PHR3042 - Acute Care: Inquiry Cases

Acute Transplant Rejection vs Chronic Transplant Rejection

• Acute rejection occurs within 1-3 months of organ transplantation

• Chronic rejection occurs within months to years of organ transplantation

Potential Contraindications for Organ Transplantation

• Active hepatitis B

• Non-curative cancers

• Motor neurone disease

• HLA mismatch

Cellular Rejection vs Antibody-Mediated Rejection

• Cellular rejection management involves targeting the depletion of T cells

• Antibody-mediated rejection involves targeting the removal of antibodies and plasma B cells

Plasmapheresis

• Filtration process that removes large proteins from the blood

• Large proteins may include harmful and helpful antibodies

• IV immunoglobulin is administered at the same time to replenish helpful antibodies that have lost

Cellular Rejection Agents

• Mild: IV methylprednisolone + oral prednisolone taper

• Moderate-to-severe: IV methylprednisolone + oral prednisolone taper, anti-thymocyte globulin

Antibody-Mediated Rejection Agents

• IV methylprednisolone + oral prednisolone taper

• Plasmapheresis + IV immunoglobulin

• Rituximab

Immunosuppressants Used Following Organ Transplantation

• Basiliximab

• Antithymocyte globulin

• Corticosteroid (e.g. prednisolone)

• Calcineurin inhibitor (e.g. tacrolimus, ciclosporin)

• Antimetabolite (e.g. MMF, azathioprine)

• mTOR inhibitor (e.g. everolimus, sirolimus)

Tacrolimus TDM

• Dosed q12h or BD

• Levels taken as trough (12 hours since previous dose and right before next dose)

• Preferably taken immediately before the 3rd dose if commencing, changing dose or using interacting medication

• CYP3A4 substrate so prone to interactions

Ischemic Stroke vs Hemorrhagic Stroke

• Ischemic stroke is more common and is caused by a blockage towards (embolic) or within (thrombotic) the brain

• Hemorrhagic stroke is less common and is caused by a bleed into the brain or surrounding brain tissue

Stroke Risk Factors

• Both: hypertension, smoking, illegal drug use

• Ischemic: age > 80 years, heart disease, diabetes, dyslipidemia, obesity, AF

• Hemorrhagic: high alcohol intake, use of blood thinners

Secondary Stroke Prevention after First Ischemic Stroke

• BP lowering agent (e.g. ACEi, CCB, thiazide diuretic) for target systolic BP of 120-140mmHg

• High dose statin (e.g. atorvastatin 80mg, rosuvastatin 40mg), can add fenofibrate or ezetimibe

• Antiplatelet therapy (SAPT or DAPT depending on NIHSS)

• Long-term anticoagulation if patient has AF

Monitoring or Physical Assessment for Acute Stroke

• Blood pressure

• Blood sugar levels

• Swallowing assessment

• Temperature

• Cardiac monitoring

NIHSS Score and Antiplatelet Therapy

• NIHSS < 4: small stroke = low risk of hemorrhagic transformation so safe to use DAPT for 3 weeks then SAPT ongoing

• NIHSS > 3: big stroke = high risk of hemorrhagic transformation so use loading dose of antiplatelet then SAPT ongoing

• If already on aspirin before stroke then do not recommence aspirin after for SAPT

• If aspirin-naive then continue aspirin monotherapy ongoing

Formulation Types Not Appropriate for Crushing

• Delayed release formulations

• Controlled release formulations

• Enteric coated formulations

• Cytotoxic medications

• Buccal and sublingual tablets

Stroke Onset and Reperfusion Therapy

• Within 4.5 hours: can use tenecteplase or alteplase

• Between 4.5 to 9 hours: can use tenecteplase or alteplase if significant amount of salvageable brain tissue remaining

Acute Blood Pressure Targets

• Ischemic stroke with medical management: SBP < 220/120mmHg

• Ischemic stroke with thrombolysis: SBP < 185/110mmHg

• Hemorrhagic stroke: SBP = 130-140mmHg

Sepsis vs Septic Shock

• Sepsis: life-threatening organ dysfunction caused by a dysregulated host response to an infection

• Septic shock: severe sepsis requiring vasopressor therapy to maintain MAP > 65mmHg and serum lactate > 2mmol/L even after adequate fluid resuscitation

Hour-1 Sepsis Bundle

• Measure lactate level and remeasure if initial lactate > 2mmol/L

• Obtain blood cultures prior to administering antibiotics

• Administer broad spectrum antibiotics

• Begin rapid administration of 30mL/kg crystalloid for hypotension or lactate > 4mmol/L

• Commence vasopressors if hypotension persists during/after fluid resuscitation to maintain MAP > 65mmHg

Aminoglycosides (e.g. Gentamicin, Tobramycin)

• Gram-negative spectrum of activity

• Negligible oral absorption so avoid oral route

• Distributed into lean tissue (hydrophilic) so use lean body weight for all patients

• Should not be used long-term (usually up to 3 days)

• Side effects include nephrotoxicity and ototoxicity

• Avoid use in history of vestibular or auditory problems

Gentamicin TDM

• Trough concentration should be measured prior to the next dose to ensure it is detectable but not elevated

• Aim is 0.5-1mg/L to minimise toxicity

• Consider changing from q8h to q12h in renal impairment to ensure trough concentration is within range

Pharmacokinetics/Pharmacodynamics in Sepsis

• Time-dependent antibiotics (T > MIC) optimise therapy by extending infusion times or being administered as continuous infusions

• Concentration-dependent antibiotics (Cmax/MIC) optimise therapy by being administered as larger doses

• Low VD = remains in plasma

• High VD = highly distributed around the body

• Leaky capillaries, altered protein binding, augmented renal clearance, extracorporeal circuits can increase VD or clearance, resulting in low plasma concentrations

• End organ dysfunction can decrease clearance, resulting in high plasma concentrations

Vancomycin TDM

• Gram-positive spectrum of activity

• Negligible oral absorption so avoid oral route (except in C. diff as it penetrates colon)

• Use actual body weight for all patients

• Aim is 10-15mg/L (higher in CNS infections and continuous infusions)

• Side effects include nephrotoxicity, neutropenia, ototoxicity

• Critically ill adults require a loading dose

• Trough level usually taken right before 4th dose (earlier in reduced CrCl)

• Infuse over 60 mins (maximum rate for 10mg/min) due to red man syndrome

Triple Whammy Interaction

• ACEi/ARB + NSAID + diuretic

• ACEi/ARB dilates efferent arteriole of glomerulus, decreasing glomerular filtration

• NSAID blocks prostaglandins and constricts afferent arteriole, decreasing glomerular pressure and GFR

• Diuretic increases fluid loss which may cause dehydration

Other Common Medications Contributing to AKI

• Gentamicin

• Amphotericin

• Pantoprazole

• Amoxicillin

• Aciclovir

• Iodinated contrast

Drugs Temporarily Avoided During a Sick Day in AKI

• Sulphonylureas (e.g. gliclazide, glipizide)

• ACE inhibitors

• Diuretics

• Metformin

• ARBs

• NSAIDs

• SGLT2 inhibitors

Monitoring for AKI

• Renal function (e.g. eGFR, CrCl)

• Fluid balance and urine output

• Electrolyte levels (e.g. serum potassium)

• Blood sugar levels

• Hemodynamically stable (e.g. HR, BP)

Electrolyte Disturbances in AKI

• Hyperkalemia → arrhythmia

• Hypermagnesemia → muscle weakness

• Hyperphosphatemia → hypocalcemia

• Accumulation of sodium bicarbonate → metabolic alkalosis, fluid overload

Management of Acute Hyperkalemia

• Calcium gluconate does not lower potassium but reduces risk of arrhythmia

• Insulin + glucose shifts potassium into cells

• Sodium bicarbonate corrects metabolic acidosis

• Nebulised salbutamol shifts potassium into cells

• Resonium binds potassium in the GI tract to increase its excretion

• Frusemide promotes renal excretion (avoid in dehydration/anuria)

• Hemodialysis

Rates of Infusions

• Bolus: less than 5 mins, less than 50 mL

• Intermittent infusion: 5 mins to 24 hours, can be a once-off dose or repeated

• Continuous infusion: constant/adjustable therapeutic concentrations, medications with short half-lives

Recommendations for Incompatibilities

• Multi-lumen central venous catheter (no mixing due to staggered exits)

• Separate IV cannula

• Change dose schedule

• Temporarily suspend

• Change route of administration (e.g. oral instead of IV)

• Use different drug (e.g. ranitidine instead of pantoprazole)

Induction and Maintenance Agents in IBD

• Induction: corticosteroids, advanced therapies, 5-ASAs

• Maintenance: 5-ASAs, thiopurines, methotrexate, advanced therapies, corticosteroids, salvage therapies

Crohn’s Disease vs Ulcerative Colitis

• CD affects any part of the GI tract from mouth to anus, affects all layers of the bowel wall, inflammation is in the form of a patchy/skip pattern, uses methotrexate

• UC affects only the colon/rectum, affects only the mucosal surface layer of the colon with a more superficial appearance, inflammation is in the form of ulcers, uses 5-ASAs and salvage therapies

Testing and Monitoring of IBD

• CRP and ESR (inflammation)

• FCP (inflammation in GI mucosa)

• Albumin, FBCs, LFTs

Types of Remission in IBD

• Clinical remission = patient feels well

• Biochemical remission = blood and stool tests suggest no inflammation

• Endoscopic remission = GI mucosa is normal with no inflammation (gold standard)

Active Disease or Flareup of IBD

• Increased bloody stools

• Increased HR

• Increased temperature

• Increased ESR

• Increased CRP

• Decreased hemoglobin

Types of Mesalazine Formulations

1. Azo-Bonded Prodrugs: mesalazine bound to an inert molecule via an azo bond that is cleaved by bacteria in the large intestine so only mesalazine is released in the large intestine

2. Time-Dependent Release Formulations (e.g. Pentasa): mesalazine encapsulated with an ethylcellulose semi-permeable membrane allows for time and moisture dependent release of the active drug so it can gradually distribute throughout GI tract from duodenum to rectum

3. Multi-Matrix System: mesalazine incorporated in lipophilic matrix and dispersed in hydrophilic matrix so enteric coated tablet dissolves at pH > 7 in terminal ileum for active drug to be dispersed slowly throughout entire length of colon

4. pH-Dependent Release Formulations: mesalazine formulated with enteric coat of resin which disintegrates at specific pH in terminal ileum and colon, do not administer with lactulose as it lowers colonic pH and may prevent/delay release of mesalazine

Thiopurines and TPMT Testing

• TPMT testing required before starting a thiopurine to predict if the patient will experience myelosuppression

• TPMT is an enzyme that converts azathioprine and mercaptopurine into inactive metabolites which reduces the risk of myelosuppression

• Wildtype (normal) = use standard thiopurine dosing

• Heterozygous (intermediate) = reduce thiopurine dosing by 50%

• Homozygous (low) = avoid use of thiopurines and consider use of methotrexate in CD

Role of Corticosteroids in IBD

• Used to treat acute flares in patients with moderate to severe symptoms who are not responding to escalated 5-ASA therapy

• Hospitalised patients may require IV corticosteroids for 3-7 days (e.g. IV hydrocortisone 100mg QID, IV methylprednisolone sodium succinate 60mg daily)

• Patients are often switched to oral corticosteroids (e.g. prednisolone 40-60mg daily) after IV therapy and the dose is tapered off after 6-8 weeks

• Do not stop abruptly due to risk of adrenal insufficiency or Addisonian crisis and risk of disease flare/rebound

• Prolonged use of corticosteroids (3-4+ weeks) can cause desensitisation of the adrenal glands and loss of ability to quickly produce cortisol

Rectal Preparations in IBD

• Suppositories: distributes to the rectum, 15-20cm, best for proctitis

• Foam enemas: distributes to the rectosigmoid, 30-40cm, best for rectosigmoid disease or poor liquid enema tolerance

• Liquid enemas: distributes left-sided to splenic fixture, 60cm, best for left-sided colitis with adequate rectal capacity

• Suppositories tend to be better tolerated than enemas and foams but they may not always reach the site of inflammation

• Rectal formulations may also be combined with oral formulations to produce an optimal response

Nutritional Deficiencies in IBD

• Iron → anaemia

• Vitamin A → night blindness

• Vitamin D → osteoporosis

• Vitamin E → peripheral neuropathy

• Vitamin K → coagulopathies

• Vitamin B12 → anaemia

• Vitamin B6 → stomatitis

• Vitamin B1 (thiamine) → Wernicke’s encephalopathy

• Calcium → osteoporosis

• Zinc → wound healing

Progression of Chronic Liver Disease

1. Fat in the liver may cause inflammation (i.e. hepatitis)

2. Untreated hepatitis may lead to scarring of the liver (i.e. fibrosis)

3. Severe scarring of the liver may disrupt liver function (i.e. cirrhosis)

4. Cirrhotic liver involves formation of hard scar tissue and is irreversible which can lead to liver cancer

Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)

• Most common cause of chronic liver disease

• Occurs when imaging/biopsy detects fat buildup in the liver AND the patient has a metabolic condition (e.g. being overweight/obese, T2DM) OR a metabolic dysregulation in patients with a healthy body weight (2+ risk factors out of: central obesity, high BP, abnormal cholesterol, pre-diabetes, insulin resistance)

• Associated with increasing incidence of cirrhosis and hepatocellular carcinoma and is a common indication for liver transplantation

Cirrhosis and Child Pugh Score

• Compensated: liver scarred but still functional, asymptomatic

• Decompensated: symptomatic

• Child Pugh score based on bilirubin, albumin, INR, ascites, encephalopathy

• Child Pugh A = mild impairment cirrhosis

• Child Pugh B = moderate impairment cirrhosis

• Child Pugh C = severe impairment cirrhosis

Portal Hypertension

• Occurs from obstruction or increased resistance to blood flow before/within/after the liver

• Clinical presentation may include ascites, splenomegaly, variceal bleeding, hepatic encephalopathy

• Treatment may include beta blockers

Cholestatic Jaundice

• Eating fatty meals causes the gallbladder to release bile

• Bile dissolves dietary fat into shorter fatty acid chains that can be reabsorbed into the bloodstream

• Bile can harden and form stones in some liver disease states which can cause obstruction and cause fever, infection, jaundice

• Jaundice is caused by a buildup of bilirubin from bile

• Accumulation of bilirubin causes jaundice, itch, nausea, abdominal pain

Oesophageal Varices (Variceal Bleeding)

• Varices are swollen or enlarged veins that are prone to rupture

• Rupture of varices can cause life-threatening hemorrhage

• Cirrhosis → portal hypertension → varices

Hepatic Encephalopathy

• Liver normally detoxifies substances by converting ammonia into urea as it is more easily removed by the kidneys and is not a harmful by-product

• Ammonia is a potential neurotoxin implicated in the development of hepatic encephalopathy as it crosses the BBB to cause confusion and altered consciousness

• Treated using lactulose as it converts ammonia into ammonium to be eliminated into the faeces

• Macrogol or rifaximin may be added for recurrent/chronic hepatic encephalopathy

Ascites

• Swelling of the abdomen due to fluid accumulating in the peritoneal cavity

• Can occur as a result of portal hypertension or reduction in serum albumin

• Complications may include infection in the peritoneal cavity (i.e. SBP)

• Management involves using an ascitic tap to remove fluid and culture it to determine to cause of infection

Liver Functions and Clinical Consequences

• Detoxification of substances → hepatic encephalopathy, drug toxicity

• Protein synthesis → increased bleeding risk, oedema, ascites

• Gluconeogenesis and glycogenolysis → hypoglycemia

• Bile production → fat-soluble vitamin deficiencies, jaundice

• Vitamin storage → nutritional deficiencies

• Production of immune factors and removal of bacteria from the bloodstream → increased susceptibility to infections

Liver Enzymes

• Raised ALT and AST are marker of hepatocellular injury (damaged liver cells)

• Raised ALP and GGT indicate cholestasis (reduced bile flow)

Medication Management in Liver Disease

• Final acting metabolites preferred (e.g. temazepam or oxazepam preferred over diazepam, desvenlafaxine preferred over venlafaxine)

• Avoid drugs that undergo first-pass metabolism

• Avoid glipizide in severe hepatic impairment

Using Medications in Fasting Prior to Anesthesia

• Adult patients undergoing elective surgeries should fast for up to 6 hours prior to anesthesia

• Patients are usually encouraged to drink up to 170mL of clear fluid per hour up until 2 hours before anesthesia to prevent dehydration

• Many prescribed medications may be taken with a sip of water (maximum 30mL including the volume of any liquid formulations) prior to anesthesia

• Certain essential medications may also need to be given preoperatively via different routes (e.g. parenteral, rectal) if necessary and the oral route cannot be used

Periprocedural Management of Antithrombotic Medications (e.g. Anticoagulants, Antiplatelets)

• Continue aspirin

• Withhold ticagrelor 3-5 days before procedure

• Withhold clopidogrel 5 days before procedure

• Withhold prasugrel 7 days before procedure

• Restart antiplatelets within 24 hours of procedure

• Management of DOACs depends on procedural bleeding risk

• Cease warfarin 5 days prior to procedure, bridging may be required if high VTE risk where INR < 2 and bridging therapy continued until 24 hours before procedure

• Restart warfarin on the evening of procedure if adequate hemostasis and continue LMWH until target INR is reached

CHA2DS2-VASc Score

• Estimates the risk of stroke in patients with AF

• Score of 0-4 = low thromboembolic risk

• Score of 7-9 = high thromboembolic risk = recommend bridging therapy

HAS-BLED Score

• Estimates the risk of major bleeding in patients with AF receiving anticoagulation

Periprocedural Management of Insulin

• Patient is operated on early in the morning

• Patient will usually take usual insulin the day before procedure

• Pre-mixed insulin (e.g. Novomix) morning dose halved, lunchtime dose omitted, evening dose unchanged if able to eat

• Co-formulated insulin (e.g. Ryzodeg) omitted on morning of procedure and give at lunchtime or when able to eat

Periprocedural Management of Other Medications

• Continue statins

• Continue beta blockers but monitor heart rate

• Withhold ACE inhibitors the morning of procedure due to risk of intraoperative hypotension, restart when hemodynamically stable

• Withhold metformin on the day of procedure due to risk of lactic acidosis, restart when eating and drinking

• Withhold SGLT2 inhibitors 2 days before and on the day of procedure due to risk of euglycemic ketoacidosis but monitor ketone levels, restart when eating and drinking

Neuromuscular Blocking Agents

• Non-depolarising (e.g. rocuronium): can be reversed using neostigmine, anticholinergics co-administered to avoid excessive cholinergic side effects, sugammadex reverses neuromuscular blockage from rocuronium

• Depolarising (e.g. suxamethonium): rapid onset and short duration of action, effect potentiated by neostigmine, can cause malignant hyperthermia so administer dantrolene

Risk Factors and Prevention of PONV

• Female gender

• Non-smoking status

• History of PONV or motion sickness

• Use of postoperative opioids

• 1-2 risk factors = give 2 agents from different classes for prevention of PONV

• 2-4 risk factors = give 3-4 agents from different classes for prevention of PONV

Risk Factors and Prevention of PDNV

• Female gender

• History of PONV

• Age < 50 years

• Opioid use in recovery room

• Nausea in recovery room

• 0-1 risk factors = only give PRN antiemetic

• 2+ risk factors = give regular antiemetic + PRN antiemetic

EOLC Symptoms

• Pain

• Nausea and vomiting

• Dyspnea

• Excessive respiratory secretions and noisy breathing

• Agitation or restlessness

6 Common Causes of Nausea and Vomiting in Palliative Care

• Central

• Intracranial

• Gastrointestinal

• Vestibular

• Psychological

• Chemotherapy/radiotherapy induced

Excessive Respiratory Tract Secretions

• EOLC patients may lose their ability to swallow/cough so they cannot clear respiratory secretions

• Accumulation of secretions may cause noisy breathing or the death rattle but does not cause discomfort

• First-line is frequent repositioning of the patient

• Anticholinergics (e.g. subcutaneous glycopyrronium, hyoscine butylbromide) can be used to reduce the production of new secretions but does not remove existing secretions

Dyspnea

• Address the underlying cause of dyspnea (e.g. lung cancer, metastases, pleural effusion, pulmonary oedema, COPD)

• Opioids at lower doses are commonly prescribed for dyspnea

• If opioid-naive then start with oral morphine 2mg PRN and escalate as needed

• Consider giving opioids q4h or switching to a long-acting opioid with PRN morphine for breakthrough symptoms if dyspnea is continuous

• Benzodiazepines (e.g. lorazepam, oxazepam, midazolam) can be used to help manage breathlessness by relieving anxiety and calming breathing patterns

Agitation

• Address identifiable causes of agitation where possible

• Benzodiazepines (e.g. midazolam) is preferred if anxiety is present

• Antipsychotics (e.g. haloperidol) is preferred if delirium is present

Treatment of Hypercalcemia of Malignancy

• IV hydration

• Bisphosphonates (e.g. zoledronic acid, pamidronate)

• Denosumab

• Calcitonin

• Corticosteroids

• Cease inducing medications (e.g. lithium, thiazide diuretics, calcium supplements)

Syringe Drivers

• Battery-operated pumps that deliver a subcutaneous infusion over 24 hours and avoid repeated administrations

• Maximum 3 medications in 1 driver

• Default diluent is sodium chloride 0.9%

• Cyclizine uses water for injection (WFI)

• For incompatible medications: cease unnecessary medications, change the route of administration (e.g. ondansetron as a wafer), use more than one syringe driver (e.g. separate cyclizine into its own driver)

• For patient-reported irritation: dilute the product by using a larger diluent volume and syringe size, separate doses using a 12 hour infusion delivered BD, inject dexamethasone at infusion site (last resort)

Opioid Titration

• Consider if pain is responsive to opioids, 3+ breakthrough doses needed in 24 hours, pain management has been reviewed and optimised, enough time has passed since last dose change to reach steady state

Opioid Rotation

• Consider if requires a more effective route of administration (e.g. oral morphine → fentanyl patch), inadequate response to a particular opioid, experiencing or at risk of side effects from a particular opioid (e.g. morphine → fentanyl patch due to worsening renal function)

• Calculate total amount of opioid used in previous 24 hours including baseline and breakthrough doses but not incidental pain relief

• Convert opioid dose into an equivalent dose of morphine

• Convert morphine dose into new opioid dose and route of administration

• Reduce this calculated dose by 25-50% (50% in frail patients, no dose reduction if changing from oral to patch)

• Calculate breakthrough dose with range being 1/6th to 1/12th of calculated background opioid dose

Reviewing Medications in EOLC

• Goals of therapy are focused on symptom relief and improving quality of life

• Remove medications that are not focused on symptom control (e.g. antihypertensives, beta blockers)

• Prescribe medications for any anticipatory symptoms