Physiological effects

Question 1

Adrenoceptors

Answer 1

• alpha-1 - vascular smooth muscle, vasoconstrict when stimulated - Gq coupled phospholipase C activated –> increase IP3 –> increase Ca++
• alpha-2 - widespread throughout the nervous system, cause sedation, analgesia and attenuation of sympathetically mediated responses when stimulated - Gi coupled adenylate cyclase inhibited –> decreased cAMP
• beta-1 - on platelets, causes platelet aggregation
• beta-1 - on the heart, causes positive inotropic and chronotropic effect when stimulated - Gs coupled adenylate cyclase activated - increases cAMP
• beta-2 - bronchi, vascular smooth muscle, uterus (and heart), relaxation of smooth muscle when stimulated - Gs coupled adenylate cyclase activated –> increases cAMP –> increases Na+/K+ ATPase activity and hyperpolarisation
• beta-3 - adipose tissue, causes lipolysis when stimulated - Gs coupled adenylate cyclase activated –> increases cAMP
• dopamine 1 - within the CNS, modulates extrapyramidal activity - Gs coupled adenylate cyclase activated –> increases cAMP
• dopamine 1 - peripherally, causes vasodilatation of renal and mesenteric vasculature
• dopamine 2 - within the CNS, causes reduced pituitary hormone output - Gi coupled adenylate cyclase inhibited –> decreased cAMP
• dopamine 2 - peripherally, inhibits further noradrenaline release

Question 2

Altitude

Answer 2

• Hyperventilation (in response to stimulation of peripheral chemoreceptors by decreased PaO2) - hypocapnia, CSF alkalosis, increased bicarbonate excretion by kidneys (24-48hrs)
• Acute left shift of oxyHb disocciation curve due to alkalosis - aids loading of O2 onto Hb
• Chronic right shift of OxyHb curve due to compensatory increased 2,3-DPG (within a week)
• Increased EPO secretion due to chronic hypoxaemia –> polycythaemia, increased thrombosis
• Increased HR, SV and myocardial work (increased viscosity of blood)
• Reduced plasma volume (increased renal perfusion due to increased sympathetic activity + increased fluid loss due to hyperventilaton and loss of appetite) –> higher Hct
• Increased hypoxic pulmonary vasoconstriction and PVR –> pulmonary hypertensino and potential development of high-altitude pulmonary oedema
• Angiogenesis
• Enzyme changes (decreased activity of temperature dependent or oxygen dependent enzymes)

Question 3

Brainstem Death

Answer 3

The reasons for the altered pathophysiology of the heart-beating brain stem dead person can be due to:
- primary pathology suffered by the patient
- complications of ITU treatment (mainly resuscitation of the injured brain)
- specific physiological changes and a systemic inflammatory response caused by the brainstem death

CVS - initial changes
- increased in ICP leads to increased MAP to maintain CPP
- brain herniation causes ischaemic changes in the brainstem and a hyperadrenergic state
- increased PVR and SVR
- episodes of ‘sympathetic storm” with tachycardia, vasoconstriction and hypertension, potentially leading to myocardial ischaemia

CVS - subsequent changes
- loss of spinal cord sympathetic activity
- reduced vasomotor tone
- reduced preload
- reduced cardiac output
- myocardial perfusion can be reduced due to low aortic diastolic pressure

CNS
- absent cranial nerve function
- coma
- flat EEG (absent electrical activity)
- spinal reflexes may be preserved (disinhibition of spinal cord reflexes) including deep tendon reflexes

Endocrine
- pituitary ischaemia —> DI, fluid and electrolyte loss —> further CVS instability
- reduced metabolic rate, loss of hypothalamic control —> heat loss and hypothermia
- loss of posterior pituitary function
- preservation of anterior pituitary function (normal TSH, reduced T3)
- hyperglycaemia

Haematological
- coagulation abnormalities - original pathology
- release of coagulation activators from the necrotic brain tissue

RS
- alveolar epithelial cell damage in response to sympathetic storm
- alveolar barrier disruption
- oxidative stress from mechanical ventilation
- neurogenic pulmonary oedema
- absent respiratory drive
- atelectasis

Other
- pro-inflammatory cytokines released

Question 4

Chronic Alcoholism

Answer 4

CNS
* depressant
* increased dosing requirements of propofol in chronic alcoholism
* decreased metabolism of opioids
* encephalopathy - hepatic/Wernickes
* CVAs
* peripheral neuropathy
* asterixis

CVS
* non ischaemic dilated alcoholic cardiomyomathy - reduced EF, LF dilatation, cardiac fibrosis
* atrial fibrillation and other dysrhythmias
* MI, hypertension
* high output cardiac failure from thiamine deficiency (wet beri-beri)

Resp
* alcoholic lung disease - decreased pulmonary glutathione –> abnormal surfactant synthesis and secretion, changes in alverolar-capillary barrier function and permeability
* increased incidence of ARDS
* impaired alveolar immune function
* increased risk of pneumonia
* risk of atypical or cavitating infections

GI
* alcoholic liver disease - fatty liver, alcoholic hepatitis, alcohol related cirrhosis
* pancreatitis
* varices/ulcers - UGIB
* oesophageal and gastric dysmotility - delayed gastric emptying
* impaired nutrient absorption
* altered acid secretion
* risk of oesophageal, gastric and liver cancer
* increased risk of HCV
* malnutrition

Haematological
* megaloblastic anaemia
* impaired erythrocyte function
* inhibition of bone marrow platelet function
* increased fibrinolysis
* decreased fibrinogen, factor VII and vWF levels
* splenomegaly

Metabolic
* vitamin deficiencies e.g. B1 (thiamine), folate
* hypomagnesaemia +/- hypocalcaemia (decreased PTH secretion)
* hypokalaemia
* hyponatraemia
* hypoalbuminaemia
* hypophosphataemia

Endocrine
* impaired response to psychological and physical stress
* hypothyroidism
* hypogonadism - infertility, impotence
* growth retardation
* DM
* metabolic syndrome
* insulin resistance

Immunological
* inhibition of proliferation of T cells
* changes to balance of proinflammatory and antiinflammatory cyctokines

MSK
* altered bone metabolism
* decreased bone mineral density and mass
* increased risk of fractures
* osteoporosis
* delayed fracture repair
* alcoholic myopathy - muscle wasting

Postoperative
* poor wound healing
* postop infections including pneumonia

Question 5

Dopamine

Answer 5

• CNS - neurotransmitter and neuromodulator, executive function, motor control, motivation, arousal, reinforcement and reward
• Pituitary - prolactin secretion
• Hypothalamus - facilitation of vasopressin release
• CVS - activation of beta-adrenergic receptors - HR/contractility
• Renal - natruiresis, diuresis, increased renal blood flow and GFR, inhibit renin release
• GIT - vomiting and nausea
• Immune - reduce activity of lymphocytes
• Pancreas - reduces insulin release from beta cells

Question 6

Exercise

Answer 6

• Increased oxygen consumption (>4000ml/min from 250ml/min at rest)
• Increased oxygen extraction
• Increased minute ventilation (>100L/min from 5-6L/min at rest) –> increased RR and TV
• Blood redistributed to skin
• Shift of oxyHb curve to right (decreased pH)
• Increased cardiac output (>30L/min) –> increased HR, increased SV, increased contractility, decreased SVR
• Increased blood flow to muscles (vasodilatory metabolites e.g. adenosine, K+)
• Minimal change to pH, pCO2, pO2
• Metabolism of free fatty acids once muscle glycogen stores become deplete

Question 7

Fluid bolus

1000ml of 0.9% saline given stat to normovolaemic 70kg adult

Answer 7

• Increased circulating volume by 20%
• Increased preload leads to increased cardiac output (Starling’s Law)
• SVR initially normal (increased CO –> increased MAP)
• Venodilation due to increased baroreceptor firing rate leading to inhibition
• Decreased venous return leading to decreased CO
• Fluid redistribution –> 75% interstitial, 25% intravenous
• Volureceptors inhibit ADH secretion (trigger 8-10% change)
• Osmoreceptors (1-2% trigger) detect decreased osmolality and decrease ADH release

Question 8

Fluid bolus

1000ml of 5% Dextrose

Answer 8

• Glucose taken up and metabolised
• 85ml per 1000ml remains in circulating volume
• ADH release decreased as free water decreases osmolality (osmoreceptors triggered)

Question 9

Haemorrhage

Sudden loss of 1000ml (20% circulating volume)

Answer 9

• Decrease in BP detected by baroreceptors (carotid sinus) and volureceptors (RA, veins)
• Redistribution of cardiac output –> decreased muscle and renal blood flow
• Catecholamines released –> increased HR, increased contractility, vasoconstriction and venoconstriction
• Recruitment of effective circulating volume from liver, lungs and muscle beds (splanchnic constriction etc)
• Translocation of fluid into the plasma
• Increased renin release –> increase in angiotensin II –> increased aldosterone release
• Increased ADH release –> conservation of water in collecting ducts
• Later response - increased plasma protein synthesis and increased EPO release –> increased reticulocyte count

Question 10

Haemorrhage

Sudden loss of 2000ml

Answer 10

• Cardiovascular - initial catecholamine surge with tachycardia followed by (?parasympathetically mediated) bradycardia
  — decreased blood pressure detected by baroreceptors that activate sympathetic response —> SVR, increased HR, increased contractility
  — leads to reduced CO (Frank Starling mechanism) and organ perfusion
  — redistribution of CO from less important organs
  — reduced organ blood flow and reduced arterial pressure leads to systemic acidosis, sensed by chemoreceptors
  — chemoreceptors further activate the sympathetic adrenergic system
  — impaired coronary blood flow causes myocardial hypoxia and acidosis - depressing cardiac function and causing arrhythmias
• Renal - kidneys release renin —> increased ATII and aldosterone —> vascular constriction, enhanced sympathetic activity, stimulation of vasopressin release, increased renal reabsorption of sodium and water to increase blood volume
• Reduced organ flow leads to accumulation of tissue metabolic vasodilator substances, impairing sympathetic mediated vasoconstriction —> loss of vascular tone, progressive hypotension and further organ hypoperfusion
• Haematological - physiological haemostasis initiated, increased thrombin generation, shutdown of fibrinolysis, platelet activation —> increased clot formation and prevention of bleeding
  — activation of protein C —> endogenous coagulopathy
  — fall in capillary hydrostatic pressure results in less fluid leaving the capillaries and net reabsorption from the tissue, leading to haemodilution of the blood
• Systemic inflammatory response —> endotoxins lead to cytokine produce, enhanced formation of NO and oxygen free radicals which cause vasodilation, cardiac depression and organ injury

Question 11

Histamine

Answer 11

Generated in granules in mast cells and in basophils. Also found in the hypothalamus and enterochromaffin-like cells of the stomach.

• CNS - neurotransmitter involved in sleep/wake cycle and activation of nociceptors, appetite regulation, body temperature control, endocrine homeostasis
• CVS - increase capillary permeability, vasodilatation, alter BP, cause tachycardia and arrhythmias
• RS - contraction of bronchial smooth muscle –> bronchospasm, increase mucosal secretion, sneezing, nasal congestion
• Immune - protect host from pathogens via systemic effects, promotion of IL release, chemotaxis of eosinophils and mast cells, ?wound healing
• GI - contraction of GI smooth muscle cells, stimulate gastric acid secretion
• GU - urinary bladder contraction/relaxation
• MSK/Derm - itch perception, urticaria

Question 12

Hypothermia

Answer 12

• Endocrine and metabolic
• decreased metabolism and O2 consumption
• decreased carbohydrate metabolism and hyperglycaemia
• decreased drug metabolism and clearance
• essentially unchanged electrolytes
• Haematological
• increased Hct and blood viscosity
• neutropenia and thrombocytopenia
• coagulopathy and platelet dysfunction
• decreased fibrinogen synthesis
• Respiratory
• decreased RR and medullary sensitivity to CO2
• development of pulmonary oedema
• increased dead space
  *Acid-base changes - alkalosis and hypocapnea
• rise of pH with falling body temperature
• fall of pCO2 with falling body temperature
• increased oxygen solubility and O2-Hb affinity (ODC shifts to the left)
  *Cardiovascular
• decreased CO and HR
• QT prolongation and J wave
• arrhythmias - AF/VF
• resistance to defibrillation (at less than 28 degrees C)
• vasoconstriction
  *Renal
• “cold diuresis” due to decreased vasopressin synthesis
• progressing to oliguria
  *CNS
• confusion and decreased level of consciousness
• shivering (down to ~ 32 degrees)
• increased seizure threshold
• altered muscle tone (initially increased, then flaccid as temperature decreases)
• areflexia
• fixed, dilated pupils at less than 30 degrees
  *Immunological
• decreased granulocyte and monocyte activity
• GI
• ileus

Question 13

Massive Transfusion

Answer 13

Definition:
- replacement of entire circulating volume in <24hrs
- replacement of 1/2 of volume in <4hrs
- rate of blood loss >150ml/min

Consequences:
- coagulopathy - secondary to consumption of clotting factors and dilutional effect
- hypothermia
- - coagulopathy
- - decreased hepatic metabolism
- - shifts oxyHb dissociation curve to left
- - shivering –> increased oxygen demand/consumption
- electrolyte derangement
- - hyperkalaemia/hypokaelamia
- - hypocalcaemia, hypomagnesaemia
- - acid-base imbalance (metabolic acidosis)

Management
- warm blood
- replace FFP +/- platelets +/- fibrinogen/cryo
- give calcium
- manage hyperkaelamia as normal
- consider dialysis for resistant acidosis

Question 14

Muscarinic Effects

Answer 14

• GIT - salivation, defecation, abdominal cramps, GI upset, vomiting
• GU - urination
• Eye - lacrimation, meiosis
• CVS - bradycardia
• RS - bronchospasm, bronchorrhoea
• CNS - agitation, confusion, seizures, coma

Question 15

Neonates

Answer 15

• Airway - large tongue, short neck, big occiput, high, anterior conical larynx, narrow airways, nose breathers
• Respiratory - small TV, increased RR, little respiratory reserve, increased lung compliance, high metabolic requirement for O2, decreased sensitivity to hypercapnia
• Cardiovascular - increased cardiac output, increased HR, increased contractility, tolerate fluid overload poorly, rate dependent circulation (transitional circulation initially once born)
• Hepatic - decreased hepatocytes, decreased phase 1 metabolism, prolonged drug effects, decreased protein binding, decreased hepatic stores, increased metabolic weight
• Renal - low GFR, tolerate fluid imbalance poorly, TBW 75-85% of weight (term-prem), expanded extracellular fluid volume - increased volume of distribution
• CNS - limited thermoregulation/heat production, cerebral autoregulation lower limit, non shivering thermogenesis

Question 16

Nicotinic Effects

Answer 16

• CVS - tachycardia, vasoconstriction, hypertension
• MSK - weakness, twitching, fasciculations, muscle cramps, hypotonia
• Eyes - mydriasis
• CNS - agitation, confusion, seizures, coma
• General - perspiration

Question 17

Obesity

Answer 17

1. Physiological (system by system)
   * airway - upper airway collapse, difficult laryngoscopy
   * OSA common
   * lung volume - reduced FRC due to weight of chest wall, closing capacity may exceed FRC –> atelectasis and VQ mismatch, decreased thoracic compliance –> increased WOB
   * gas exchange - increased O2 consumption and CO2 production (due to increased tissue mass) –> increased MV
   * asthma
   * increase in intravascular volume and CO to compensate for excess body mass
   * systemic hypertension and heart disease common
   * respiratory changes –> HPV –> pulmonary hypertension and increased RV work –> RV hypertrophy and failure (cor pulmonale)
   * increased risk of VTE
   * GORD - lower oesophageal sphincter incompetence and increased intragastric pressure
   * gallstone disease and NASH common
   * insulin resistance/T2DM
   * hyperlipidaemia
   * OA and gout
   * low grade inflammation stimulated by obesity
2. Practical
   * venous access/IV lines
   * BP monitoring
   * difficult regional/neuraxial anaesthesia
   * surgical access
   * limb tourniquets
   * positioning and manual handling
   * weight limits of beds/trollies
3. Pharmacological
   * increased TBW but lower proportion due to excess weight of fat - increased Vd for water soluble drugs
   * excess poorly vascularised adipose tissue - sequestration of lipid soluble drugs, increased doses needed to account for increased Vd
   * increased LBW and CO –> increased clearance
   * increased plasma proteins –> increased protein binding
   * use adjusted body weight (ideal + 40% excess) for propofol and remifentanil infusions, neostigmine, sugammadex and antibiotics
   * use lean bodyweight for propofol induction, thiopentone, non-depolarising NMBDs, LAs, paracetamol, opioids
   * use total body weight for sux and LMWHs (titrate dose with Xa levels)

Question 18

Old Age

Answer 18

1. Physiological
   * airway - often edentulous –> more challenging BMV but intubation usually easier
   * upper airway prone to collapse
   * atrophy of inspiratory muscles (diaphragm and intercostal muscles) –> more susceptible to respiratory muscle fatigue
   * thoracic cage more rigid (calcification of costal cartileges) –> decreased thoracic wall compliance
   * degeneration of elastic fibres of alveolar septae –> airway collapse in expiration –> VQ mismatch, increased lung compliance
   * FRC at higher lung colume due to reduced recoil
   * A-a gradient increased due to increased closing capacity, decreased activity of HPV and reduced diffusion capacity of alveoli
   * decreased sensitivity of chemoreceptors to pO2/pCO2
   * stiffening of arteries –> systemic hypertension –> LVH –> impaired diastolic relaxation –> diastolic dysfunction
   * decreased response to beta-adrenergic stimulation
   * conduction system abnormalities
   * cardiac valve degeneration
   * loss of brain cells, sensory impairment and cognitive impairment
   * decreased GFR and reduced renal plasma flow
   * obstructive nephropathy (prostatism)
   * reduced liver size and hepatic blood flow –> reduced hepatic drug clearance
   * decreased synthesis of plasma proteins –> albumin and plasma cholinesterase reduced
   * reduced s/c tissue, thin skin and fragile veins
   * loss of muscle mass (sarcopenia)
   * arthritis and bony deformity
   * impaired thermoregulation - reduced BMR, reduced peripheral vasoconstrictor response to cold exposure, shivering impaired by sarcoprenia
2. Practical
   * fragile skin
   * pressure sores
   * extravasation
   * IV access
   * regional/neuraxial difficulties (calcified ligaments)
   * positioning - bony deformities
3. Pharmacological
   * reduced blood volume, decreased total body water –> decreased Vd for water-soluble drugs
   * increased BA due to reduced 1st pass metabolism (reduced blood flow to liver)
   * decreased renal and liver blood flow
   * decreased plasma proteins - decreased drug protein binding –> higher free drug concentration
   * drug accumulation from reduced renal function and reduced liver metabolism
   * reduced MAC
   * increased sensitivity to central depressants
   * polypharmacy
   * reduced CO –> prolonged arm-brain circulation time and onset of drugs

Question 19

Parasympathetic

Answer 19

• CVS - negative inotropy of atria, negative chronotropy, dilation of blood vessels (especially genital)
• RS - bronchoconstriction, stimulation of mucus secretion
• GIT - increased motility, relaxation of sphincters, stimulation of digestive secretions
• GU - contraction of bladder
• Eye - pupillary constriction, adjustment of eye for near vision
• Liver - glycogen synthesis

Question 20

Pregnancy

Answer 20

1. Physiological
   * airway mucosal friability and oedema
   * increased MV by 50% at term (driven by 40% increased in TV), low PaCO2
   * increased dead space due to progesterone-induced bronchodilatation
   * decreased FRC by 30% in supine position due reduced RV as a result of upward displacement of diaphragm
   * increased O2 consumption by 20% at term (increased further in labour)
   * reduced thoracic wall compliance by 20% (displacement of diaphragm)
   * increased blood volume (40% at term) - red cell mass increased 20-30%, plasma volume increased 45% –> anaemia of pregnancy
   * CO increased 50% at term due to progesterone induced decreased in SVR (20%), increase in HR (25%) and increased blood volume (preload) - further increased in labour
   * Autotransfusion following delivery (500ml)
   * aortocaval compression –> reduced venous return and reduced CO –> nausea, hypotension, fetal hypoperfusion
   * progesterone induced relaxation of LOS
   * mechanical displacement of stomach and duodenum
   * increased intragastric pressure
   * delayed gastric emptying in labour
   * increased gastric pH
   * elevated WCC (increased neutrophils)
   * decreased platelet count
   * hypercoagulable state - increased fibrinogen and factors VII, X and XII
   * dilation of ureters/renal pelvis –> increased UTIs/pyelonephritis
   * increased GFR due to increased renal blood flow (50%)
   * proteinuria - tubular mechanisms insufficient to matcg increased GFR
   * increased T3/T4
   * increased epidural pressure due to venous engorgement
   * GGT, ALT, ALP and LDH slightly elevated
   * overall decreased plasma protein concentration as hepatic protein synthesis does not keep pace with increased plasma volume - lower albumin, lower plasmacholinesterase
   * ligamentous laxity
   * relative insulin resistance, increased insulin synthesis and secretion
2. Practical
   * left lateral tilt to minimise aortocaval compression
   * positioning for neuraxial procedures
   * large breasts
   * difficult airway
   * aspiration risk
   * VTE prophylaxis
3. Pharmacological
   * MAC reduced
   * altered drug bioavailability and delayed time to peak levels after oral administration due to delayed gastric emptying and increased gastric pH
   * increased elimination for some drugs due to increased CO
   * altered drug disposition, increased Vd for hydrophilic drugs due to increased TBW and extracellular fluid
   * decreased elimination of lipid soluble drugs and increased Vd for hydrophobic drugs due to increased fat compartment
   * increased renal clearnace due to increased renal blood flow and GFR
   * increased free fraction of drug due to decreased plasma protein concentrations
   * altered oral bioavailability and hepatic elimination due to altered enzyme activity eg. CYP450 and UGT

Question 21

Premature neonate

Answer 21

• Airway - smaller tubes
• Immature respiratory and cardiovascular physiology - poor lung compliance, closing capacity encroaches on FRC, blunted chemoreceptor response, relatively fixed SV, increased blood volume but small absolute volume
• Neurovascular fragility - inadeqaute cerebral autoregulation
• Anaemia, thrombocytopenia, coagulopathy - HbF
• Thermolability - non shivering thermogenesis (high metabolic requirement)
• Fluid balance
• Glucose homeostasis - limited stores, increased BMR
• Immature pharmacodynamics and pharmacokinetics
• Oxygen toxicity

Question 22

Prone Position

Answer 22

Respiratory
* potential impedement to abdominal movement –> reduces FRC
* if abdominal movement unimpeded –> increased FRC and PO2 increased, with unchanged chest wall and lung compliance
* Gravitational theory –> better VQ matching, recruitment of alveoli
* facilitates drainage of secretions

Cardiovascular
* decrease in CO as a result of reduced SV secondary to reduced pre-load
* compensatory tachycardia and increase in peripheral vascular resistance
* blood sequestration in dependent body parts, caval compression, increased intra-thoracic pressure with poor positioning and chest wall compression, positive pressure and PEEP –> reduced pre-load

CNS
* reduced CBF and raised ICP by partial occlusion of vessels and compression of venous drainage with a rotated head position - aim to keep neutral

Renal
* slight increase in UO

Question 23

Response to Aortic Cross Clamping (and release)

Answer 23

Response to cross clamping
- effects vary with level of clamp in relation to the main aortic branches and presence of collateral circulation
- potential dislodgement of atheromatous plaques —> vascular embolization and organ ischaemia
- sudden increase in SVR
- increased afterload and sudden increase in arterial pressure proximal to the clamp
- increased LVEDV
- increased myocardial contractility
- increased myocardial oxygen supply
- increased venous return
- increased lung and intracranial blood volume

Response to release of cross clamp
- reduced peripheral vascular resistance
- reduced arterial pressure
- blood sequestration in distal areas
- ischaemia-reperfusion injury
- washout of anaerobic metabolites
- myocardial suppression
- profound peripheral vasodilatation
- decreased coronary blood flow and LVEDV
- malignant arrhythmias
- hyperkalaemia
- metabolic acidosis

Question 24

Response to ECT

Answer 24

CVS
- initial parasympathetic discharge (10-20 secs) - bradycardia, hypotension, and asystole
- sympathetic surge leading to tachycardia, hypertension and increased myocardial oxygen demand
- increased tissue oxygen consumption
- potential for myocardial ischaemia or infarction, especially in those with pre-existing LV impairment or coronary artery disease
- LV systolic and diastolic function may remain decreased up to 6hrs following ECT

CNS
- increased cerebral oxygen consumption, blood flow and ICP
- post procedure cognitive deficits - confusion, drowsiness, retrograde or anterograde amnesia
- raised IOP
- headache
- rare effects include transient ischaemic deficits, ICH, cortical blindness, prolonged seizures/status epilepticus

GI
- raised intragastric pressure (not felt to be clinically significant)
- nausea
- anorexia
- increased salivation

MSK
- myalgia
- weakness
- fractures (rare with NMBAs)

Other
- dental damage
- lips/tongue lacerations

Question 25

Serotonin

Answer 25

• CNS - mood, sleep, memory, learning, behaviour, cognition, anxiety
• GIT - appetite and digestion, vomiting
• Immune - wound healing
• Bone - bone health
• Sexual function

Question 26

Smoking

Answer 26

• Respiratory - decreased oxygen carriage (carbon monoxide), hypoxaemia, hypersensitive airway reflexes, decreased ciliary function, decreased FEV1, increased closing capacity, increased risk of bronchospasm/laryngospasm, mucus hypersecretion and retained secretions, damage to ciliary structure and function, infection (decreased neutrophil and lymphocyte activity)
• Cardiovascular - adrenergic agonist effects of nicotine –> increased HR, SVR and BP, increased myocardial oxygen demand, decreased coronary blood flow, cardiac dysrhythmias
• Haematological - increased platelet aggregation and haematocrit –> increased incidence of thromboembolic events, polycythaemia
• CNS - relaxation, addiction
• GI - relaxation of LOS, increased GORD and gastric ulceration, decreased PONV, increased incidence of Crohn’s, decreased incidence of UC
• Immune - inhibition of immune function
• Pharmacological - induction of CYP450 1A2 and 2B6 enzymes, greater opioid requirements
• Surgical - tissue hypoxia –> delayed fracture healing (abnormal bone metabolism), anastamosis healing and wound healing, post operative pulmonary infection
• Co-morbidities - cancer, atheromatous disease (IHD, PVD, CVA), COPD, VTE, SAH, erectile dysfunction, miscarriage and still-birth, Crohn’s

Intraoperative Complications
- reintubation after planned extubation
- laryngospasm
- bronchospasm
- aspiration
- hypoventilation
- hypoxaemia
- pulmonary oedema
- (increased risk if younger and/or obese)

Postoperative Complications
- increased mortality
- increased rate of all cardiac, pulmonary and septic complications
- pneumonia, unplanned intubation, mechanical ventilation
- cardiac arrest, MI
- CVA
- superficial wound infection, deep wound infection
- delayed fracture healing
- poor anastomosis healing

Effect of GA on smokers
- central respiratory

Question 27

Smoking cessation

Answer 27

Stopping smoking before surgery reduces the risk of postoperative complications. Evidence varies as to the optimum time to quit - it is likely that even a brief period of smoking cessation may confer some benefit.

• within minutes - BP and HR decrease (nicotine), relaxation of LOS returns to normal
• within 48hrs - nerve endings and sense of smell/taste start recovering
• within days - CO levels in blood decrease to normal
• within a week - mucociliary clearance starts to improve
• within weeks - cough and wheeze decrease
• within 3 months - circulation and lung function improve - goblet cell hyperplasia regresses and alveolar macrophages decrease
• within 1yr - decrease in cough and SOB
• within 1-2yrs - risk of CAD halves
• within 5-10yrs - risk of stroke falls to the same as that of a non smoker, risks of many cancers also decrease significantly
• within 10yrs - risk of dying from lung cancer is halved, risks of laryngeal and pancreatic cancers decrease
• within 15yrs - risk of CAD drops to the level of a non smoker, lowered risk for developing COPD

Effects may be permanent
- alveolar destruction
- smooth muscle hyperplasia
- fibrosis

Question 28

Standing from Supine

Answer 28

• Gravity —> increased pooling in capacitance vessels —> decreased venous return (preload), decreased SV, decreased CO and BP
• Baroreceptors - decreased firing rate results in decreased inhibition of vasomotor centre —> increased sympathetic outflow
• Peripheral vasoconstriction —> increased SVR and BP
• Peripheral vent constriction —> increased preload
• HR and contractility increase to restore CO
• Baroreceptors therefore increase firing rate again

Question 29

Starvation

Answer 29

Physiological goal - preserve plasma glucose levels for brain metabolism
1-6hr
- liver - glycogenolysis (glycogen —> glucose under action of G6P) + gluconeogenesis (glycerol and gluconeogenic amino acids —> glucose)
- decreased insulin, increased glucagon —> increased hepatic glycogenolysis, gluconeogenesis, amino acid uptake, urea genesis and protein catabolism
- catecholamine secretion —> stimulation of lipolysis and glucogenolysis
- cortisol secretion —> enhanced extra-hepatic protein catabolism and hepatic utilisation of amino acids for gluconeogenesis

6h-48h
- glycogen stores are depleted by ~24hrs (8000kJ in 70kg male)
- remaining glucose shunted to brain, RBCs, inflammatory cells, wound tissue (glucose metabolism is shut down in other tissues)
- amino acid demand is met by skeletal muscle proteolysis
- respiratory quotient falls to 0.7 (RQ = CO2/O2 ratio when fat is catabolised)
- 500ml fluid deficit met through venous capacitance vessels in lower limb and increased ADH production

48h-2w
- body starts to conserve protein
- FFAs and TGs are used as fuel sources
- lipase in adipose tissue hydrolyses TGs —> long chain FFAs and glycerol
- some FFAs —> used directly
- some FFAs —> liver and metabolised to ketones —> used by most tissues and as a back up substrate in the brain
- cori cycle - allows lipid-derived energy in glucose to be shuttled to peripheral glycolysis tissues, which in turn sends the lactate back to the liver for re-synthesis to glucose
- brain switches to ketoacids for fuel
- with prolonged fasting, amino acids from skeletal muscle become predominant substrate for gluconeogenesis

2w
- reduced BMR
- body weight reduced to about 85% of normal
- starvation occurs when fat stores are depleted and proteolysis is the only remaining energy source

Question 30

Surgery

Answer 30

1. Neuroendocrine-metabolic response
   * activated by hypothalamus in response to hypotension/inflammation
   * SNS activation and release of adrenaline and noradrenaline –> increased glucagon and decreased insulin from pancreas, vascoconstriction of arteriolar smooth muscle leading to reduced renal blood flow –> increased renin, angiotensin and aldosterone
   * CRH secretion activating HPA axis –> release of ACTH and GH –> cortisol secretion
   * GH secretion –> hepatic and muscle lipolysis and glycogenolysis increase –> hyperglycaemia
   * GH –> insulin resistance
   * increased cellular metabolic activity
   * increased coagulability of blood
   * action on posterior pituitary increases ADH release –> reduced UO, retention of salt and water
   * increased prolactin
   * reduced testosterone, T3/T4 concentrations
   * blunted action of normal feedback mechanisms
2. Inflammatory-immune response
   * local tissue damage –> innate immune cells act locally (neutrophils, macrophages, NK cells)
   * release of proinflammatory cytokines (IL-1B, IL-6, IL-8, TNFa) and acute phase reactants
   * relative increase in t-helper 2 lymphocytes reslutng in impaired immunity
   * neuro-endocrine response to local tissue damage –> release of cortisol, adrenaline and norad –> activation of immune cells in blood –> release of anti-inflammatory cytokines (IL-4, IL-10, TGFB)
3. Psychological
   * fatigue
   * behavioural change

Question 31

Sympathomimetic

Answer 31

• CVS - chronotropy, inotropy, vasoconstriction
• RS - bronchodilation, inhibition of mucus secretion
• GIT - decreased motility, contraction of sphincters, inhibition of digestive secretions
• GU - relaxation of bladder
• Eye - pupillary dilatation, adjustment for far vision
• Liver - glycogenolysis (release of glucose)
• Adipose cells - lipolysis (release of FFAs)

Question 32

Valsalva (40mmHg for 10 secs)

Answer 32

Phase I
- sudden increase in intrathoracic pressure leads to increased venous return from compressed capacitance vessels
- BP increases (according to Starling’s Law) —> increased firing of Baroreceptors with compensatory decreased HR
Phase II
- decreased venous return, decreased preload —> decreased CO, decreased Baroreceptor firing and decreased inhibition of sympathetic outflow
- HR increases and vasoconstriction occurs
Phase III
- release of pressure, BP falls, blood pools
Phase IV
- increased venous return, increased CO and BP as blood is ejected into squeezed vessels
- baroreceptor firing increases resulting in decreased HR as sympathetic outflow is inhibited