Case presentationCase presentation

A Case of Acute Intermittent Porphyria for Elective Caesarean Section

By: Dr.Somashekar Reddy.P.V

Moderator: Dr.Sushil Bhati, Professor, Dept of Anaesthesia

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HistoryHistory

Name: Meenakshi W/o Vikas Plot no 35, Krishna colony, Jaipur Age:25yrs Date of Admission:7th Feb 2012 at Zenana Hospital Reg no.4606,Unit VI Chief complaints: C/o Amenorrhea for 8 months. History of Presenting Illness:I Trimester- No h/o fever, burning micturition, radiation and drug

exposure,II Trimester-Tetanus vaccination taken,Foetal movement feltIII Trimester- H/o of increase in BP, on Tab.Labetolol 100mg TDS.No h/o leak pv,bleeding pv,pain abdomen.

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Cont..Cont..

Past history: Previous menstrual cycles normal. In 1999, She was admitted in JK Lone hospital with h/o of severe

pain abdomen, convulsions(GCTS type,5 episodes, self aborting),Reddish discoloration of urine & Hypertension after intake of a drug for fever and cough.

Was admitted in ICU for one week. She was diagnosed with Acute Intermittent Porphyria. Family history- Father and younger sister are also suffering from

Porphyria.

Three of her siblings passed suddenly away during childhood.

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ExaminationExamination Conscious, Oriented, Normal builtNo pallor,icterus,cyanosis,clubbing,edema.PR-80beats per min,BP-136/98mmHg,CVS-S1S2 heard, no murmursRS-B/L air entry equal, no added sounds.P/A- Uniform distention corresponding to34 wks of pregnancyCNS- No focal neurological deficitsSkin- NormalMouth opening was three fingers, no loose teeth, TM joint mobility was

normal,MP Grade-INeck movements were normalSpine- Normal.

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InvestigationsInvestigations

Hemoglobin-10.6gm% TLC-7800/mm3 Platelet count-2.6 lac/mm3 RBS-62mg% Blood urea-68mg% S.Creatinine-1.37mg% S.Uric acid-7.63mg% HIV/HbSAg-Negative

Diagnosis Primigravida with 8 months of Pregnancy with Acute

Intermittent Porphyria with Pregnancy Induced Hypertension.

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ManagementManagement Pre anaesthetic evaluation was done one week before the surgery

and again on the day of surgery. She was explained about the procedure and the type of anaesthesia in detail.

Elective Caesarean Section on 22 feb 2012. Preloaded with 500ml of DNS.

Premedication-Inj Ondansetron 4mg. Spinal Anaesthesia was given in L3-L4 space with Hyperbaric

Bupivacaine 10mg. Intraoperative vitals maintained within normal limits & patient

exhibited no signs of an acute porphyric crisis Inj.Paracetmol was given for Intraoperative & Postoperative

analgesia.

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Cont..Cont..

The patient was supplied with sufficient amounts of glucose solutions in order to avoid a hypoglycemic state during perioperative and early postoperative period.

Postoperative follow up was done for 3 days and patient was discharged home on 28th Feb.

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DiscussionDiscussion

The porphyrias are a group of inherited or acquired

enzymatic defects of heme biosynthesis.. Porphyrins are widely distributed throughout the body, they are

essential for oxygen transport, electron transport, various oxidation and hydroxylation reactions.

Each type of porphyria has a characteristic pattern of overproduction and accumulation of heme precursors based on

the location of the dysfunctional enzyme in the heme

synthetic pathway .

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Heme SynthesisHeme Synthesis

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Heme is a component of microsomal and mitochondrialcytochrome systems and is synthesized and usedin all cells. The two major quantitative sites of hemesynthesis are erythropoeitic and hepatic cells whereheme is incorporated into hemoglobin and hepaticcytochromes. Erythropoeitic porphyrias cause extremeskin sensitivity buy lack neurologic involvementand are not associated with drug-precipitatedcrises. Treatment of known hepatic porphyria consists of

prophylaxis and treatment of the acute attack.

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Classification of PorphyriasClassification of Porphyrias

1)Hepatic • Acute intermittent porphyria (AIP)• Hereditary coproporphyria (HCP)• Variegate porphyria (VP)• ALA dehydratase deficiency porphyria • Porphyria cutanea tarda Familial Acquired

2)Erythropoietic• Erythropoietic porphyria• Uroporphyria• Protoporphyria

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AcuteHepatic acute porphyrias Acute intermittent porphyria (AIP) Hereditary coproporphyria (HCP) Variegate porphyria (VP)

Non acute•Erythropoietic Erythropoietic porphyria Uroporphyria Protoporphyria•Porphyria cutanea tarda

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Implications for anaesthesiaImplications for anaesthesia

It might be expected that the cytochrome‐mediated metabolism and high lipid solubility of many anaesthetics would make many of them porphyrinogenic, and anaesthesia has certainly been implicated in the triggering of a number of severe porphyric reactions.

Two scenario are possible:

1. Case of latent porphyria

2. Case of an acute attack

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Acute presentationsAcute presentations

Characterized by severe abdominal pain, autonomic instability, electrolyte disturbance and neuropsychiatric manifestations.

Features of the Acute Porphyric Attack

1)Nervous system dysfunction Autonomic neuropathy

Abdominal pain, Vomiting, Tachycardia, Hypertension, Supine hypotension Peripheral neuropathy

Paresis, flaccid quadriplegia, Respiratory Paralysis Bulbar Involment

Vagal CN involvment-Dysphagia,Dysphonia, Cerebral Involment

Mental status changes,Anxiety,Seizures,Coma

2)Lab Changes

Dark colour(Reddish) urine,Hyponatremia,Hypokalemia,Hypomagnesemia,

Hypochloremia.04/08/23 07:56 Anaesthesia and Porphyria 14

Frequency of symptomsFrequency of symptoms

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Precipitating factorsPrecipitating factors

Fasting/dehydration Infection Psychologic stress Physiologic hormone variation Excessive alcohol Smoking Intake, and administration of specific drugs Barbiturates, sulfonamide,anticonvulsants, and oral contraceptives

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Frequency of Precipitating factorsFrequency of Precipitating factors

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Pathophysiology of acute attack

The manifestions of the disease are thought to be due to increased ALA synthetase activity, increased porphyrin accumulation in the tissues, or decreased heme production .

Increased levels of heme precursors(ALA & PBG) proximal to the site of the specific enzyme deficiency. These precursors are highly reactive oxidants and neurotoxic.

The accumulation of porphyrins in the epidermal skin layers lead to cutaneous photosensitivity.

Acute porphyria often causes severe neuropathy, the basis for multisystem impairment.

Changes in autonomic ganglia, anterior horns of the spinal cord,peripheral neves, brainstem nuclei, cerebellar axons,Schwann cells, and myelin sheaths have been demonstrated.

Neuronal damage and axonal degeneration may be the primary pathologic lesions, with, later axonal changes leading to secondary demyelination

Many hypotheses have been porposed to explain the mechanism of porphyric neuropathy Two of the most plausible attribute the neuronal dysfunction to direct neurotoxicity of ALA , or to diminished intraneuronal heme level or both .

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Diagnostic recommendationsDiagnostic recommendations

Initial diagnosis: The two most important diagnostic recommendations are to

1) maintain a high index of suspicion,

2) be aware that laboratory testing is available that can readily make a diagnosis of acute porphyria or rule it out

Laboratory diagnosis of porphyric crisis can involve fecal analysis

& quantification of urinary porphyrin and porphyrinogen precursors Measuring urinary PBG is most important for diagnosis of acute

porphyrias

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Treatment: Acute CrisisTreatment: Acute Crisis

Reverse factors which increase ALA synthetase activity, Withdrawal of offending drugs, Treatment of symptoms with appropriate medications, Appropriate patient monitoring.

Primary Treatment The most effective therapy for the acute attack is hemin or heme

arginate .It is specific, because it corrects the deficiency of regulatory heme in the liver and down-regulates ALAS.

The standard hemin treatment course is 3-4 mg/kg by vein once daily for 4 days.

Intravenous glucose loading (at least 3 L of 10% glucose daily) should be used only for mild attacks or while waiting for Panhematin® to become available

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Cont..Cont..

1. Hydration,

2. Electrolyte imbalance correction,

3. Propranolol (which may decrease enzyme activity as well as control hypertension, tachycardia & anxiety)

4. Treatment of underlying infection

Pain associated with an acute attack is treated by giving opoids. Phenothiazines are used to treat neuro-psychiatric disturbances and

vomiting Diazepam, Gabapentin & Vigabatrin has been recommended for

acute seizures Magnesium sulfate has been used to control seizures. Mortality in porphyic crises is about 10% with current treatment

regimens.

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Pregnancy Pregnancy

Pregnancy may exacerbate or provoke an acute attack.

Avoidance of planned pregnancy until I-yr latent

period has elapsed is recommended. The mortality

rate from acute attack among pregnant patients has

been reported to be as high as 42% .

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Recommendations applied to drugsRecommendations applied to drugs

Category Description

Use Drug is safe & can be used freely

Use with caution (UWC) Safety is not established beyond doubt ,the evidence suggests that drug is unlike to prove unsafe.it may be used if safe alternative is not available

Use with Extreme Caution Only (UWECO)

Evidence suggest that drug may prove unsafe or little evidence is available to prove it safe.should only be used if benefits overweigh risks and adverse outcome must be anticipated.

Avoid There is evidence that such drugs have precipitated acute attack

No Data/ Avoid There is too little evidence to draw a conclusion

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PremedicationPremedication

Prolonged fasting in the pre-operative period should be avoided where possible.

Glucose-saline should be administered by infusion; 5% dextrose is hypotonic and is best avoided, since hyponatraemia

is associated with acute attacks and a risk of further electrolyte imbalance.

Inj Midazolam used for premedication are considered safe. Phenothiazines may have particular advantage.

When antacid administration is considered appropriate, Sodium Citrate may be given & Inj.Ranitidine can be given.

Metoclopromide should be avoided.

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Regional anaesthesiaRegional anaesthesia

Acute porphyria is not an absolute contraindication to

regional anesthesia but in the setting of peripheral

neuropathy, detailed preoperative exmination and

documentation is essential. Mental status should be normal. Regional anesthesia should probably be avoided in

the setting of acute porphyric crisis. Hypovolemia and a labile autonomic response,

characteristic of acute porphyric crisis, increase the

risk of hemodynamic instability in the setting of a sympathectomy.

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•Regional Anaesthesia Cont..Regional Anaesthesia Cont..

Bupivacaine is considered safe for regional anesthesia. Although some evidence suggests that lidocaine may increase ALA

synthetase activity in animal tissue culture cells, no clincial exacerbations have been reported.

Ropivacaine should be avoided. Prilocaine, Tetracaine & Procaine are safe

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General anaesthesiaGeneral anaesthesia

Intraveous Induction Agents The barbiturates are the inducers of ALA synthetase, and all

barbiturates, including thiopental, must be considered unsafe. Etomidate is potentially porphyrinogenic in animal models,so it

should be avoided. Ketamine is probably safe; However, an increase in ALA, PBG and

other porphyrins after ketamine has been reported in a patient in the latent phase of AIP, and it would seem wise to reserve ketamine for use where hemodynamic or other considerations make it the drug of choice

Protocol can safely be used for induction of anaesthesia.

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Inhalational agentsInhalational agents

Nitrous oxide UseCyclopropane UseHalothane UseIsoflurane UWCEnflurane UWCSevoflurane UWCDesflurane UWC Halothane would appear to be the current agent of choice, and

isoflurane may be a satisfactory alternative

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Neuromuscular BlockersNeuromuscular Blockers

Succinylcholine Use d- Tubocurarine Use Pancuronium Use Atracurium UWC Rocuronium UWC Mivacurium UWC Vecuronium UWC

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Analgesic agentsAnalgesic agents

Acetaminophen Use

Alfenanil Use

Aspirin Use

Indomethcin Use

Buprenorphine Use

Codiene Use

Fentanyl Use

Pethidine Use

Morphine Use

Naloxone Use

Sufentanil Use

Pentazocine Avoid

Brufen UWC

Diclofenac UWECO

Ketorolac UWECO

Phenacetin UWECO

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Cardiovascular DrugsCardiovascular Drugs

Epinephrine,Magnesium,Phentolamine,Procainamide,alpha agonists, beta blockers & agonists are safe.

Diltizem,Disopyramide,Sodium Nitroprusside & Verapamil should be used with caution.

Nifidepine, alpha methyl dopa & Hydralazine should be avoided.

NM Block Reversal agents Atropine,Glycopyrolate & Neostigmine can be used safely.

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Inadvertent use of porphyrinogenic drugsInadvertent use of porphyrinogenic drugs

It is recommended that oral carbohydrate supplements should be given with a target of 200 kcal 24 h–1. If oral feeding is impossible, a 10% dextrose–saline infusion should be given.

The patient should be monitored carefully with urine sampling for porphyrins for at least 5 days and supportive therapy given if necessary.

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Postoperative ManagementPostoperative Management

Monitoring for the potential onset of porphyric crisis

should be continued for up to 5 days, since onset may

be delayed.

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ConclusionConclusion

The acute porphyrias are rare but they are important in anaesthesia because of the wide range of agents that can trigger an acute crisis.

If an acute attack is suspected,immediate empherical therapy should be started

The simplest course for the practising anaesthetist to adopt is not to attempt to remember a large range of drugs that are potentially hazardous, but rather to develop a simple, safe technique based on agents that have minimal risk of triggering a porphyric crisis

The choice of agent may be based more on the patient’s anaesthetic and surgical requirements, rather than governed by the specific requirements imposed by porphyria.

Any suspicion must lead to diagnosis assessment and

possibly to research into the family history.

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Thankyou

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