Adrenoceptors
- 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
Altitude
- 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)
Brainstem Death
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
Chronic Alcoholism
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
Dopamine
- 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
Exercise
- 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
Fluid bolus
1000ml of 0.9% saline given stat to normovolaemic 70kg adult
- 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
Fluid bolus
1000ml of 5% Dextrose
- Glucose taken up and metabolised
- 85ml per 1000ml remains in circulating volume
- ADH release decreased as free water decreases osmolality (osmoreceptors triggered)
Haemorrhage
Sudden loss of 1000ml (20% circulating volume)
- 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
Haemorrhage
Sudden loss of 2000ml
- 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
Histamine
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
Hypothermia
- 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
Massive Transfusion
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
Muscarinic Effects
- GIT - salivation, defecation, abdominal cramps, GI upset, vomiting
- GU - urination
- Eye - lacrimation, meiosis
- CVS - bradycardia
- RS - bronchospasm, bronchorrhoea
- CNS - agitation, confusion, seizures, coma
Neonates
- 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
Nicotinic Effects
- CVS - tachycardia, vasoconstriction, hypertension
- MSK - weakness, twitching, fasciculations, muscle cramps, hypotonia
- Eyes - mydriasis
- CNS - agitation, confusion, seizures, coma
- General - perspiration
Obesity
- 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 - Practical
* venous access/IV lines
* BP monitoring
* difficult regional/neuraxial anaesthesia
* surgical access
* limb tourniquets
* positioning and manual handling
* weight limits of beds/trollies - 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)
Old Age
- 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 - Practical
* fragile skin
* pressure sores
* extravasation
* IV access
* regional/neuraxial difficulties (calcified ligaments)
* positioning - bony deformities - 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
Parasympathetic
- 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
Pregnancy
- 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 - Practical
* left lateral tilt to minimise aortocaval compression
* positioning for neuraxial procedures
* large breasts
* difficult airway
* aspiration risk
* VTE prophylaxis - 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
Premature neonate
- 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
Prone Position
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
Response to Aortic Cross Clamping (and release)
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
Response to ECT
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
