Porphyria Flashcards
Anaesthesia can be given safely to pts with a Dx of AHP provided what conditions are avoided?
Prolonged fasting
dehydration
porphyrinogenic medications
adequate analgesia
When is haem alginate indicated?
severe complicated acute attacks or if the episode of acute hepatic porphyria isn’t resolving after 12-18hrs
inications= progressive neuropathy, hyponatremia, convulsions & persistent pain/vomiting not responding to conservative measures
Are there any specific risks of anaesthesia associated with non-acute porphyria?
No
What are porphyrias? how do they develop?
mostly inherited conditions resulting from partial deficiency in activity of the enzymes involved in haem synthesis, except one cutaneous porphyria causes by increased activity of ALA synthase
What are the clinical features of porphyria? What causes attacks in acute hepatic porphyria?
they depend on the quantity & type of haem biosynthetic intermediates that accumulate
Main features= acute neurovisceral attacks or photosensitive skin features or both
when hepatic haem requirements are increased by physiological & environmental precipitants, excess metabolites accumulate & are released into the circulation, eg. ALA which is the metabolite most likely to be responsible for acute neurological dysfunction with acute attacks.
What’s the most common acute hepatic porphyria?
Acute intermittent porphyria
What’s the principal behind how haem arginate works?
Providing exogenous haem down-regulates excess production of haem precursors
What factors may precipitate acute attacks?
Drugs (prescribed & illicit)
calorie restriction (eg. prolonged fasting)
fluctuating sex hormone concentrations
pregnancy generally well-tolerated but acute attacks can occur particularly in 1st trimester
binge drinking
physiological stress including infection
How may drugs cause an acute attack of porphyria?
by causing hepatic haem depletion by induction or irreversible inhibition of cytochrome P450 enzymes which up-regulates the haem biosynthetic pathway
How may pts with genetically proven but latent acute porphyria present?
May be asymmptommatic throughout their life until an environmental trigger risks symptoms
Most present age 15-40, the older the pt the less likely the first acute attack becomes, more likely in female vs male
How does the presentation in AIP vary compared with VP & HCP?
in AIP, symptoms only develop during acute attacks
In HCP & VP, photosensitive skin lesions can occur during acute attacks or in isolation
Most symptomatic pts have one or a few attacks over a short period then the disease becomes inactive again
About 5% of pts with AIP have repeated severe debilitating attacks; this is rare in VP & HCP
Describe acute neurovisceral crises in acute hepatic porphyria?
They relate to CNS, PNS & ANS.
main manifestation= severe diffuse abdo pain (90%), back or leg pain may be prominent.
Associated nausea, vomit, constipation along with HTN/tachycardia.
Rarely cardiac arrhythmias.
Peripheral neuropathy is generally a motor neuropathy affecting distal muscles, mild sensory symptoms (eg. paraesthesia) have been described. Can progress to motor paralysis which may affect resp & pharyngeal muscles & cause bladder dysfunction.
CNS: seizures, psychiatric manifestations (psychosis, confusion, agitation, depression, insomnia, anxiety)
Hyponatremia: common, can be severe, develop rapidly & increase risk of seizures.
How diagnose?
Acute: Pts who know their condition often can recognise symptoms of an impending attack.
Must exclude other causes (eg. intra-ado pathology) but should recognise early as delays in Dx & Rx may worsen outcomes.
Urine ALA & PBG (always increased in acute attack)- protect from light enroute to lab.
PTs with AIP may have raised PBG excretion between attacks so qualitative testing may not be helpful, need to know the pts baseline excretion btwn attacks, porphyria specialist should be consulted.
For initial Dx, porphyrin analysis of light-protected plasma & faecal samples in specialist lab to confirm Dx & identify type.
Refer to porphyria specialist for follow-up, genetic testing offered.
What are the 2 broad groups of pts with AHP?
Those with latent AHP & those with active or recently active AHP, who are more likely to develop perioperative symptomatic acute porphyria (should discuss with their porphyria specialist). Those with latent porphyria are unlikely to develop an acute attack preoperatively if limit fasting time & dehydration, ensure adequate analgesia & avoid porphyrinogenic medications.
Principles of anaesthesia for pts with known acute porphyria:
Minimise fasting time (early on list) & dehydration- standard fasting time of 6hrs solids, clear fluids up to 2hrs preop (clear fluids containing carbohydrates may prevent catabolic state) however as per the 2020 AAGBI statement, risk stratify each pt & procedure wrt aspiration risk & fasting prior to procedural sedation.
Discuss clinical status of pts with active or recently active acute porphyria attacks
Ensure adequate analgesia & anti-emetics, consider premedication (limit perioperative stress)
Local anaesthesia, regional or neuraxial safe.
Can safely perform GA provided only safe medications are used, Porphyria association of Australia can be contacted & referral centres are listed
In life-threatening emergency no medication should be witheld if no acceptable alternative, even if porphyrinogenic
Barbiturate anaesthesia must be avoided- acute attacks are rare postop now that thiopentone rarely used.
AVOID ketamine or esketamine, etomidate, thiopentone, halothane.
Having an onsite stock of haem arginate before surgery is rarely required
If unable to establish early postop eating & drinking, administer glucose-containing fluid to limit catabolism- if prolonged period anticipated, dietician advice re: alternative calories (eg. NGT or TPN).
Ensure pt eating & drinking normally before discharge, return precautions.
Is data available on procaine use in porphyria?
no
Which GA agents must be avoided in acute porphyria?
ketamine esketamine halothane thiopentone etomidate
Is there an issue with any of the neuromuscular blocking or reversal agents in porphyria?
No
Which analgesic must be avoided in acute porphyrias?
dexmedetomidine
Which ABx avoid in acute porphyrias?
fluconazole itraconazole rifampicin sulfamethoxazole trimethoprin clarithromycin erythromycin clindamycin
Which cardiovascular medications avoid in porphyrias?
amiodarone diltiazem HYDRALAZINE indapamide methyldopa spironoloactone verapamil
no data on metaraminol & vasopressin enoximone
Which CNS medications are to be avoided in acute porphyrias?
phenytoin phenobarbital sodium valpropate nitrazepam flunitrazepam
which obstetric meds avoid in acute porphyrias?
ergometrine (except if obstetric emergency)
mifepristone
Which miscellaneous medications have not data for use in acute porphyrias?
dantrolene
phentolamine
Who contact for further advice for pts with acute porphyrias or re: medication management for pts with acute porphyria?
Porphyria association of Australia
Do the partial enzyme deficiencies of AHPs impact haem synthesis for erythropoiesis?
No
Is the risk of allergic reaction higher in pts with acute porphyrias?
no
Is anaemia a feature of AHP?
No- anaemia in pts with porphyria should be managed as for any other pt
Can flucloxacillin be safely used in acute porphyrias?
Evidence is conflicting- use only if no safe alternative
Is there anything special about the approach to VTE prophylaxis in AHPs?
There is no report of increased VTE risk in AHP, use thromboprophylaxis as per any pt, using meds identified as safe by porphyria association.
Is there anything special about the approach to VTE prophylaxis in AHPs?
There is no report of increased VTE risk in AHP, use thromboprophylaxis as per any pt, using meds identified as safe by porphyria association.
Are aspirin & ibuprofen safe to use in AHP?
Yes
How does pregnancy impact acute porphyrias?
Most pts have normal pregnancies with no clinical issues related to porphyria
can safely treat acute attacks in pregnancy with haem arginate
Limit fasting during labour
ensure good labour analgesia to minimise stress (consider early epidural)
use drugs from safe list- avoid ergometrine (unless obstetric emergency) & mifepristone (antiprogestogen & antiglucocorticoid & antiangrogen- used with misoprostol (prostaglandin analogue) for medical abortion
How does a Dx of porphyria impact anaesthetic management in paediatrics?
acute porphyria very seldom manifests before puberty
adhere to non-porphyrinogenic medications a precaution
if family concern, discuss case with porphyria specialist
is there a risk of acute porphyria crisis with CPB?
potentially (case reports theoretical risk) due to stress from blood loss, hypothermia, many medications but no evidence that these factors directly precipitate acute attacks, CPB has successfully been performed provided general measures to limit precipitation of acute porphyria are adhered to.
How are acute neurovisceral attacks managed?
get advice from a porphyria specialist.
initial phase esp mild (mild pain, no neuropathy, no hyponatremia), pts may respond to conservative measures @ home eg. increase oral carbohydrate intake.
remove precipitants, use non-porphyrinogenic medications.
exclude other causes of abdo pain (surgical/postop, gynaecologist, obstetric)
if neurological features or no response to conservative Mx within 12-18hrs, admit for:
-monitoring (HR, BP, ecg to identify any arrhythmias, RR, SpO2, ABG if resp function concern)
-screen for precipitants (eg, infection)
-Assess electrolytes esp Na+
-observe for signs of motor or ANS neuropathy
-consider ICU if progressive neuropathy (a medical emergency)- specialist neurology & metabolic advice
Terminate convulsions with midaz, lorazepam or diazepam- a safe long-term anticonvulsant is levetiracetam
-analgesia (pain often severe, may require parenteral opioids), APS consult, consider PCA
-anti-emetics
-fluid replacement & correct electrolyte disturbance- avoid glucose-only solutions as risk exacerbating hyponatremia, if unable to tolerate PO consider 5% glucose with 0.9%NaCl
-manage any HTN, tachycardia (eg. B-blocker, nifedipine)
-possibly IV haem arginate for severe neurovisceral attacks
-collect a urine sample for PBG, send to lab light-protected
What proportion of pts with acute neurovisceral attacks get hyponatremia? how is it generally treated?
40%, it can be severe
seek cause & assess volume status
typically hyponatremia caused by an acute attack of acute porphyria doesn’t respond to fluid restriction alone; may require HTS
Does haem arginate reverse established nerve damage in acute neurovisceral attacks?
No, but it reduces severity & duration of attacks
Dose of Haem arginate? how give? main adverse effect & how minimise?
3mg/kg (max 250mg) daily on 4 consecutive days
dilute the concentrate in 100mL saline & infuse over 30-40mins
localised perivascular irritation/thrombophlebitis- swap arms daily if peripheral infusion - monitor for extravasation- minimise by giving through large-bore IVC or CVC & flush with 250mL NaCl after infusion
Dose of Haem arginate? how give? main adverse effect & how minimise?
3mg/kg (max 250mg) daily on 4 consecutive days
dilute the concentrate in 100mL saline & infuse over 30-40mins
localised perivascular irritation/thrombophlebitis- swap arms daily if peripheral infusion - monitor for extravasation- minimise by giving through large-bore IVC or CVC & flush with 250mL NaCl after infusion
Acute attacks of porphyria are initiated by increased demand for the haem enzymes from where?
liver
Which metabolite is the most likely toxin causing neurological damage in acute porphyria attack?
ALA
