Diarrhoea

Diarrhoea is both a symptom and a sign. As a symptom, it is whatever the patient says it is. As a sign, diarrhoea is an increase in stool weight of more than 200g per 24 hours in a person on a western diet.

Pathophysiology:

The pathophysiological mechanisms resulting in diarrhoea can be divided into 4 major groups.

1) Osmotic diarrhoea occurs when non-absorbable solutes accumulate within the small intestine - Carbohydrates, Fat, bile salt and other substances such as lactulose & magnesium.

It is helpful to know the effect of fasting on stool output: when the diarrhoea ceases with fasting, a dietary component is likely to be the cause.

The most common carbohydrate malabsorption is lactose intolerance secondary to primary lactase deficiency or lactase nonpersistance.

2) Secretary diarrhoea results when the secretagogues increase the chloride secretion through the activation of cystic fibrosis transmembrane regulator ( CFTR ) or inhibit the sodium and chloride absorption.

Bacterial toxins are the common cause of secretary diarrhoea. However, Non-osmotic laxatives, bile salts and short chain fatty acids are other agents that can damage electrolyte transport and result in secretary diarrhoea. Hormonal secretion from tumor can also cause secretary diarrhoea ( such as gastrin and vasoactive intestinal peptide ).

3) Inflammatory diarrhoea - includes invasive infective agents, irradiation, cancer, inflammatory bowel disease, gluten sensitive enteropathy, ischaemia and drugs.

4) Dysmotility such as thyrotoxicosis, diabetes mellitus, irritable bowel syndrome and laxative abuse.

WHO definition of bone mass

Normal bone mass: T score > -1
Low bone mass: T score -1 to -2.5
Osteoporosis: T score < - 2.5
Established ( severe ) osteoporosis: T score < - 2.5 and one or more osteoporotic fractures

Foot Drop

Foot drop is due to weakness of tibialis anterior, a muscle supplied by the common peroneal nerve ( L4/5 roots ).

Anatomy of sciatic nerve:

It is derived from spinal nerves L4 through S3. It supply adductor magnus in thigh and finally gives off common peroneal branch and tibial nerve.

Common Peroneal Nerve supplies

• Tibialis anterior causing dorsiflexion
• Peroneal longus causing eversion
• Extensor digitorum longus and extensor hallucis longus causing extension of toes
• Sensory supply to anterolateral aspect of leg and dorsum of foot

Tibial Nerve supplies

• Tibialis posterior causing inversion of foot
• Gastronemius, soleus and plantaris causing planter flexion
• Flexor digitorum longus and flexor hallucis longus causing flexion of toes
• Sensory supply to sole of the foot

Causes of foot drop:

Without weakness of inversion

• Common Peroneal nerve palsy

With weakness of inversion

• Sciatic nerve palsy ( give rise to common peroneal nerve and tibial nerve )
• Peripheral neurone disease
• L4/5 root lesion including Cauda equina lesion
• Spinal cord lesion
• Cortical lesion

How to differentiate?

Weak dorsiflexion and eversion without weak inversion. ( patient will also have weak externsor hallucis longus ) - Common Peroneal Nerve lesion.

If there is involvement of inversion, then the patient has sciatic nerve lesion, L4/5 root/ plexus or cord lesion ( depending on whether it is LMNL or UMNL ).

L4/5 lesion alone causes weak dorsiflexion, eversion and inversion. It also causes weakness of hip abduction and sensory loss in L4/5 distribution.

ECOG PERFORMANCE STATUS - ECOG
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours
3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5 Dead

Surgical Filter
Congenital
Acquired -

• It - Infective
• Is - Inflammatory
• Very - Vascular
• True - Trauma
• That - Tumour
• All - Autoimmune
• Is - Idiopathic
• Mine - Metabolic

Causes of Carpal Tunnel Syndrome

• Idiopathic- although you tend to find this in obese females,
• Pregnancy,
• Contraceptive pill,
• Endocrine causes- acromegaly, hypothyroidism,
• Rheumatoid arthritis,
• Amyloidosis,

Gradations of Murmurs

Grade 1 Very faint, heard only after listener has "tuned in"; may not be heard in all positions.

Grade 2 Quiet, but heard immediately after placing the stethoscope on the chest.

Grade 3 Moderately loud.

Grade 4 Loud, with palpable thrill (ie, a tremor or vibration felt on palpation).

Grade 5 Very loud, with thrill. May be heard when stethoscope is partly off the chest.

Grade 6 Very loud, with thrill. May be heard with stethoscope entirely off the chest.

Perioperative Medicine - Cardiac

Mechanism of Peri-operative MI:

• Plaque fissuring due to Inflammatory state and stress
• Hypercoagulability precipitating acute coronary thrombosis.
• Hypoxic state secondary to anaesthesia, hypothermia, bleeding and anaemia.

Peri-operative cardiac risk can be assessed by many different methods:

Eagle Criteria

1. Age more than 70 yrs.
2. DM - requiring therapy other than diet
3. CCF
4. MI - q wave on ECG
5. History of angina

2 Risk factors - < 5% risk
3 or more risk factors - 30 - 40 % risk

Revised Cardiac Risk Index ( Lee et al )

1. High risk surgery - AAA repair, thoracic and abdominal
2. IHD - AMI, Q wave, angina, nitrates, EST positive
3. CCF
4. CVA - stroke, TIA
5. Pre-op insulin
6. Serum creatinine > 180 micromol/L

3 risk factors - intermediate
4 or more risk factors - high risk

High Risk patient can be further assessed by doing Dobutamine Stress Echocardiogram.

• If ECG changes at high work load - 20 % risk
• If ECG changes at low work load - 70 % risk

Management,

Cardiac Prophylactic measures include:

• Coronary revascularisation ( PCI or CABG )

• Adjuvant therapies - Beta blockers & Aspirin

• No high quality evidence of decreased perioperative cardiac risk according to: other anti-anginal medications and type of surgery - open vs laproscopic
  

Coronary revascularisation ( PCI or CABG )

The underlying mechanism of perioperative cardiac event is different from usual cardiac event as described before. The decision for revascularisation should rest on proven indications in non-operative setting - for symtomatic control or for prognosis.

Indications in which PCI is beneficial for prognosis include:

1. Left main coronary lesion
2. Proximal LAD lesion
3. Triple vessel disease
4. Ejection Fraction less than 40 %

If PCI is done, surgery should be deferred for 6 weeks or longer. ( within 6 weeks - 20 % mortality, 18 % non-fatal MI and 28 % major bleeding )

Classification of Antibiotics by Target site of activity:

1. Inhibitors of cell wall synthesis

Beta - lactam:

• Penicillins

• Cephalosporins

1st generation ( cephalexin ) has good G positive cover.
2nd generation ( Cefoxitin ) has good G negative and anaerobic cover.
3rd generation ( Ceftriaxone, Cefotaxime and Ceftazidime ) has good G negative cover.
4th generation ( Cefepime ) has good cover for both G positive and negative cover.

• Carbapenem - imipenem, meropenem and ertapenem

Imipenem and meropenem are essentially the same as giving combination of ampicillin, flucloxacillin, gentamycin and metronidazole. However, they don't cover Stenotrophomonas and E. faecium.
Ertapenem does not cover Pseudomonas and Acinectobacteria
Can be used in renal failure.

• Monobactam - Aztreonam

Aztreonam has the same antibiotics spectrum as gentamycin but it does not have renal toxicity.

Glycopeptides:

• Vancomycin

• Teicoplanin

Others:

• Cycloserine

• Bacitracin

2. Inhibition of protein synthesis

30s ribosomal subunit:

• Aminoglycosides

• Tetracycline

50s ribosomal subunit:

• Chloramphenicol

• Clindamycin

• Macrolides

• Fusidic Acid

3. Inhibition of nucleic acid synthesis

Block folic acid synthesis:

• Trimethoprim

• Sulphonamides

DNA Gyrase inhibition:

• Fluoroquinolones - Norfloxacin, Ciprofloxacin, Moxifloxacin, Gatifloxacin.

Covers G negative aerobic including Legionella
Only ORAL antibiotics which cover Pseudomonas
Cipro has poor G positive cover
Moxi and Gati have good G positive cover but slightly less G negative cover than Cipro
Cipro has poor anaerobic cover but Moxi and Gati has better anaerobic cover.

RNA polymerase inhibiton:

• Rifamycin e.g., Rifampicin

4. Inhibition of cell membrane function e.g., Colistin.

5. Newer antibiotics:

• Quinupristin - dalfopristin
• Linezolid - only ORAL antibiotics that cover Vancomycin resistant MRSA ( VRSA )
• Daptomycin
• Tigecycline - affect G positive ( including VISA, VRSA, MRSA, PRSP ), G negative and anaerobes but it does not cover Proteus mirabilis, Pseudomonas aeruginosa and Burholderia cepacia.

Mechanism of Antibiotics Resistance:

Four broad categories of resistance mechanism

1. Antibiotics Inactivation
2. Alteration in antibiotics target sites
3. Decreased antibiotics permeability of the cell wall preventing drug access to its target
4. Active antibiotics efflux from the bacteria

Antibiotics Inactivation

A. Beta lactamases: can be inhibited by clavulanic acid, tazobactam and sulbactam.

B. Inducible chromosomally mediated beta - lactamase production:

• Inactivate third generation cephalosporins.
• In particular, organisms which demonstrate this important form of Beta lactamase productions are ' ESCAAPPM ' -do not treat with penicillins or cephalosporins
  

• E - Enterobacter species
• S - Serratia species
• C - Citrobacter
• A - Acinectobacter
• A - Aeromonas
• P - Proteus
• P - Providentia
• M - Morganella morganii

C. Aminoglycoside modifying enzymes

D. Others - ESBL ( extended spectrum beta lactamase )

• now being common in large hospital.
• inactivate all cephalsporins.
• Klebsiella pneumoniae and E. coli are the usual organism to harbour ESBLs.
• Treatment is with meropenum or cotrimoxazole.

E. MBL - Metallobetalamase

Chronic Myeloid Leukaemia

A balanced translocation between chromosomes 9 and 22 [t(9;22) the Philadelphia chromosome] creates a unique gene designated BCR-ABL, which codes a 210-kDa protein (p210) that functions as tyrosine kinase. The t(9;22) is not only diagnostic of CML, it is also the causative genetic event.

In a patient with CML, all cells of the hematopoietic lineage contain this translocation, proving clonality at the stem cell level and the proliferative advantage of cells with BCR-ABL gene expression. After several years of this proliferative phase (also called the chronic phase), additional genetic abnormalities lead to loss of differentiation and progression into acute leukemia (blast crisis) that is fatal within a few months.

Imatinib mesylate is an oral drug that targets and inhibits the BCR-ABL tyrosine kinase and thereby suppresses or eliminates the CML clone. 85% of patients taking imatinib achieved complete cytogenetic remission on karyotype analysis. When the dose of imatinib mesylate was increased, a significantly higher number of patients achieved a molecular complete remission with reduction in progression to blast crisis.

The majority of these patients continue to have evidence of the CML clone when investigated with sensitive techniques such as PCR, indicating that they are still at risk of relapse. Recent studies suggest approximately a 4% annual relapse rate during imatinib therapy. Patients with no detectable CML clone by PCR analysis had long-term CML-free survival.

Some patients develop re-emergence of the CML clone with resistance to imatinib mesylate due to mutations or amplifications of BCR-ABL. New targeted drugs show promise in treating patients refractory to imatinib due to these mutations. Second generation Tyrosine Kinase Inhibitors are: Nilotinib, Dasatinib, Bosutinib and MK - 0457.

Hydroxyurea and interferon with or without low-dose cytarabine can be used to normalize blood counts and control the disease manifestations in patients intolerant to imatinib mesylate.

Allogeneic stem cell transplantation can bring about long-term survival in CML. The best results are obtained in patients with HLA-identical sibling donors transplanted during early chronic phase, that is, within 1 year of diagnosis. Transplant-related mortality increases as these variables change.

Relapse after allogeneic transplantation is uncommon if transplantation is performed during chronic phase, and post-transplant relapse can be successfully treated with infusion of donor lymphocytes without any need for cytotoxic therapy. Only one third of patients are candidates for allogeneic stem cell transplantation, and because of the effectiveness of imatinib mesylate, the selection of patients and the timing of this toxic procedure require careful consideration.

Eastern Cooperative Oncology Group ( ECOG ) performance status scale:
STATUS Description
0 Asymptomatic, fully active and able to carry out all predisease performance
without restriction.

1 Symptomatic, fully ambulatory but restricted in physically strenuous activity and
able to carry out performance of a light or sedentary nature.

2 Symptomatic, ambulatory and capable of all self-care but unable to carry out any
work activities. up and about more than 50%of waking hours: in bed less than
50%of day.

3 Symptomatic, capable of only limited self-care, confined to be or chair more than
50% of waking hours, but not bed ridden.

4 Completely disabled. Cannot carrry out any self-care. Totally bedridden.

Adverse Drug Reactions

Type A - Augmented response
usually due to high plasma concentrations
can occur at normal plasma concentrations, reflecting inter-individual variability
Type B - unpredictable, dose independent and often serious.

Carbamazepine Core ADRs:

• Dizziness, drowsiness
• Rashes/SJS ( increased risk with carbamazepine if HLA - B1502 allele positive.
• Hyponatremia
• Leukopenia
• Hepatitis

Important causes for Stevens Johnson syndrome:

• Cotrimoxazole
• Lamotrigine
• Carbamazepine
• Phenytoin
• Barbiturate
• Sulfasalazine

Drugs probably not associated with Serious Cutaneous adverse reactions:

• ACEI
• Beta-blocker
• Calcium channel blocker
• Diuretics
• Sulfonylurea
• Insulin

Risk Factors for Rhabdomyolysis with Statins:

• Increased plasma concentrations
• CYP3A4 inhibitors
• Gemfibrozil
• Advanced age
• High statin dose

CYP2D6 - codeine and metoprolol
CYP2A6 - valporate and paracetamol
CYP2C9 - warfarin