves, so may need to add
glucose
o Careful monitor K
 Total body K is low despite
hyperkalemia because lost in urine
 Insulin can lead to hypokalemia
 Usually need to administer K in IV
HYPERGLYCEMIC HYPEROSMOLAR SYNDROME
 Life-threatening more common in T2DM
 Pathophysiology:
o Markedly elevated high glucose (can be
>1000)  diuresis  severe dehydration
o Differences from DKA:
 Few/no ketone bodies (insulin here)
so no acidosis either
 Very high serum osmolarity 
CNS dysfunction
 Clinical presentation:
o Dehydration
o Mental status changes: confusion, coma
 Treatment:
o Similar to DKA (insulin, IVF)
T1DM TREATMENT
 Treated mainly with insulin
TYPES
 All administered SQ at home
 Vary by time to peak, peak effect, duration of
action
 Fast peak, short duration  slow peak, long
duration:
o Rapid acting insulin  regular insulin 
NPH insulin  Detemir  Glargine
INSULIN HEXAMERS
 Insulin forms hexamers in body
o Six linked together = stable structure
 Activity relates to speed of absorption
o Hexamers  slower onset of action
o Monomers  faster onset of action
INSULIN ANALOGS
 Analogs do not contain human insulin molecules
o Modified insulin structure
o Rapid-acting, detemir, glargine
 Regular insulin, NPH contain human insulin
RAPID ACTING (PRANDIAL) INSULIN
 AA-modified human insulin
 Aa mods reduce hexamer/polymer formation
o Onset: 15 minutes
o Peak: 1 hour
o Duration: 2-4 hours
 Often used pre-meal
REGULAR INSULIN
 Synthetic analog of human insulin made by
recombinant DNA techniques
o Onset: 30 minutes
o Peak: 2-3 hours
o Duration: 3-6 hours
 Only type given IV
o Regular and rapid-acting have same onset
when given IV; rapid only faster when SQ
 Commonly used in hospitalized patients
o Blood sugar elevated commonly with
infection/surgery
o “Regular insulin sliding scale”: sliding
scale dose given based on finger stick blood
sugar
 IV insulin also used in DKA/HHS and
hyperkalemia (given with glucose)
NPH INSULIN
 Regular insulin combined with neutral protamine
 Slows absorption
o Peak: 4-8 hours
o Duration: 12-16 hours
 Historical mainstay, been replaced by other types
GLARGINE
 Insulin with modified aa structure
o Soluble in acidic solution for dosing
o Precipitates at body pH after SQ
o Insulin molecules slowly dissolve from
crystals
 Low, continuous level of insulin
o Onset: 1-1.5 hours
o Duration: 11-24 hours
 Injected OD (“basal/background insulin”)
DETEMIR
 Insulin with FA side chain
o Aggregation in subcutaneous tissue
o Also binds reversibly to albumin
 Slowed absorption but less continuous
o Onset: 1-2 hours
o Duration: >12 hours
 Injected OD or BID
o May cause less weight gain
INTEGRATED REGIMEN
 Used to be NPH with insulin
 Now OD glargine or detemir with rapid-acting at
mealtimes
SIDE EFFECT
 Major of all insulin regimens is hypoglycemia:
o Tremor, palpitations, sweating, anxiety 
pts will eat cookie/cracker/juice
o Seizure, coma if severe
 Adjust dosages, frequency to 1) avoid low glucose
but 2) maintain lowest possible HbA1c value
 *Always check blood sugar in unconscious
patients because easily reversible cause
 Another major side effect is weight gain:
 Occurs in most patients because promotes FA and
protein synthesis
T2DM TREATMENT
 Initial: oral or SQ drugs that 1) boost amount of
insulin production or 2) increase sensitivity
 Advanced: insulin required
LIFESTYLE MODIFICATIONS
 First line in non-severe newly diagnosed T2DM
 Blood glucose control
 Weight loss, exercise improves glucose levels
o Usually 3-6 month trial if initial A1c not
markedly increased
 Blood pressure control
 Improved lipid profile with statin therapy
  exercise, smoking cessation, balanced diet and
nutrition esp. high-fibre, self-management
education
ALGORITHM
 HbA1C target <7% (53 mmol/mol)
 If target not reached within 3 months with
conservative measures, go to next step
 1. Lifestyle modification
 2. Monotherapy
o Drug of choice is metformin
o If contraindicated, sulfonylurea
 3. Dual therapy
o Metformin +
o Oral antidiabetic: dipeptidyl peptidase-4
inhibitor; sulfonylurea, thiazolidinedione,
meglitinides, SGLT-2 inhibitors, a-
glucosidase inhibitors, amylin analogs
o GLP1- receptor agonists
o Or basal insulin
 4. Triple therapy
 5. Combination injectable therapy
o Metformin + basal insulin + mealtime
insulin or GLP-1 receptor agonist
SCREENING
 Regular monitoring of weight, abdominal
circumference, blood pressure, blood lipids,
HbA1C, renal function
 Yearly eye exam more frequently in patients with
abnormal findings
 Annual urine testing for microalbuminuria
 Neuropathy: tuning fork (vibration goes first),
pinprick and temperature assessment
 Foot exam for neuropathy and ulcers
ORAL/SQ ANTIDIABETIC AGENTS
BIGUANIDES (METFORMIN)
 Many nitrogen molecules
 Oral therapy with unknown exact mechanism
 Primarily decreases hepatic glucose production
(inhibits GNG)
 Lowers serum free FAs  decreases substrates for
GNG, decreases TG, small decrease in LDL, small
increase in HDL
 Other effects
o Reduced glucose absorption from GI tract
o Direct stimulation of glycolysis in tissues
 increased glucose uptake
o Reduced glucagon levels
o  leads to increased insulin
effect/sensitive.
 Insulin falls slightly in therapy
 Usually 1st line therapy in T2DM
o Associated with weight loss
o Rarely causes hypoglycemia unlike insulin
or sulfonylureas
o Can be given to patients with advanced
T2DM because not dependent on beta cells
 Adverse effects:
o Most common GI upset:
 Nausea, vomiting, sometimes
metallic taste in mouth
o Rarely lactic acidosis: can be life-
threatening
 Controversial mechanism
 Possibly because increase
conversion of glucose to lactate 
beneficial for lowering glucose 
but excess is LA
 Metformin not used in conditions that are always
associated with LA:
o Renal insufficiency, liver disease or alcohol
abuse, acute HF, hypoxia, serious acute
illnesses
o Not used in low GFR, held when patients
acutely ill, held during IV contrasts which
can cause renal insufficiency
SULFONYLUREAS
 Urea attached to sulfonyl moiety
 Oral therapy
 Bind to sulfonylurea receptor in beta cells  closes
ATP-dependent K+ channels  raises RMP 
depolarization  Ca2+ influx  release insulin
o More sensitive to glucose/amino acids
o Increases insulin release “secretagogues”
 Each generation more potent
o Decreased usage  decreased side effects
o 1st gen: tolbutamide, chlorpropamide,
tolazamide (not used anymore)
o 2nd gen: glyburide, glipizide
o 3rd gen: glimepiride
 Adverse effects:
o Hypoglycemia, so metformin preferred
 Glucagon falls
 May occur w/ exercise/skip meals
o Weight gain
 Due to insulin release
 Adverse effects of chlorpropamide:
o Flushing with alcohol consumption due to
inhibition of acetaldehyde dehydrogenase
o Hyponatremia due to increased ADH
activity
MEGLITINIDES (REPAGLINIDE, NATEGLINIDE)
 No sulfur moiety so used in sulfa allergy
 Oral therapy
 Different chemical structure to sulfonylureas but
similar mechanism
 Short acting, given prior to meals
 Adverse effect: hypoglycemia
THIAZOLIDINEDIONES/GLITAZONES
 Oral therapy all ending in glitazone
 Decreases insulin resistance
 Bind to peroxisomal proliferator activated receptor
(PPAR-y) in nucleus of adipose (highest), muscle,
 liver, other tissues  TZD/PPAR bind retinoid X
receptor (RXR)  entire complex modifies gene
transcription
o Fibrates activate PPAR-a which lower TGs
 Potential mechanisms:
o 1) Upregulate GLUT-4
o 2) Upregulate adiponectin (adipocyte
secretory protein)  increased insulin
sensitivity via several mechanisms
o 3) Decrease TNF-a which is associated with
resistance
 Adverse effects:
o Weight gain
 May cause proliferation of
adipocytes + edema
o Edema
 Due to PPAR-y effects in nephron
 increased Na retention
 Risk of pulmonary edema, so not
used in advanced HF
o Risk of hepatotoxicity
 Troglitzone removed
GLUCOSIDASE INHIBITORS
 Three classes: acarbose, miglitol, voglibose
 Taken orally before meals  less spike in glucose
 lowers A1c AND less insulin used (insulin
sparing)
 Competitive inhibitors of intestinal a-glucosidases
which hydrolyze 1,4 bonds in glucose molecules 
slows absorption of glucose  less in upper small
intestine, more in distal small intestine
o Brush border enzymes that hydrolyze
starches, oligosaccharides, disaccharides
e.g. sucrase, maltase, glucoamylase,
dextranase
 Adverse effects:
o GI upset: flatulence, diarrhea
AMYLIN ANALOGS (PRAMLINTIDE)
 Physiological role of amylin not understood
 Given SQ with meals AND always together with
insulin (type 1 or type 2)
 Amylin analogs has several effects:
o Suppresses glucagon release
o Delays gastric emptying, reduces appetite
o  allows insulin to work more effectively
 Side effect:
o Hypoglycemia  need to decrease insulin
o Nausea
GLP-1 ANALOGS
 Exenatide: usually given SQ prior to meals but
once weekly version available
 Liraglutide: SQ OD
 Similar function to GLP-1
 Adverse effects: nausea, vomiting, diarrhea
DPP-4 INHIBITORS
 Oral drugs OD
 DDP-4: dipeptidyl peptidase 4
o Enzyme expressed on many cells
o Inhibits release of GIP and GLP-1 
increased levels of these
 Adverse effects: infections (e.g. urinary,
respiratory) hypothesized due to immune
disturbances
SGLT2 INHIBITORS
 Oral drugs OD
 SGLT2:
o Expressed in PCT reabsorbs ~90% glucose
 Inhibition of SGLT2  loss of glucose in urine 
mild osmotic diuresis
 Good effects:
o Lead to mild weight loss due to glucosuria
o May improve outcomes in HF due to
diuresis
 Adverse effects:
o Vulvovaginal candidiasis and UTIs due to
glucose as food for fungi and bugs
o Not recommended with advanced renal
disease
TIPS
 Renal failure: avoid metformin (LA)
 Advanced HF: avoid metformin (LA ) and TZDs
(fluid retention)
 Insulin generally safe with any comorbidity
MONITORING WITH HBA1C
 Too high = increased risk of complications  more
tx
 Too low = risk of hypoglycemia  less tx
 Goal <=7.0% used in most patients
NONPURULENT SSTI
 Erysipelas: superficial skin infection, upper dermis
 Cellulitis: local infection, deep dermis and
subcutaneous tissue
ETIOLOGY
 Beta-hemolytic streptococci: mostly group A
streptococcus
 Less common
o S. aureus
o Pasteurella multocida (gram-, encapsulated
coccbacillus), secondary to dog/cat bites
PATHOPHYSIOLOGY
 Entry most commonly minor skin injury (rhagades,
athlete’s foot, ulcers, blisters, insect bites)
 Erysipelas can spread via superficial lymphatic
vessels
 Can progress to deeper tissues: cellulitis,
necrotizing fasciitis, osteomyelitis
CLINICAL FEATURES
 Erythema, edema, warmth, tenderness
o Common locations: lower limbs and face
o Erysipelas: raised, sharply demarcated
o Cellulitis: poorly defined with induration
 Additional
o Cutaneous lymphatic edema
o Lymphangitis: red streaks radiating from
lesion following direction of lymph vessels
o Lymphadenitis: swollen, tender, regional
lymph nodes
o Purulent exudate
DIAGNOSIS
 Usually clinical
 Lab
o CBC for possible leukocytosis
 o BMP for signs of underlying risk factors
(e.g. DM, CKD)
o Inflammatory markers may be elevated
 Imaging
o Soft tissue U/S
o CT/MRI considered if concern for
complications (e.g. pyomyositis,
osteomyelitis)
TREATMENT
 Empiric antibiotic against streptococci and S.
aureus mainstay of treatment for nonpurulent
o Mild oral: penicillin VK, clindamycin
o Moderate IV: penicillin, ceftriaxone,
cefazolin, clindamycin
o Severe IV: vancomycin + pip/tazo
 Supportive care NECROTIZING SOFT TISSUE INFECTIONS
o Elevation of affected limbs
o Acute pain management  Life-threatening infection involving necrosis of
ORBITAL CELLULITIS tissue
 Infection of orbital contents, such as fat and  Superficial and/or deep tissues (necrotizing
extraocular muscles cellulitis, fasciitis, or myositis)
 The eye globe is not affected o Fasciitis: superficial and deep fascia and
ETIOLOGY overlying subcutaneous fat
 Most commonly upper resp. infection, specifically  Fournier gangrene: fasciitis of external genitalia
bacterial rhinosinusitis that can spread rapidly to anterior abdominal wall
 The ethmoid sinuses and orbits are separated by a and gluteal muscles
thin bony plate lamina papyracea, route of infection ETIOLOGY
 Other causes:  Polymicrobial: wide variety of aerobic and
o Acute dacryocystitis anaerobic pathogens, often of intra-abdominal or
o Infection of teeth, middle ear, face genitourinary infection (E. coli, bacteroides spp.)
o Infected mucocele  Monomicrobial: commonly group A streptococcus,
CLINICAL FEATURES peptostreptococcus spp., S. aureus
 Proptosis and ophthalmoplegia  Fournier gangrene: usually mixed with facultative
 Fever and malaise pathogens (E. coli, klebsiella, enterococcus) and
 Reduced vision: diplopia, RAPD, dyschromatopsia anaerobic bacteria
 Inflammation  Clostridial myonecrosis: produces toxins and gas
gangrene (crepitus)
o Ocular pain PATHOPHYSIOLOGY
o Eyelid swelling and erythema  Fasciitis: rapidly transits muscle fascia  vascular
o Chemosis (conjunctiva edema) occlusion, tissue necrosis, ischemia
DIAGNOSIS  Skin appears unaffected initially  erythematous,
 Primarily clinical reddish-purple to bluish-gray, indurated, swollen,
 Lab shiny, warm  skin breakdown in 3-5 days
o CBC for leukocytosis accompanied by bullae and cutaneous gangrene
o Blood and tissue fluid cultures  Pain secondary to thrombosed small vessels and
 Imaging destruction of superficial nerves in subcutaneous
o CT to confirm diagnosis and complications; CLINICAL FEATURES
orbital abscess or intracranial extension  Fever, chills, altered mental status
TREATMENT  Cutaneous findings
 Empiric IV antibiotic treatment o Diffuse erythema mimicking cellulitis but
 If intracranial extension suspected, metronidazole to does not respond to initial antibiotic
cover anaerobes o Spread along fascia before superficial
 Surgical drainage if abscess cutaneous 
COMPLICATIONS  Extreme tenderness and pain
 Blindness due to involvement of ON disproportionate to area of
 Brain abscess erythema
 Cavernous sinus thrombosis rare  Significant induration
o Crepitus: production of methane and CO2
by bacteria
o Bullae
o Purple skin discoloration (necrosis)
 Loss of sensation
DIAGNOSIS
  Usually by visualization of tissue during surgery,  Secondary to infected foot ulcer
and causative pathogen is by deep tissue culture  Iatrogenic (e.g. postoperative
 **following should not delay surgery infection of joint implant)
 Lab CLINICAL MANIFESTATIONS
o CBC for leukocytosis  Suspect in patients with focal symptoms (point
o Inflammatory markers elevated tenderness) and nonspecific signs of inflammation
o CK elevated  Acute: days or weeks
 Microbiology o Pain at site of infection possibly related to
o Blood cultures (two sets) movement
o Gram stain and cultures from deep tissue o Point tenderness, swelling, redness, warmth
 Superficial not accurate o Malaise, fever, chills
 Imaging o Common locations
o CT/MRI for gas in soft tissue, fascial  Infants: long bone metaphysis,
thickening and edema joints
o X-ray may detect gas  Children: long bone metaphysis
TREATMENT  Adults: vertebral involvement
 Immediate surgical exploration with debridement  Chronic: months or years
and obtaining deep tissue samples o Recurrent pain with asymptomatic periods
 Broad-spectrum antibiotic therapy o Swelling, redness
o Vancomycin + pip/tazo o Associated with avascular bone necrosis
o If evidence of toxic shock syndrome and sequestrum formation (necrotic
include antitoxin active antiobiotics (e.g. fragment detached from original bone)
clindamycin)  Brodie abscess: intraosseous abscess
COMPLICATIONS o Fibrous and granulation tissue formation
 Severe necrosis requiring amputation around pyogenic (pus-forming) focus
 Sepsis o Commonly distal femur and proximal tibia
 Disseminated intravascular coagulation o Frequently asymptomatic or only mild
 Organ dysfunction symptoms
o X-ray, MRI – well-circumscribed, thick-
OSTEOMYELITIS walled cystic lesion in metaphysis and
epiphysis of long bones
DIAGNOSIS
 Infection of bone and bone marrow, though osteitis  Lab
is technically of bone o CRP and ESR, possible leukocytosis
EPIDEMIOLOGY
o Blood cultures before first antibiotic
 Hematogenous osteomyelitis
 Imaging
o More common in children and adolescents
o X-ray <2 weeks of symptom onset no
o Vertebral osteomyelitis occurs mainly in pathological findings, later bone
adults aged >50 years destruction, sequestrum formation,
 Exogenous osteomyelitis periosteal reactions
o More common in adults o MRI signs of inflammation <=5 days after
ETIOLOGY onset, showing cortical destruction, bone
 Local risk factors marrow inflammation
o Poor tissue perfusion, open fractures,  Biopsy only one that is confirmatory
severe soft tissue injury o MRI/CT-guided needle or open biopsy,
 Systemic risk factors followed by gram staining, culture,
o Impaired immunocompetence histology
o Systemic diseases (DM, atherosclerosis) o Should be performed whenever feasible
o IV drug use before performing antibiotics
PATHOGENS DIFFERENTIAL
 S. aureus most common  Septic arthritis
 S. epidermis (patients with prosthetics),  Bone tumors (Ewing sarcoma, osteoid osteoma)
pseudomonas aeruginosa, mycobacterium  Avascular bone necrosis
tuberculosis, Pasteurella multocida (cat and dog TREATMENT
bites)  Should not be delayed especially in children
 Fungi e.g. candida because bone development
PATHOPHYSIOLOGY  Antibiotics: vancomycin plus antipseudomonal
 Hematogenous cephalosporins or fluoroquinolones
o Usually single pathogen  Surgical: debridement of necrotic bone and tissue
 Exogenous refractory to antibiotics, drainage of abscess,
o Usually multiple pathogens infected prosthetic removal, revascularization in
o Posttraumatic: following deep injury case of poor wound healing
o Contiguous: from adjacent tissue
CHRONIC VENOUS INSUFFICIENCY

 Protracted valvular incompetence of superficial,

deep, or perforating veins that connect them 
reflux or obstruction of venous flow  venous
hypertension of lower extremities (pain, edema,
venous microangiopathy)
o Some patients hyperpigmentation because
RBCs extravaste into tissue
o Some lipodermatosclerosis, thickening
from fibrosis of subcutanoues fat
 Superficial incompetence
o Weakened or abnormally shaped valves or
widened venous diameter
o Leaky valve most cases near termination of
greater saphenous into common femoral
vein
o Congenital, trauma, prolonged standing,
hormonal changes, thrombosis
 Deep vein dysfunction
o Previous DVT resulting in inflammation,
valve scarring and adhesion, luminal
narrowing
o Perforating vein valvular failure  higher
pressure enters superficial system 
dilation prevents proper closure of valve
cusps
 Risk factors: age, DVT, sedentary, OCPs, leg
injury, hypertension

AMPUTATION

 Debridement/minor amputation
o Good blood supply but infected
o Small vessel disease and gangrenous toes
o Neuropathic foot with little arterial disease
o Osteomyelitis with little arterial disease
 Primary amputation
o Wet gangrene
o Life-threatening sepsis
o Extensive muscle necrosis
o Revascularization technically impossible
o Bed-ridden patients/functionally useless
limbs

Review congestive heart failure and other arrhythmias
Metabolic stuff from Ali Khan
APPROACH TO ACID-BASE DISORDERS
 1. See pH relative 7.4, PaCO2 relative 40,
bicarbonate relative 24, AG relative 12 meq/L
 2. If pH and PaCO2 in opposite direction, then
primary respiratory
o If in same direction, then primary metabolic
 3. Calculate compensation to check for concurrent
primary disorder in other system
o Metabolic acidosis: decrease in HCO3- 1,
decrease pCO2 1.2
o Metabolic alkalosis: increase in HCO3- 1,
increase pCO2 0.8
o Respiratory acidosis: increase in pCO2 10
 Acute: increase HCO3- 1
 Chronic: HCO3- 3
o Respiratory alkalosis: decrease in pCO2
10
 Acute: decrease HCO3- 2
 Chronic: decrease HCO3- 4
 4. Calculate anion gap if metabolic acidosis
o AG = NA - Cl - HCO3-
ACUTE KIDNEY INJURY
 Azotemia: an excess of urea and other nitrogenous
wastes in the blood due to kidney insufficiency
DEFINITION
 Abrupt loss of kidney function which results in:
o Retention of urea and other nitrogenous
waste products (most important is
creatinine), and
o Dysregulation of volume and electrolytes
 Quantitatively,
o Cr rising and/or UO dropping off
o Can use RIFLE, AKIN, or KDIGO
RIFLE criteria: proposed by Acute Dialysis Quality
Initiative (ADQI) group
o Risk, injury, failure, loss of function, end-
stage renal disease
o Problems: baseline creatinine not always
available, early damage not reflected by
creatinine rise, no easy way of measuring
GFR clinically, urine output data not
always available, imbalance between
SCr/GFR and urine output criteria, GFR-
estimating equations should only be used
in steady state  not applicable to AKI
 Cr takes time to reach steady state
 AKIN staging in 2007: removed L and E of rifle
o From stages 1-3
o Creatinine: increased Cr.*1.5 or >=0.3
mg/dL | Cr*2 | Cr*3 or Cr >= 4mg/dL
o Urine output: UO<0.5 mL/kg/hr*6h |
<0.5mL/kg/hr*12hr | <0.3mL/kg/hr *24h
OR anuria * 12hr
 KDIGO guideline 2012
o From stages 1-3
o Creatinine: 1.5-1.9*baseline OR >=0.3
mg/dL increase | 2-2.9*baseline |
3*baseline OR increase >= 4.0 mg/dL OR
initiation of RRT OR in patients <18 years,
decrease eGFR <35/mL/min/1.73m2
o Urine output: UO<0.5 mL/kg/hr*6-12hr |
<0.5mL/kg/hr*12-24hr |
<0.3mL/kg/hr*>24h OR anuria*>12hr
ETIOLOGY
 Pre-renal: not enough circulation reaching kidneys
o Hypovolemia: bleeding, GI fluid loss,
burns, diuretics
o Distributive: nephrotic syndrome,
cirrhosis, ileus, vasodilation (sepsis,
anaphylaxis, etc.)
o Decreased cardiac output
o Constriction of renal arteries:
vasopressors, cocaine
 Renal (intrinsic): inside kidneys
o Anatomic components: tubular,
glomerular, interstitial, vascular
o Tubular:
 Acute tubular necrosis (ATN)
 Ischemic: prolonged hypoperfusion
of kidneys
 Nephrotoxic:
 Exogenous: myoglobin,
proteins, etc.
 Exogenous: antibiotics,
contrast, metals, etc.
 Pathology: dilation of tubules,
flattening of epithelium,
interstitium relatively unaffected,
contrast AIN
 Epithelium good at regeneration 
recovery of function in patients
whose underlying problem solved
o Glomerular:
 Acute glomerulo-nephritis: lupus
nephritis, post-strep GN, etc.
  Rapidly progressive glomerulo-
nephritis (RPGN)
o Interstitial:
 Acute interstitial nephritis (AIN):
 ‘kidney allergy’
 Commonly drugs (antibiotics,
NSAIDs) and diseases (legionella,
sarcoidosis)
o Vascular:
 Thromboemboli (blood clot)
 Atheroemboli (cholesterol)
 Microangiopathies: scleroderma,
DIC, HUS-TTP, pre-eclampsia,
malignant HTN, vasculitis
 Post-renal: blockage of urine flow that obstructs all
functioning kidneys
o Renal pelvis: stone (staghorn), papilla
(necrosis)
o Ureter: stone, blood lots, retroperitoneal
fibrosis
o Bladder: prostate, stone, spasm
 Most common etiologies: ATN, pre-renal, acute-on-
chronic, obstructive
EPIDEMIOLOGY
 Seen in 1.9% of all hospitalizations
 Affect 40-70% of ICU
 If require dialysis, associated with 45-65%
mortality
 It is not AKI that causes mortality
o People who develop AKI in ICU have more
severe illness (e.g. sepsis) than those with
same illness but did not develop AKI
o If patients don’t die from illness, good
chance kidney function will return
 If have AKI in the past, more likely to develop
CKD
PATHOPHYSIOLOGY
 GFR = KF [(PGC - PT)] - [(ΠGC - ΠT)]
o KF is capillary SA and permeability
 K = filtration coefficient, P = hydrostatic pressure,
Π = oncotic pressure, GC = glom. capillary, T =
tubule
o Decreased PGC in prerenal
o Increased PT in postrenal but both kidneys
must be affected
o For intrinsic:
 Acute interstitial nephritis:
o Cause of hypersensitivity: drug alters host
tissue to become immunogenic | drug or
metabolite immunogenic | drug or
metabolite bound to self-protein (hapten)
immunogenic | antibody bound to drug or
metabolite immunogenic
o Host response either type I (IgE-mediated,
early) or type IV (T cell-mediated, late)
o Process endocytosed by tubular epithelial
cells  1) activate macrophages and
fibroblasts in kidney interstitium 
contribute to inflammatory response | 2)
present to dendritic cells  activated DCs
migrate to lymph node and present antigen
via MHC II to naïve T cell
 Cytokines facilitate immune
response including recruiting
infiltrating inflammatory cells such
as neutrophils
 If not halted early, damage by
immune cells and fibrosis (matrix
synthesis) by fibroblasts
 Ischemia/reperfusion: tubular injury from decreased
blood flow  activate tubuloglomerular feedback
 afferent arteriolar constriction (decreased P GC)
 Toxin-mediated: oxidative stress and ATP depletion
 release of vasoactive substances and mesangial
contraction (decreased KF)
 Cellular injury: denudement of basement membrane
 back leak of solutes (increased ΠGC)
 Tubular obstruction: secondary to cell injury 
sloughing of cellular matter and Tamm-Horsfall
protein casts (increased PT)
INVESTIGATIONS
 History:
o Prior renal function (history of AKI/CKD)
o Decreased perfusion: hypotension, bleed,
sepsis, ileus, ascites, heart failure
o Exposure to toxins: drugs (antibiotics,
NSAIDs), IV contrast
o Other stressors: ACE inhibitor/ARB make
things worse but do not cause AKI
 Physical exam:
o Volume status (BP incl. postural), JVP
 Edema is misleading; someone can
be edematous but hypovolemic
o Pericardial rub / CNS: severe
o Livedo reticularis  vasculitis
o Rash/fever  AIN
o Enlarged bladder  post-renal
o Urine: amount, colour
 Investigation:
o Most important: full CBC with differential,
urine dipstick, urine microscopy/sediment,
renal ultrasound, serum calcium
 Creatinine time course
 Urea (relative to creatinine)
o Electrolytes, Ca, pH
o Urinalysis
 Blood, protein, SpGr
 UNa, FENa, UOsm
o Special tests: RBx, ANCA, antiGBM
 Biopsy: confirmatory
APPROACH
 Context:
o ICU vs. office, old vs. young, M vs. F
 Rule out post-renal and pre-renal:
o Insert urinary (Foley) catheter, may get
renal US  cannot be faulted unless rare
cases
 o Give trial of IV fluids (fluid challenge)
 Prevent worsening of ARF:
o Stop medications that lower GFR
(NSAIDS, ACE-I, ARB)
o Avoid giving diuretics just to make urinary
output >=30 mL/hour
 Consider other causes (ATN by exclusion)
CLINICAL PRESENTATION
 Depends on etiology of AKI
 Because nephrons not working, hyperkalemia and
metabolic acidosis (not excreting either)
 Pre-renal due to hypovolemia
o History of volume loss, low BP (or postural EPIDEMIOLOGY
drop) and flat JVP
 Post-renal due to enlarged prostate
o History of decreasing urinary flow, then
sudden anuria, large bladder, large prostate
 Renal AKI due to AIN
o History of new drug, now rash and joint
pain
 Renal AKI due to RPGN such as GPA-W
o History of sinus problems with
cough/hemoptysis
TREATMENT
 Address reversible causes
o If obstructed: relieve obstruction
o If hypovolemic/mal-distributive: give IV
fluids
 Fluids can be colloidal
o If medications/toxin: remove
o If immune: consider steroids
 Deal with complications
o If volume overloaded: avoid giving fluids
o If hyperkalemic or academic: treat those
o May start dialysis/CRRT while waiting
 Many kinds: dialysis vs.
hemofiltration, continuous vs.
intermittent, no clear winner
 Educate patient to prevent AKI from recurring
 Overall: no specific treatment except wait for
recovery
INDICATIONS FOR ACUTE DIALYSIS
 AEIOU: acidosis, electrolytes, intoxications,
overload, uremia
 Fluid/electrolyte problems refractory to therapy
o Volume overload, hyperkalemia (will stop
heart), severe metabolic acidosis
 Severe uremic symptoms
o Encephalopathy, pericarditis
 Certain intoxications
o Aspirin, lithium
CHRONIC KIDNEY DISEASE
DEFINITION
 General term for heterogeneous disorders that affect
the structure and function of the kidney, with
progressive decline in GFR
 1. Kidney damage (either structural or functional)
for >=3 months, with or without decreased GFR,
manifest as either:
o Pathological abnormalities, or
o
Markers of kidney damage, including
abnormalities in composition of blood or
urine, or abnormalities in imaging tests
 2. GFR <60mL/min/1.73m2 for >=3 months, with or
without kidney damage
CLASSIFICATION
 GFR categories from G1-G5
o G5 = kidney failure = <15 mL/min
 Albuminuria categories from A1-A3
o A3 = severely increased = >30 mg/mmol
 Highest risk: A1 G4 (<3, 15-29), A2 G3b (3-30, 30-
44), A3 G3a (>30, 45-59)
 CKD is silent disease affecting ~10% adults
 Approximately 2/3 of people with CKD will have
major risk conditions
o Diabetes, HTN, or both
 CKD prevalence is growing because # of people
diagnosed with type 2 DM, aging population
PATHOGENESIS
 Multi-hit hypothesis: multiple factors that induce
nephron loss
o Decreased nephron endowment: risk is
lower birth weight
o Acquired nephron loss: primary renal
disease, hereditary nephropathies, aging,
nephrotoxins
 1. Early on, remaining nephrons  compensatory
hypertrophy and hyperfiltration + activation of
RAAS via vasoactive hormones, cytokines, growth
factors
o Increased PGC and single nephron GFR
o Risk factors that promote hyperfiltration
state: DM, obesity, high-protein diet,
anemia
 2. AGII + hyperfiltration state  proteinuria,
dyslipidemia, nephrotoxic inflammation and
remodelling
 3. Later on, focal segmental glomerulosclerosis
(FSGS) and tubular interstitial fibrosis (TIF)
o Decreased GFR, decreased urine output,
and systemic complications
 In AD-PCKD: cysts compress blood vessels  low
perfusion  local ischemia  RAAS activation
(doesn’t help) and eventual nephron loss
ETIOLOGY
 Diabetic CKD:
 Non-diabetic CKD:
o Vascular (w or w/o hematuria or
proteinuria)
 Large-vessel disease: renal artery
stenosis
 Small-vessel disease: HTN,
vasculitis, microangiopathy
o Glomerular (hematuria or albuminuria)
 Primary nephritis, autoimmune
disease, systemic infection,
malignancy, drugs, hyperfiltration
(reduced renal mass, obesity)
o Tubulointerstitial (w or w/o proteinuria or
pyuria)
  Autoimmune disease, drugs,
obstruction, post-acute kidney
injury
o Cystic (evident on imaging)
 Autosomal dominant PCKD
 Leading categories: diabetic nephropathy, HTN-
related (renovascular), glomerulonephritis,
autosomal dominant polycystic kidney disease,
other cystic and tubulointerstitial nephropathy
 Risk factors: small gestation birth weight, obesity,
HTN, DM, autoimmune (lupus, rheumatoid
arthritis), advanced age, African ancestry, family
history of kidney disease, previous AKI, structural
abnormalities of urinary tract
INVESTIGATION
 History: HTN, diabetes, NSAIDs, family history of
kidney failure
 Physical examination: BP, abdominal bruits (renal
artery stenosis), palpable kidneys in AD-PCKD
 Assess kidney function (as below)
 Consider kidney biopsy if etiology not clear
ASSESS KIDNEY FUNCTION
 GFR: CKD-EPI equation
 Loss of kidney mass or nephron mass not always
associated with reduction in nephron function
o Adaptive hyperfiltration
 How to measure eGFR:
o Serum creatinine, Cockcroft-Gault formula,
modification of diet in renal diseases
(MDRD), CKD-EPI equations most
popular
o Inulin more for research
 Proteinuria: albumin-to-creatinine ratio (ACR)
o Normal (associated with A1)
 <2.0 mg/mmol in M
 <2.8 mg/mmol in F
o Microalbuminuria (A2)
 2-20 mg/mmol in M
 2.8-28 mg/mmol in F
o Macroalbuminuria (A3)
 >20 mg/mmol in M
 >28 mg/mmol in F
 Urinalysis: blood supports glomerular cause
 Imaging: renal ultrasound
o Size
 <8-9cm length is abnormal
 >2cm between kidneys abnormal
 Small kidney could be congenital,
vesico-ureteric reflux, prolonged
obstruction, renovascular disease
o Cortical thickness thins with CKD
o Echogenicity approaches ‘’ liver with CKD
o Rule out obstruction
o Stone, tumor, cysts: incidental
o Doppler assesses blood flow mainly in
transplantation
KIDNEY FAILURE RISK EQUATION
 Four (mostly used) and eight variable variants
 Gender, age, eGFR, ACR
MANAGING CKD
 Slow loss of GFR, treat underlying condition,
specific treatment, treat complications, prepare for
ESRD
SLOW LOSS OF GFR
 Control BP (<130/80 in DM, <140/90 all others)
 Block RAAS with ACE-I or ARB, especially
diabetic nephropathy or other proteinuric CKD
o Acute decline in GFR, hoping for
subsequent slow chronic decline
o Check K, eGFR 7-10 days after starting,
can tolerate up to 30% in GFR decline
 Dietary protein restriction
o Recommended 0.8-1g/kg/day
 Smoking cessation
TREAT UNDERLYING CONDITIONS
 CVD assessment and treatment
o CVD is leading cause of death in CKD
 DM
o Target HbA1C 7%
 Systemic diseases with renal involvement
 Primary glomerulonephritis, renal vasculitis
o Immunosuppression with corticosteroids,
cyclophosphamide
MANAGEMENT OF COMPLICATIONS
 Stages 1-3 CKD generally asymptomatic
(eGFR>30mL/min)
 Stages 4-5 CKD have clinical manifestations
(<30mL/min/1.73m2)
 1. Impaired Na balance  Na retention and volume
overload: Na restriction, diuretics, anti-HTN
 2. Impaired K excretion  hyperkalemia: K
restriction, avoid NSAIDs, K binders
 3. Impaired H secretion  metabolic acidosis 
sodium bicarbonate (typically <22 mmol/L)
 4. Impaired calcium/phosphate balance  increased
phosphate and PTH, decreased Ca and calcitriol
(active Vit D)  renal osteodystrophy and vascular
calcification if untreated
o Because no activation of vitamin D (so
parathyroid), and absorb calcium
o Increased PO4: phosphate binders (e.g.
calcium carbonate)
o Secondary hyperparathyroidism: active vit
D (in CKD), calcimimetics (in dialysis)
 5. Impaired erythropoiesis  anemia:
erythropoiesis-stimulating agents, iron replacement
END-STAGE RENAL DISEASE
 Accumulation of toxins, fluid, electrolytes normally
excreted leads to uremic syndrome
o Urea and creatinine serve as surrogate
markers for all toxic compounds
 Syndrome leads to death unless treated:
o Dialysis: hemodialysis or peritoneal
o Transplantation: living or deceased donor
o Conservative management: palliation
 Indications for RRT (dialysis, transplant)
o eGFR < 10mL/min/1.73m2 (<15 if diabetes)
o Refractory hyperkalemia, metabolic
acidosis, or fluid overload
o Uremic pericarditis and encephalopathy
o Other non-specific uremic symptoms:
anorexia and nausea, impaired nutritional
status, increased sleepiness, decreased
energy level, attentiveness, cognitive tasks
 Dialysis survival lower with advanced age
  Transplantation is most cost-effective modality
o Longer and better QOL compared to
dialysis
o Early transplantation (pre-emptive or within
1 year of dialysis initiation) best results
HEMODIALYSIS
INDICATIONS
 AKI
 Toxic ingestion
CONTRAINDICATIONS
 Inability to secure vascular access (absolute)
 Difficult vascular access, needle phobia, cardiac
failure, coagulopathy (relative)
PERITONEAL DIALYSIS
INDICATIONS
 Inadequate vascular access
 Prefer self-therapy
CONTRAINDICATIONS
 Absolute: loss of peritoneal function, adhesions
that limit dialysate flow, recent abdominal wounds,
abdominal fistulas, abdominal wall defects
 Relative: abdominal wall infection, frequent
diverticulitis, IBD, ischemic colitis, morbid obesity,
peritoneal leaks, severe undernutrition
GENERAL ANESTHESIA
INDICATIONS
 Surgery requiring deep relaxation for long periods
of time
 Operations likely to result in significant blood loss
or in which breathing affected
 Uncooperative patients
CONTRAINDICATIONS
 No absolute contraindications
 Patients with medical conditions not optimized
o Should be maximized preoperatively; for
example treat unstable angina with cardiac
catheterization or bypass
 Difficult airway
 Significant comorbidities (e.g. aortic stenosis,
significant pulmonary disease, CHF)
 History of malignant hyperthermia and
pseudocholinesterase deficiency
SPINAL ANESTHESIA
INDICATIONS
 Commonly surgery involving lower abdomen,
pelvis, perineal and lower extremities
 Short procedures; general usually for longer or
would compromise respiration
CONTRAINDICATIONS
 Absolute: elevated ICP primarily due to intracranial
mass and infection at site of procedure
 Relative: preexisting neurological diseases
(particularly those that wax and wane, e.g. MS),
severe dehydration (hypotension),
thrombocytopenia or coagulopathy (epidural
hematoma), mitral and aortic stenosis and LV
outflow obstruction
INDIGENOUS HEALTHCARE CANADA
REPORT BY PUBLIC HEALTH AGENCY OF
CANADA
 Indigenous people view health in balanced and
holistic way, with connections between spiritual,
emotional, mental, and physical dimensions
 Proximal determinants
o Health behaviors
 Intermediate determinants
o Community infrastructure, kinship
networks, relationship to land, language,
ceremonies, and knowledge sharing
 Structural determinants
o Historical, political, ideological, economic,
social foundations
HISTORY
 Colonial structure sought to assimilate Indigenous
peoples into dominant Euro-Canadian culture 
responsible for destabilizing determinants of
Indigenous health
 Forced displacement of First Nations into remote
communities and reserves that with poor living
conditions and lack of resources
 Claimed traditional areas rich in resources
 Oppression created by Indian Act
 Damaging legacy of Residential Schools
 Systemic discrimination against Indigenous across
social, criminal justice, health care, and
employment environments
 Lack of public or private economic development
investments
DATA
 Some populations consistently less favorable results
o Low SES, First Nations, Inuit, Metis
peoples
 Some populations mixed
o Recent immigrants, racial minorities
 Findings
o Life expectancy and health-adjusted life
expectancy lower
o Infant mortality and unintentional injury
mortality higher
o Suicide mortality higher
o Mental illness hospitalization rates higher
o Arthritis, asthma, diabetes, obesity, active
tuberculosis prevalence higher
o Living conditions
 High alcohol consumption and
smoking
 Food insecurity
 Working poverty
BARRIERS TO CARE IN REMOTE REGIONS
 Great distances  travel, compounded by harsh
weather conditions, expensive, social
responsibilities
 Not only distance but limited number of
practitioners
 Higher turnover of staff
 Health care reform: shift to community-based care
over hospital-based without compensatory increase
in community-based services
 Cultural and language barriers
 Lack of familiarity with health system
  Poverty, unemployment, socioeconomic disparities
CYSTIC FIBROSIS
 Autosomal recessive caused by defective cystic
fibrosis transmembrane conductance regulator
(CFTR) due to mutation in CFTR gene
o Most common mutation is delta F508,
codon deletion of F in position 508
EPIDEMIOLOGY
 Second most common genetic metabolic disorder
after hemochromatosis in individuals of Northern
European descent
PATHOPHYSIOLOGY
 CFTR protein component of ATP-gated chloride
channel in cell membranes
 Misfolded  stays in rER  absence of chloride
channel on cell surface of epithelial cells
throughout
 In sweat glands
o Transport Cl- from lumen into cell
o Inability to reabsorb Cl-  reduced
absorption of Na+ and H2O  excessive
loss of salt and elevated NaCl in sweat
 Exocrine glands (GI tract or lungs)
o Transport Cl- from cell into lumen
o Reduced secretion of Cl-  decreased
inhibition of Na reabsorption  both lead
to increased intracellular H2O 
hyperviscous mucous  blockage of small
passages  chronic inflammation and
remodeling  organ damage
o Increased Na reabsorption also causes
negative potential difference to increase
CLINICAL FEATURES
 Gastrointestinal common in children
o Meconium ileus
o Failure to thrive due to malabsorption
o Pancreatic disease
 Pancreatitis
 Exocrine pancreatic insufficiency
 foul-smelling steatorrhea,
malabsorption, diarrhea,
hypoproteinemia
o Liver and bile duct
 Cholecystolithiasis, cholestasis,
increase chance of cholangitis
 Biliary cirrhosis with portal
hypertension, jaundice, varices
o Intestinal obstruction: abdominal distention,
pain, palpable mass
 Respiratory common in adulthood
o COPD (pulmonary emphysema) with
bronchiectasis
o Chronic sinusitis, nasal polyps may develop
o Recurrent or chronic productive cough and
pulmonary infections
 S. aureus, P. aeruginosa,
Burkholderia cepacian, S.
pnuemoniae, H. influenzae,
Aspergillus
o Pulmonary obstruction and airway
hyperreactivity  expiratory wheezing
and/or dyspnea
Renal
o Sweat losses of NaCl and H2O can lead to
RAAS activation  excretion of H+ and
K+  alkalosis and hypokalemia
 Sweat glands
o Particularly salty; possible electrolyte
wasting
 Urogenital
o Males usually infertile
 Obstructive azoospermia common
 Vas deferens may be absent
o Women reduced fertility
 Viscous cervical can obstruct
fertilization
NEWBORN SCREENING
 Newborn blood spot test, via heel prick in first 24-
48h
 1) Immunoreactive trypsinogen
o Elevated = CF possible
 2) CFTR mutation testing
o Most common CF-causing CFTR mutations
DIAGNOSIS
 Suggestive:
o Positive NBS
o First-degree family member with CF
o Typical clinical features of CF
 Confirmatory testing:
o Sweat chloride test with chloride value
>=60 mmol/L
o Evidence of two CF-causing CFTR gene
mutations and sweat chloride test result
>=30 mmol/L
o Positive physiologic CFTR testing with
abnormal nasal potential difference or
intestinal current measurement
 Imaging:
o CXR (air trapping, hyperinflation, reticular
nodular pattern, bronchiectasis)
o CT opacification of nasal sinuses
MANAGEMENT
 Non-pharmacologic
o Airway clearance techniques:
conventional chest physiotherapy (drainage
with percussion and/or clapping), high-
frequency chest compression, positive
expiratory pressure devices
o Exercise improve airway clearance and
functional lung capacity
o Nutrition: high-energy diet, pancreatic
enzyme supplements, additional NaCl
intake, supplementation of fat-soluble
vitamins
 Pharmacologic
o High-dose ibuprofen (advil)
o Bronchodilators: SABA, LABA
o Mucolytics: hypertonic saline nebulization
with mucociliary and osmotic effect;
dornase alfa is recombinant DNase that
breaks down extracellular DNA in sputum
 Prevention of infection
 o Treatment after early detection during
routine surveillance sputum cultures
 CFTR modulators
o Targets specific defects in CFTR protein
o Potentiators: increase CFTR Cl- channel
gate opening and conductance
o Correctors: improve protein folding,
stability, and transport of function to cell
surface
 Other
o Oxygen therapy
o Double-lung transplant for patients with
end-stage
TRANSPLANTATION BIOLOGY
DEFINITIONS
 Autograft: recipient themselves
 Isograft: genetically identical person
 Allograft: genetically different person
 Xenograft: different species
MHC AND HLA
 HLC: gene cluster on chromosome 6 coding for
MHC
 MHC: proteins on surface of cells displaying
antigenic peptides so can be recognized by T cells
as self or non-self
 HLA I cluster, three loci HLA-A, B, C, codes for
class I MHC
 HLA 2 cluster, three loci HLA-DR, HLA-DP,
HLA-DQ, codes for class II MHC
ALLORECOGNITION
 Recognition of foreign antigen as non-self by host
 Indirect: HLA molecules of allograft treated as
foreign by APCs, broken down, and presented
 Direct: HLA molecules of allograft presenting own
antigens directly stimulate T cells without being
broken down (more severe)
 Pathway: activation of T cell  clonal
proliferation mediated by IL-2  acute rejection
o CD8 recognize other HLA class 1
molecules on all cells in graft and cell death
o CD4 recognize HLA class II molecules on
dendritic cells; recruit macrophages and
help plasma cells produce alloantibodies
 Neutralization (not), complement
cytotoxicity, opsonization
PREREQUISITES FOR ORGAN MATCHING
 Cross-matching
o Recipient serum searched for preformed
antibodies against donor T (only I) and B
cells (both I and II)
o Negative = lower risk of rejection reactions
o Negative T but positive B = higher risk of
acute rejection, performed with caution
o Positive both = high risk of hyperacute, not
performed
 ABO compatibility
o Hematopoietic: preferred but
incompatibility can be tolerated
o Solid organ transplantation: ABO
compatibility required, not Rh
 Histocompatibility
o MHC matching at HLA-DR, HLA-A, and
HLA-B loci; HLA-C, HLA-DP, HLA-DQ
preferred but not always required
o 0 = no mismatch
o 1 = mismatch on either paternal or maternal
chromosome
o 2 = mismatch on both chromosomes
o 000 = complete match
o 222 = complete mismatch
o Odds: probability patient has HLA
compatible sibling is 1 – (0.75)n, where n is
number of siblings
INDICATIONS AND CONTRAINDICATIONS
 Contraindications
o Malignancy
 Non-curable or metastatic
 High risk of transmission
o Donor sepsis
o Transmissible spongiform encephalopathies
o Cardiac arrest occurring before brain death
(low blood flow high risk of thrombosis
and ischemia of organs)
 NOT contraindications
o Hepatitis B or C
o HIV infection
o Low-grade, localized tumors
o History of malignancy with disease-free
duration >5 years
POST-TRANSPLANT IMMUNOSUPPRESSIVE
 Intense in early postoperative 3-6 months
(likelihood of rejection decreases over time)
 Low doses of multiple drugs
 Excessive = risk of infections and malignancy
1. INDUCTION THERAPY
 Anti-T-cell antibodies
 Nondepleting antibodies (monoclonal): basiliximab
 Lymphocyte-depleting antibodies (polyclonal):
thymoglobulin
2. MAINTENANCE THERAPY
 Commonly triple-drug regimen
 Corticosteroids
 Calcineurin inhibitor (inhibit IL-2 production in T
cells): cyclosporine and tacrolimus
 Antiproliferative agents: azathioprine,
mycophenolate mofetil, sirolimus
COMMON TYPES
 Heart, lung, liver, kidney, pancreas
 Liver and kidney only organs can be performed
using living donors
o Warm ischemia (from taking organ to cold
organ preservation)
o Cold ischemia (from cold preservation to
restoration of blood perfusion)
 Lung
o Indications: advanced lung disease
refractory to maximal medical or surgical
therapy, disabling symptoms during daily
living, and risk of death >50% over next 2
years
 COPD, idiopathic pulmonary
fibrosis, genetic such as CF and a1-
antitrypsin, idiopathic pulmonary
arterial hypertension
 o Relative contraindications
 Age >75, BMI 30-35, progressive
or severe malnutrition, severe,
symptomatic osteoporosis, prior
chest surgery with lung resection BRAIN DEATH DETERMINATION
o Contraindications
 Malignancy in past 2 years; chronic
advanced illnesses; untreatable
infection; poor cardiac function;
acute medical conditions; HIV
infection, chest wall or spinal
deformity; BMI >= 35; active
substance use disorder
o Post-transplant care
 Serial monitoring of lung function
(PFT, CT chest, broncoscopy)
o Prognosis
 Median survival for all adult: 5.7
years
 1-year survival: 78%
 5-year survival: 51%
ETHICAL ISSUES
 Should those with better chance for survival be
given priority?
 Should parents of young children be given priority?
 Should those whose lifestyle choices damaged
existing organs be given chance at organ transplant?
 Should everyone be required to indicate wishes
regarding transplantation on tax forms or driver’s
license?
 Who should pay for transplants?
CPAP VS. BiPAP
 Continuous or bi-level positive airway pressure
therapy: using compressed air to open and support
airway during sleep
 CPAP
 Direct pressurized air between 4-20 cm H2O
 One setting rather than varying in pressure, which
can cause people to feel like choking
 BiPAP
 Direct 4-25 cm H2O
 Two settings: one for inhalation and one for
exhalation, to allow user to breathe more naturally
o Spontaneous switching: senses user’s
breathing pattern (standard)
o Timed switching: user control to ensure
correct # of breaths
o Spontaneous/timed switching: timed
switching on when user dropped below # of
breaths per minute
 Choice
 CPAP may be used for OSA, preterm infants
 BiPAP for OSA who respond poorly to CPAP,
central sleep apnea, COPD, congestive heart failure,
Parkinson’s disease, ALS
EFFECTS OF CHRONIC HYPOXIA ON LUNG
 Low oxygen saturation = constriction of small
pulmonary arteries = pulmonary hypertension =
right-sided hypertrophy
ACID-BASE DISTURBANCES WITH RESP. FAILURE
 Decreased breathing = build-up of CO2 =
conversion to acid (acidosis) = compensation with
bicarbonate by renal
 Established cause
 Comatose state with absence of motor responses
excluding spinal reflex
 Absent brainstem reflexes gag, cough
 Bilateral absent corneal, pupillary reflex, VOR
response
 Absent respiratory effort (apnea testing)
 Absence of confounding variables that can mimic
neurologic death
1. Establish clinical prerequisites
1. Cause of brain death is known (history,
examination, neuroimaging, and
laboratory tests)
2. Core temperature >36C (97F); warming
blanket may be required
3. Systolic BP >100 mmHg; vasopressors
may be required
4. No severe electrolyte, acid-base,
endocrine, or circulatory disturbance
5. No drug intoxication or poisoning,
including CNS depressants and
neuromuscular blocking agents
2. Perform neurologic examination. Must
demonstrate absent cerebral and brainstem
function with all of following findings:
1. Coma
1. Lack all evidence of
responsiveness: eye opening or
eye movement to noxious
stimuli absent
b. Absent brain-originating motor
response, including response to pain
stimulus above neck (e.g. pressure
over supraorbital nerve, angle of lower
jaw normally produces facial muscle
movement)
c. Absent pupillary light reflex in both eyes
using bright light
1. Normally fixd in midsize or
dilated position (4-9 mm)
2. Constricted pupils suggest
possibility of drug intoxication
d. Absent corneal reflex (cornea touched
with cotton swab or squirts of
water/saline, normal if eyelid moves)
e. Absent oculoencephalic (move head
and neck; normal if eyes do not turn
with head) and oculovestibular reflexes
(irrigate ear canal, normal if eyes
conjugately move toward irrigated side)
f. Absent jaw jerk
 g. Absent gag reflex (posterior pharyngeal
wall touched with tongue depressor and ADVANCED TRAUMA LIFE SUPPORT (ATLS)
palate observed for elevation)
h. Absent cough with tracheal suctioning  Prevention
i. Absent sucking or rooting reflexes o Addressing harmful behaviors, planned or
j. Apnea as demonstrated by apnea test unplanned
 Goals
Perform apnea test (CO challenge)
2
o Identify and treat threats to life, then limb,
a. Core temperature >36C (97F), systolic then eyesight
BP >100 mmHg, euvolemia, eucapnia o Prevent exacerbation of existing injuries or
(35-45 PaCO ), absence of hypoxia, no
2 occurrence of additional
prior evidence of CO retention (e.g.
2 o Return to level of function as close to pre-
COPD, severe obesity) injury as possible
b. Positive if no respiratory response to  Principles
PaCO >60 mmHg or 20 mmHg greater
2
o Treat greatest threat to life first
than baseline values and final arterial o Definitive diagnosis not immediately
pH of <7.28 important
o Time matters (golden hour)
Perform ancillary tests if clinical criteria cannot be
o Do no further harm
confidently applied (e.g. cranial nerves o Assess, intervene, reassess physiology
cannot be adequately examined,  Field triage
neuromuscular paralysis present, heavy o Assess basic physiology
sedation, apnea test not valid or cannot be  Systolic BP < 90
completed, confounders such as multi-organ  Respiratory rate <10 or >29
failure render clinical examination unreliable,  Glasgow Coma Scale <14
shorten duration of observation period) o Assess anatomy of injury
a. Cerebral angiography approximates  Penetrating injury
 Open or depressed skull fracture
gold standard but invasive, risky  Flail chest
1. Cerebral angiography  Crushed, degloved, or mangled
2. Transcranial Doppler extremity
3. MR angiography  Paralysis
4. CT angiography o Assess mechanism of injury
5. Nuclear medicine  Falls >6m adults, >3m or 2-3 times
b. Profound hypotension and when cranial the height in children
 High-risk auto crash
vault breached by trauma, surgery,
o Assess special patient or system
ventricular drain, or cranial sutures → considerations
electroencephalography or  Age
somatosensory evoked potentials may  Anticoagulation and bleeding
be superior disorders
 Burns
FRACTURES  Time-sensitive extremity injury
 Open/compound: break of skin near broken bone (open fractures, vascular
 Closed/simple: no break through skin compromise)
 Partial: incomplete break of bone  ESRD
 Complete: separated into pieces  Pregnancy >20 weeks
 Stable: broken ends of bone line up and have not  Initial assessment
moved out of place o Primary survey  resuscitation  adjuncts
 Displaced: gap between broken ends of bone to primary  secondary survey  adjunct
PATTERN to secondary  ongoing post-resuscitation
monitoring and reevaluation  definitive
 Transverse: straight line care  tertiary survey
 Spiral: in long bones, from twisting injuries PRIMARY SURVEY AND RESUSCITATION
 Stress: crack-like  Brief history: age, gender, mechanism of injury
 Compression: wider and flatter than before  Airway with cervical spine control
 Oblique: diagonal  Breathing with oxygenation and ventilation;
 Impacted: broken ends jammed together respiratory exam
 Segmental: same bone fractures in two places,  Circulation
leaving ‘floating’ segment of bone o Stop external hemorrhage
 Comminuted: bone broken into 3 or more pieces o Tissue perfusion: BP, pulse, oximetry, skin
 Avulsion: fragment pulled off bone by tendon or color, temperature, capillary refill, mental
ligament status, urine output
 o Gain vascular access, administer initial
volume (2L lactated Ringer’s)
o Responder: bleeding <20%; transient :20-
40%, needs blood; >40%, needs blood and
intervention to stop internal bleeding
o Intervene to stop hidden sources of
bleeding
o Consider non-hemorrhagic sources of
shock: tension pneumothorax, cardiac
tamponade, neurogenic shock
 Disability
o Brief neurologic exam: LOC, pupil
symmetry and reaction to light, lateralizing
signs
o Temporize for evidence of increased ICP;
elevated head of bed, mild hyperventilation
to paCO2=35, mannitol 1 gm/kg
 Exposure/environmental
o Assess temperature
o Maintain normothermia/prevent
hypothermia: warm room, fluids, blankets
ADJUNCTS TO PRIMARY
 Hemodynamic monitoring for BP, HR, rhythm
 Respiratory monitoring with pulse oximetry,
capnography, rate
 Arterial blood gas and lactate monitoring
 CBC, electrolytes, glucose, creatinine, INR
 Foley placement to monitor urinary output but
withhold if urethral injury
 Gastric tube placement to prevent gastric dilatation
 Assessment of intraperitoneal injury
o Focused assessment by sonography in
trauma
o Diagnostic peritoneal lavage
 Radiographs
o AP chest, tube and line placements, and
subclinical hemopneumothoraces
o Pelvis, pelvic fracture as source of hidden
bleeding
o Cervical spine, to assess source of
neurogenic shock
 CT better if available
SECONDARY SURVEY
 Complete, head-to-toe physical examination to
identify all anatomic injuries
 Complete history
o Cardiac, anticoagulation, diabetic
medications
o Last meal eaten
o More detailed mechanism of injury: blunt
(fall, crush, motor vehicle), penetrating
(gunshot, stab), environmental (burn, cold,
chemical/radiological/biological), primary
pressure wave
 Explosions combine all four and
produce multi-dimensional injuries
 Head
o GCS, open skull fractures, eyes (VA< pupil
size and reactivity, globe integrity and
foreign body, extraocular muscle
movement), ears, nose (epistaxis), mouth
 Neck
o Subcutaneous emphysema, cervical spine
tenderness, paravertebral swelling
 Chest
o Breath sounds, hyperresonance or dullness
to percussion, subcutaneous emphysema
 Abdomen
o Distention, tenderness
 Pelvis
o Bony tenderness, urethral injury
(hematoma, lacerations, blood at meatus),
anal tone, voluntary contraction
 Extremities: use symmetry
o Deformity and limb length: fracture,
dislocation
o Swelling: fracture, soft tissue and joint
injury
o Neuromuscular function
o Circulation: brachial, radial, femoral,
posterial tibial, dorsalis pedis
 Back
o Tenderness, deformity
o C5: shoulder abduction
o C6: elbow flexion
o C7: elbow extension
o C8: grip
o T1: finger spread
o T4: nipple level sensation
o T10: umbilical level sensation
o L2: hip flexion
o L3,4: knee extension
o L5: big toe dorsiflexion
o S1: ankle plantarflexion
GENERAL MANAGEMENT PRINCIPLES
 Red flags
o Hypotension
o Truncal gunshot wounds
o Pelvic fractures
o Acidemia and hypothermia, on the way to
coagulopathy (triad of death)
 Transfer to higher level/facility of care if injuries
exceed treatment capabilities
 Clinical clearance of cervical spine
o Awake and alert, neurologically normal, no
intoxication, no distracting injuries, no neck
pain, no midline neck tenderness, full
voluntary range of neck motion without
pain
o When in doubt, leave collar and proceed
with radiological examination
 Equivocal abdomen
o Altered sensorium, distracting injuries
(pelvic, lower rib, lumbar spine)  requires
further evaluation (FAST exam, DPL, CT
scan)
 CT scans in stable patients, consider CT angiogram
o Head: bleeding, edema, ventricular
effacement
o Neck: C-spine, CTA carotid and vertebral
arteries
o CAP: blunt aortic injury, solid organ injury
 Interventional radiology to control arterial
hemorrhage
 o Liver & some spleen, pelvic glutea
EXTREMITY TRAUMA
 Reduction and splinting for bleeding and pain
 If pulse is lost after doing so, release and reapply
traction/splint
 Open fractures
o Rapid washout with Betadine solution
o Reduce and splint
o As contaminated or dirty wound, needs
treatment with IV antibiotics
o Operative intervention within 6 hours
improves outcome
 Crush syndrome
o Direct muscle injury + muscle ischemia 
rhabdomyolysis
 Hypovolemia, acidemia,
hyperkalemia, hyperphosphatemia
and hypocalcemia, DIC
o Manage with intravascular saline volume
expansion to promote diuresis, goal 100
cc/h
 Compartment syndrome
o Elevated pressure within osteofascial
compartment that compromises perfusion
o Risks
 Tibial and forearm fractures
 Crush injury
 Ischemia/reperfusion injury
 Tight dressings or casts
 Circumferential burns
o Diagnosis
 Pain out of proportion to injury;
tense compartment swelling
 Neurological and vascular
compromise are late findings
o Management
 Preemptive fasciotomy for risks 1-3
 Remove/bivalve casts
 Escharotomy for circumferential
full-thickness burns
SPECIFIC TREATMENTS
 Cardiac tamponade:
o Diagnose with FAST exam with pericardial
fluid; pericardiocentesis, subxiphoid
pericardial window
o Relatively stable: median sternotomy
o Unstable: resuscitative thoracotomy
 Indications for laparotomy
o Blunt or penetrating abdominal trauma with
suspected causing hypotension
o Peritonitis
o Evisceration
o Free intraperitoneal air
o Evidence of ruptured diaphragm, GI tract,
intraperitoneal bladder, and
pancreaticoduodenal complex
 Contrast urography for lower urinary tract
o Retrograde urethrogram for urethral
o Cystogram to define bladder injury
 CT or interventional diagnostic angiography
o Penetrating zone I or III neck injuries
o Concern for blunt carotid or vertebral artery
injury
o Severe fractures
o Knee dislocation (popliteal artery)
ONGOING ASSESSMENT
 Post-resuscitation monitoring
o Vital signs and organ perfusion, urinary
output, ABG, pulse oximetry, end-tidal
carbon dioxide, mentation, skin color,
temperature, capillary refill
 Assess for analgesia and comfort
o Short-acting narcotics administered IV
o Benzodiazepines for non-hypoxic anxiety
 Repeat primary and secondary exams within 24
hours as tertiary survey to prevent missed injuries
o Wrist and ankle films for falls
o Skeletal survey in obese for subclinical
fractures
o Complete spin films in patients with one
spinal fracture or calcaneal fractures
DVT PROPHYLAXIS
 Consider DVT prophylaxis in every hospitalized
patient
 Risk factors: elderly, immobile, history of
DVT/PE, critically ill, stroke with lower extremity
paralysis, advanced CHF, active cancer, acute
respiratory failure, thrombophilia, recent surgery or
trauma, obesity, ongoing hormonal therapy
 Low-risk: young patients no risk factors
o No need
 Moderate-risk: at least 1 risk factor
o Pharmacological preferred with or without
mechanical prophylaxis
 High-risk: multiple risk factors
o Both pharmacological and mechanical
 LMWH preferred due to effectiveness and ease of
administration; unfractionated in low GFR
o Contraindications: active bleeding, recent
bleeding, high risk for bleeding,
coagulopathy, planned surgery in next 6-12
hours, thrombocytopenia
 Mechanical: intermittent pneumatic compressions,
graduated compression stockings, venous foot
pump
o Contraindications: limb ischemia due to
PVD, skin breakdown
ORTHOPEDIC SURGERIES
 VTE risk high when undergoing major orthopedic
surgeries such as hip and knee
  LMWH, apixaban, and rivaroxaban preferred
 Fondaparinux, UFH, warfarin if can’t use
 Preferably 35 days from day of surgery
NON-ORTHOPEDIC
 No DVT prophylaxis if very low-risk, mechanical if
low risk, pharmacological with/without mechanical
if moderate to high-risk
HYPOTHERMIA
 Core body temperature <35C/95F
ETIOLOGY
 Primary (environmental exposure to cold) or
secondary (inadequate temperature regulation)
 Increased heat loss: vasodilation drugs,
erythroderma (burns, psoriasis), surgery, sepsis,
multiple trauma
o Evaporation from the wound,
peripheral vasodilation
impaired sympathetic due to anesthetics,
and cold or room-temperature infusions
 Decreased heat production: endocrine
(hypopituitarism, hypoadrenalism,
hypothyroidism), severe malnutrition,
hypoglycemia, damage to posterior hypothalamic
nucleus
 Impaired thermoregulation: damage to preoptic
nucleus of hypothalamus due to CNS trauma,
strokes, toxicologic and metabolic derangements,
intracranial bleeding, PD, tumors, Wernicke, or MS
 Other: malignancy, uremia, shock, cardiac arrest,
vascular insufficiency
PATHOPHYSIOLOGY
 Body loses heat through radiation (most
significant), conduction, convection
 Hypothalamus maintains 36.5-37.5 by:
o Conserving heat (peripheral
vasoconstriction by direct and sympathetic)
o Increasing heat production (shivering
increases metabolic activity and heat
production)
 Organ effects
o General tissue oxygen demand decreases by
6% per degree below 35
o Decreased depolarization of cardiac 
decreased CO  decreased mean arterial P
CLINICAL FEATURES
 Determine core temperature with low-reading
temperature probe in bladder, rectum, or esophageal
 Mild, 32-35C: confusion, amnesia, ataxia, apathy,
tachycardia, tachypnea, cold diuresis (fluid shifts to
core from peripheral vasoconstriction, central
volume receptors)
 Moderate, 28-32: worsened CNS depression,
stupor, may mimic brain death, hypoventilation,
hyporeflexia, oliguria, bradycardia, cardiac
arrhythmias
 Severe, <28: Vfib or pulselessness, fixed pupils,
pulmonary edema, apnea, hypotension, coma
DIAGNOSIS
 Mainly to assess comorbidities
 ECG: prolongation of all intervals, elevated J point PRINCIPLES
(J or Osborn wave)
 CXR to exclude pulmonary edema or aspiration
pneumonia
 Complete metabolic panel, CBC, arterial blood gas
TREATMENT
 ABCDE approach; place two large (14 or 16 gauge)
peripheral IVs
 Prevent further heat loss and begin rewarming
o Mild: passive external rewarming (remove
wet clothes, cover blankets, warm room)
o Moderate, refractory mild: active external
rewarming (warm blankets, radiant head,
forced warm air)
o Severe, refractory moderate: active
internal/core rewarming (IV warmed
crystalloid, warmed irrigation of
peritoneum, thorax, extracorporeal blood
rewarming)
 Cold-induced injuries with supportive care or
surgery as needed
CAUTIONS
 Avoid rough handling and always warm trunk
before extremities; else recirculation of cold,
academic blood
 Cardiopulmonary resuscitation not be performed
until core body temperature 30-32 as may not be
responsive
ALCOHOL WITHDRAWAL
 CIWA-Ar protocol: grades severity
o Nausea/vomiting, tremor, paroxysmal
sweats, anxiety, agitation, tactile
disturbances, auditory disturbances, visual
disturbances, headache/fullness in head,
orientation/clouding of sensorium
 Adjust pharmacotherapy according to severity
o First-line: benzodiazepines
 Short or intermediate (oxazepam,
lorazepam) in patients with slow
metabolism (elderly, liver failure)
 Longer acting (diazepam) in all
other patients
o Second-line: anticonvulsants as adjunct or
if contraindications for benzodiazepines
 Supportive care
o IV fluid therapy and fluid monitoring
o Multivitamins, folate, electrolyte repletion,
oral glucose, thiamine supplementation
(therapeutic dose if Wernicke, prophylactic
dose otherwise)
 Manage complications
o Seizures: IV benzodiazepines
o Psychotic disorder: low-dose
antipsychotics (haloperidol, risperidone) in
combination with benzodiazepines
o Delirium: critical care unit for high-dose
IV benzodiazepines
 Offer treatment of alcohol use disorder
TRAUMA-INFORMED CARE
 1. Safety
  2. Trustworthiness and transparency
 3. Peer support  Coagulopathy if sepsis suspected – always order
 4. Collaboration and mutuality  Blood cultures to confirm what will kill you
 5. Empowerment, voice, and choice  Problems with general
 6. Cultural, historical, and gender issues o Autonomic blocks – BP
RE-TRAUMATIZATION o Mechanical ventilation needed
 Touch, smell, noises o Aspiration risk
 Power dynamics o Could die more – that’s why prefer regional
 Gender of provider anesthetic
 Loss of and lack of privacy
 Look of environment
 Specific wording or words
PRACTICE
 Culturally safe and welcoming waiting area and
meeting room (e.g. resources, Indigenous art)
 Allow multiple no shows but explore barriers
 Continuous assessment of body language for stress:
crying, sweating, fidgeting, shaking, gripping table
 Awareness of own prejudices
 Given individuals lots of options and avoid jargon
 Respond appropriately and apologize when needed
 Other from top to bottom:
o Screening for trauma, collaboration and
understanding other professionals’ roles,
understanding health effects of trauma,
patient-centered communication skills

OPEN FRACTURE CLASSIFICATION

 Type I: open fracture with wound less than 1 cm
long and clean
 Type II: open fracture with laceration greater than
1 cm long without extensive soft tissue damage,
flaps, avulsions
 Type III: open segmental fracture, open fracture
with extensive soft tissue damage, or traumatic
amputation
o A: open fractures with adequate soft tissue
coverage of a fractured bone despite
extensive soft tissue laceration or flaps, or
high-energy trauma regardless of wound
size
o B: open fractures with extensive soft tissue
injury loss with periosteal stripping and
bone exposure
o C: open fractures associated with arterial
injury requiring repair

EXTRA