Cell Cycle

Actively dividing cells undergo a series of stages known as the cell cycle.

  • Gap 0 (G0; quiescent phase)
    • Most non-proliferative cells in the body are in this phase and are not actively replicating.
  • Interphase
    • Gap 1 (G1)
      • Metabolic changes prepare the cell for division.  At a certain point (restriction point or G1 checkpoint), the cell is committed to division and moves onto S-phase
    • Synthesis phase (S phase)
      • DNA synthesis replicates the genetic material such that each chromosome is duplicated into two chromatids
    • Gap 2 (G2)
      • Metabolic changes assemble the cytoplasmic materials required for mitosis and cytokinesis
  • Mitotic phase (M phase)
    • Prophase
      • Nuclear membrane breaks down into a number of small vesicles
      • Centrosome duplicates and each one migrates to opposite poles of the cells where they organise production of microtubules that form spindle fibres (mitotic spindle)
      • Chromosomes condense into compact structures.  Sister chromatids are held together via the centromere structure
    • Prometaphase
      • Chromosomes migrate to the middle of the cell (the metaphase plate).
      • Spindle fibres attach to centromeres of the chromosomes.
    • Metaphase
      • Chromosomes align along the metaphase plate
    • Anaphase
      • Centromeres divide and daughter chromatids are pulled apart by spindle fibres
    • Telophase
      • Nuclear membrane reforms around the new chromosomes at either pole of the cell.
      • Chromosomes uncoil and become diffuse once more and spindle fibres are broken down
    • Cytokinesis
      • Constriction of the cytoplasm to divide into two new cells.

Preoperative management of PMHx/Drugs

See also Diabetes and Surgery

Cardiac disease

  • Drugs:
    • Statins can be continued as normal
    • Beta-blockers can be continued (but should not be started if patient was not previously taking them)
    • Antiplatelets should be withheld 7-14 days prior
    • ACE inhibitors and ARBs should be withheld the day of surgery (they can cause marked hypotension with GA)
    • Diuretics should also be withheld on the day of surgery
    • Warfarin should be withheld 3-5 days before surgery (see below)
    • Calcium channel blockers can be continued
  • Pre-operative risk and management
    • Get a cardiology review if there is any concern over the patient’s fitness for surgery
    • For patients undergoing non-cardiac surgery, the ACC/AHA have produced the following guide flow-chart

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    • **Risk**
      • Using the Revised Lee Cardiac Index (RLCI)
        • Any 2 or more of the following would be high risk (>1% risk of major cardiac event)
          • PMHx of MI, (positive ETT, Angina, use of GTN, ECG with pathological Q waves or signs of ischaemia)
          • PMHx of CCF/HF; (pulmonary oedema, PND, bilateral rales or S3 gallop, CXR showing pulmonary vascular redistribution)
          • PMHx of stroke/TIA
          • Preoperative treatment with insulin
          • Preoperative eGFR <30ml/min
    • **METs** (Metabolic equivalent- 1= 3.5ml O2 uptake/kg/min (resting O2 intake))
      • These are similar to assessing someone’s exercise tolerance
        • Self care, eat, dress, toilet etc – 1 MET
        • Walk up a flight of stairs/hill or walk briskly for prolonged time (~4 METs)
        • Can do heavy work, or climb 2 flights of stairs (6-10 METs)
        • Can do strenuous exercise (10+ METs)
  • In patients with unstable Coronary artery disease, it may be appropriate to perform revascularisation (PCI) prior to surgery.  However, this would only represent a minority of patients.
  • Patients with Valvular disease (in particular stenoses) should be considered for peri-operative antibiotic therapy to reduce the risk of endocarditis
  • Post-operatively
    • Make sure to monitor any signs of silent ischaemia (cardiac monitoring) and heart failure

Respiratory Disease

  • The main issue with surgery in patients with respiratory disease is due to anaesthesia
    • Sedation can cause hypoventilation and atelectasis, worsening hypoxaemia and hypercapnia, increased V/Q mismatch
    • Airway manipulation can cause a reactive bronchospasm which can be severe in patients with airways disease
    • Controlled ventilation may cause impaired airflow and increased hyperinflation of the lungs in patients with COPD (and even ‘dynamic hyperinflation’ i.e. continuous inflation of the lungs
    • As such, if possible, avoid general anaesthesia (i.e. use regional anaesthesia)
  • Assessing/managing risk
    • Pulmonary function tests are crucial.  Note that most operations will result in a reduction in pulmonary function peri- and postoperatively, and this should be taken into account when deciding if surgery is appropriate
      • Deep breathing exercises +/- chest physiotherapy/rehabilitation is often useful in patients with COPD to improve function prior to surgery
      • If FEV1/FVC ratio <50%- risk of respiratory failure following surgery is increased dramatically
    • Smoking cessation- this will reduce the risk of post-operative complications including wound healing and pulmonary complications
    • Intra-operative PEEP (positive end expiratory pressure) and post-operative non-invasive ventilation (CPAP or BIPAP) may prevent respiratory failure
    • Make sure to correct any exacerbations prior to surgery
  • Drugs
    • Inhalers/nebulisers should be taken pre-operatively (ideally close to induction)
    • For steroid use, see below
    • Note that anaesthetic drug choice may be important
      • Nitrous oxide may rupture bullae in COPD and cause pneumothorax
      • Opiates usually cause respiratory depression
      • Post operative pain may result in respiratory depression
      • General anaesthesia
        • Reduces muscle tone and thus residual capacity
        • Increases airway resistance and reduces lung compliance
        • Causes atelectasis in dependent zones (causing increased V/Q shunting)
        • Increases ventilatory dead space

Liver Disease

  • Assessment
    • Contraindications to surgery include Acute or fulminant hepatitis, alcoholic hepatitis and severe chronic hepatitis
    • For other patients with liver disease, there are several scoring systems used to categorise risk (Child-Pugh and MELD scores)
      • In general, CP class A/MELD score <10 can undergo elective surgery; CP class B/MELD score 10-15 can undergo elective surgery with caution (see below) and CP class C/MELD score >15 should not undergo elective surgery
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  • Optimisation
    • In patients with prolong PT- vit K can be given pre-operatively to correct this
    • In patients with ascites and oedema, diuretics may be used to reduce this (alternatively ascites may be drained intraoperatively)
    • Electrolyte abnormalities should be corrected and renal function evaluated/optimised.
    • Patients with gastroesophageal varices should be treated optimally (whether with betablockers/nitrates or with banding/ligation) prior to surgery
    • Where possible, correct any jaundice prior to surgery

Diabetes (see diabetes and surgery)

Thyroid disease

Hypothyroid

  • Potential adverse outcomes
    • Low cardiac output and increased risk of CVD (increased risk of MI; hypotension)
    • Blood loss poorly tolerated
    • Respiratory centre less responsive to O2 and CO2 pressures (hypoventilation; acidosis)
    • More sensitive to opiates
    • Hypothermia
    • Hypoglycaemia
    • Hyponatraemia
  • Management
    • In overt hypothyroidism- correction (levothyroxine) should ideally be given prior to surgery where possible
      • In severe cases (myxoedema coma)- T3 and T4 may be given prior to surgery

Hyperthyroid

  • Increased risk of
    • tachycardia; labile BP and arrhythmias (increased output and contractility due to increase in O2 demand)
    • dyspnoea (similar reason)
    • Thyroid storm- an uncontrolled release of thyroid hormone.  Causes hyperthermia and metabolic acidosis (high mortality)
      • Note that treatment is the same as for hyperthyroidism but increased dose/frequency and adequate ITU support. 
  • Management
    • Ideally controlled with carbimazole or propylthiouracil prior to surgery
      • If surgery is urgent and hyperthyroidism not controlled- potassium iodide drops may temporarily halt to the release of hormones (not temporarily)
    • Propanolol can be used for symptomatic relief

A note about some drugs

  • Steroids
    • Ideally, patients should not be on steroids, as they can lead to
      • Poor wound healing
      • Infection
      • Impaired glucose tolerance
      • Muscle wasting
      • Electrolyte disturbances
      • Masking of sepsis
    • However, patients that are taking or have recently (< 3 months) taken steroids at a dose of >10mg/day are at risk of adrenocorticoid insufficiency should they be stopped.
      • Peri-operatively, this could potentially cause cardiac failure or an Addisonian crisis
      • As such, steroids should be given to cover for this in these patients
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        • Dosing equivalents: Prednisolone 10 mg is equivalent to Betamethasone 1,5 mg or Cortisone acetate 50 mg or Dexamethasone 1.5 mg or Hydrocortisone 40 mg or Deflazacort 12 mg or Methylprednisolone 8 mg
  • Warfarin
    • Due to the risk of bleeding, warfarin should ideally be stopped 3-5 days prior to surgery (INR <1.5)
    • If the risk of thrombosis is high (e.g. metallic heart valve); then warfarin should be replaced with heparin.  If the risk is relatively low e.g. AF (without previous CVA), then it may be possible to stop without any heparin substitute.
  • Antiplatelet agents (aspirin, clopidogrel etc)
    • Should be stopped 7-14 days prior to surgery due to risk of bleeding.
  • Anti-epileptics
    • Should be continued where possible

Olfactory Nerve (CN I) and Smell

Background

  • CN I/Olfactory nerve is the shortest cranial nerve and consists of special unmyelinated sensory nerves responsible for sense of smell
    • They are, however, covered in Schwann cells

The olfactory pathway

  • Odourant molecules can enter your system via your nose or mouth and nasopharynx.
  • They reach an area called the olfactory mucosa in the nasal cavity
    • Here, they come into contact with the olfactory receptor neurons and activate receptors to initiate an action potential
      • The axons of these cells traverse the cribiform plate of the ethmoid bone at the roof of the nasal cavity and become the olfactory bulb.
    • In the bulb, these neurons communicate with specialised mitral cells at the synaptic glomeruli.  These then pass posteriorly into the olfactory tract
      • This runs along the inferior aspect of the frontal lobe.  At the anterior perforated substance, the tract divides into medial and lateral stria.
        • Medial stria connects to the limbic system and communicates with the contralateral olfactory medial stria
        • Lateral stria continues to the primary olfactory cortex in the temporal lobe, which goes on to communicate further with the limbic system (amygdala, piriform cortex and olfactory tubercle) and orbitofrontal cortex.
  • Note
    • CN I is covered by pia and arachnoid layers (i.e. continuation of the brain).  It does also not join with the brainstem.
    • The olfactory nerve is capable of regeneration.

Olfactory Dysfunction (Anosmia)

  • Temporary anosmia is not uncommon in local conditions of the nose e.g. infection.
  • Other causes of anosmia/abnormal sensation of smell include
    • Tumours in the olfactory groove (meningioma)
    • Head injury- damage to the cribiform plate may cause damage to the olfactory receptors
    • Neurodegenerative disease e.g. Parkinson’s Disease, Huntington’s and Alzheimer’s disease
    • Genetic conditions e.g. Kallman Syndrome, Primary ciliary dyskinesia, Foster Kennedy Syndrome
    • Partial epilepsy (pre- and post-ictal)

Testing CN I

  • Ask the patient if they have noticed a change in their sense of smell.
  • A more formal assessment of smell can involve using common smells

Slipped Upper Femoral Epiphysis

Background

  • One of the most common adolescent hip problems (around 10/100,000 children per year)
    • The epiphysis usually slips posteriorly relative to the diaphysis of the femur
  • Most common in boys and occurs usually around the growth spurt in adolescence (mean age 13)
    • More common in overweight children; left hip slightly more prevalent
    • Whilst weight and mechanical factors (as well as others e.g. hypothyroidism; hypopituitarism; radiation treatment) may play a role, SUFE represents an underlying instability of the proximal growth plate- the exact cause of which is unknown

Classification

  • The most important classification is whether the joint is
    • Stable (90%) i.e. the patient is still able to weight bear (function relatively unimpaired)
    • Unstable (10%) the patient is unable to weight bear- requires urgent management
  • Other classifications include
    • time-based i.e. acute (symptoms for < 3 weeks); chronic and acute on chronic
    • Southwick angle classification (measurement of the difference between both hips in the femoral head-shaft angle on the frog radiograph)
      • Mild <30°; Moderate 30-50° and severe >50°
    • Grading by degree of slippage
      • I (Up to a third); II (up to a half); III (more than half)

Presentation

  • Most commonly presents with hip and/or groin pain
    • Often an acute event but may present but can have had mild symptoms preceding this
    • Can present as radiated knee pain
    • Worse on movement/weight bearing
    • May cause antalgic gait
    • May limit hip movement- particularly internal rotation and abduction (indeed the leg may rest in external rotation/adduction)
  • Differential
    • Perthes disease
    • Septic arthritis
    • Developmental dysplasia
    • Synovitis

Investigation

  • X-rays
    • An x-ray of the pelvis will usually detect a SUFE
      • Trethowan’s sign
        • Klein’s line (the line drawn up the lateral edge of the neck of the femur) should intersect the femoral head. It fails to do so in SUFE due to slip.
      • You may also see widening of the growth plate (epiphysiolysis) and blurring of the proximal femoral metaphysis (overlapping of the metaphysis and displaced epiphysis)
  • Occasionally, where diagnosis is in doubt, a CT or MRI may help confirm the diagnosis

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Management

  • Surgical management of the affected side
    • Percutaneous fixation with cannulated screw(s)
  • There is some controversy as to whether to fix the other side also (bilateral in up to 20% of cases)- currently not recommended
  • Without fixation, particularly in unstable cases, there is a risk of osteoarthritis; chondrolysis (breakdown of cartilage and subsequent bony degeration/damage) and avascular necrosis of the femoral head

Scoliosis

Abnormal curvature of the spine in the coronal plane (>10°).

Background/epidemiology

  • Scoliosis <10° is not abnormal (considered a normal variation)
    • Around half of patients with AIS (adolescent idiopathic scoliosis- most common form) develop a curvature >70°
  • It is estimated to affect 2-3% of the population; 80% is idiopathic
  • The most common type is adolescent idiopathic scoliosis (affects between 0.5 and 3% of people, most commonly between the ages 12-14, and, in IAS, is much more common in females (90%)
    • Other common types include
      • Juvenile idiopathic scoliosis (aged between 3 and 10; more common in females; likely to progress/require surgery due to curvature presenting prior to growth spurt at puberty)
      • Infantile idiopathic scoliosis (< age 3; more common in males)
      • Congenital idiopathic scoliosis
      • Neuromuscular and Pathologic Scoliosis (Secondary conditions)
  • In older children, curvature is usually to the right.  In infants, left sided curvature is more common.
  • As curvature progresses, vertebral bodies rotate towards convexity and spinous processes away from convexity.  In severe cases, this can impair cardiorespiratory function.

Presentation

  • May be asymptomatic and detected by chance- note that screening is not routinely offered in the UK (some patients also have a family history)
  • Usually present with back (thoracic) pain
  • On examination (see back examination)
    • Shoulders/waistline may not be level and/or ribs/scapulae may be more prominent in certain areas
    • Note that the hip usually protrudes on the concave side
    • Adam’s Test
      • Ask the patient to bend forward- a fixed scoliosis becomes more prominent
    • It is important also to look for leg length inequality; any focal neurology (change in reflexes) or any signs of congenital/hereditary conditions e.g. midline skin defects, cafe au lait spots.

Investigations

  • XR spine
    • Calculating the Cobb angle (between the uppermost and lowermost vertebra of the primary curvature seen on erect AP XR) is important in deciding management/prognosis

Management

  • Exercises
    • Back exercises have very little effect on curvature but can maintain mobility/range of movement and may improve pain
  • Bracing
    • Used mainly for curvatures between 20° and 40°, which are well balanced (i.e. have a compensatory secondary curve), and in patients who are growing (in puberty) in which a brace may halt the progression and occasionally improve the deformity
    • Usually not definitive- used mainly to maintain curvature stability in younger patients until adolescence when operative management may be more suitable
  • Surgery
    • Spinal fixation (posterior spinal fusion most common) can be used in patients with a curvature of >40°
      • rare but carries risk of neurological complications

Kyphosis and Scheuermann’s disease

Kyphosis is the apical-dorsal curvature of the spine in the sagittal plane (i.e. curves away from the body).  There is normal thoracic kyphosis of around 20-40°.  Abnormal kyphosis is a curvature (measured as Cobb’s angle (between T2-T12)) of >45°.

Background/Aetiology

  • Pathological kyphosis most commonly occurs in the thoracic spine although rarely can occur elsewhere in the spine.
  • It is not uncommon amongst the elderly population (occurs in around 20-30% of patients >65) and is more common in women
  • Risk factors include
    • Osteoporosis; vertebral (wedge) fractures and degenerative disc disease
    • Problems with proprioception; poor posture; spinal muscle weakness/attenuation
    • Other causes include trauma; ankylosing spondylysis and other arthritides; and rarely neoplasms and infections
  • Kyphosis can impair physical functioning; quality of life and mortality directly and indirectly
    • Increased risk of vertebral fracture
    • May affect balance and likelihood of falls
    • Decline in gait speed/mobility
    • In some cases, can impair pulmonary, GI and gynaecological function

Presentation

  • Most patients are asymptomatic and kyphosis is purely aesthetic
  • Some may present with back pain
  • On examination, there is usually a thoracic kyphosis and there may also be compensatory lumber hyperlordosis
    • Tight hamstrings/difficulty with straight leg raise may also be present
  • Rare but important features include those of myelopathy i.e. neurological problems (including pain/altered sensation, weakness, altered tone/reflexes, problems with gait etc)
  • Indications for surgical management (note not absolute)
    • Neurological deficits
    • Kyphosis >70° (no pain) or >65° with pain
    • Loss of anterior vertebral height >50%

Management

  • For purely postural related kyphosis, exercises and education about posture may benefit patient symptoms (may not entirely relieve kyphosis)
  • Surgical management is reserved only for severe cases
    • Smith-Peterson osteotomy, pedicle subtraction and vertebral column resection can all be options for corrections
    • Anterior release spinal fusion may also be used in Scheuermann’s disease/severe cases

Scheuermann’s disease

  • In children and adolescents, abnormal kyphosis can occur as what is thought to be the result of a genetic defect causing collapse of the vertebrae
    • A family history is common
    • Patients
  • Classically defined as anterior wedging of >5° across three consecutive vertebrae, and is different from postural kyphosis by the rigidity of the kyphosis (not corrected by hyperextension)

IgA Nephropathy

Background

  • Also known as Berger’s disease
  • Most common form of idiopathic glomerulonephritis resulting in CKD
    • Around 30-40% of patients go on to develop end-stage CKD within 20 years.
    • Usually presents in young adults and there is a slight male predominance (males tend to have a poorer prognosis)
    • Can be associated with a number of other conditions
      • e.g. Henoch Schonlein purpura; SLE; autoimmune hepatitis; ankylosing spondylitis

Pathophysiology

  • Characterised by IgA- and C3- complex deposition in the glomerular mesangium
  • It is uncertain as to the exact mechanism by which this occurs but patients with IgAN seem to have an raised level of circulating IgA
    • It is thought that a specific type of IgA (galactose-deficient IgA) is responsible
  • As the disease progresses, several features may be seen (all contribute towards a poorer prognosis- collectively known as Oxford classification)
    • Increased mesangial cellularity
    • Segmental glomerulosclerosis
    • Endocapillary hypercellularity
    • Tubular atrophy/interstitial fibrosis

Presentation

  • Usually presents with frank haematuria following an upper respiratory tract infection
    • May also present with microscopic haematuria (more common in older adults) or an AKI
  • Usually this resolves in several days
    • If haematuria persists, there is usually progression to renal failure

Investigation

  • Urinalysis (dipstick)
    • Usually shows protein and blood
  • Urine microscopy (red cells, leukocytes and casts)
  • Urinary protein and creatinine (24 hour-collection)
  • Plasma IgA may be raised in around 50% of cases
  • Renal biopsy will give a definitive diagnosis

Management

  • Manage any hypertension – ACE inhibitors have shown to be beneficial
    • ACEIs plus Angiotensin receptor blockers may have additional benefit
  • Steroids (a 6 months course of prednisolone) is thought to be protective against progression to ESKD
  • Regular monitoring of renal function is important