Anesthetic Implications in Porphyria

Introduction:

When patients suffering from porphyria undergo anesthetic intervention for a surgical procedure, they tend to become quite challenging cases to anesthesiologists as the drugs given to induce and maintain anesthesia may trigger or worsen the attacks. In order to manage the anesthetic implications, the patient’s medical history should be carefully assessed as there will be a high chance of missing the diagnosis, and in case of suspicion, the patient should be sent to undergo investigations that confirm the condition.

What Is Porphyria?

Porphyria is a genetic disease associated with defective functioning of the enzymes involved in heme (iron-containing pigment of blood) biosynthesis. This results in increased production and accumulation of heme precursors failing to form the end product (heme) based on the location of the defective enzymes involved in the heme biosynthesis pathway. The word ”porphyria” is derived from the Greek word “porphyros” due to the accumulation of porphyrins in the tissues and subsequent reddish discoloration of urine in porphyria patients.

How Does Porphyria Occur?

• The heme synthesis mostly occurs in the liver and bone marrow. Genetic defects of the enzymes responsible for heme synthesis cause porphyria.

• Heme synthesis starts when succinyl co (coenzyme) A and the amino acid glycine undergo condensation and decarboxylation with the help of the enzyme ALA (aminolevulinic acid) synthetase to form aminolevulinic acid (ALA) and continues to form various substrates (precursors) on which specific enzymes of the pathway act to give rise to a final end product that is heme.

• Genetic defects of the various enzymes involved in heme synthesis result in the over-accumulation of early metabolic compounds and failure to produce heme, resulting in the accumulation of these precursor compounds in the peripheral tissues of the body, leading to cutaneous symptoms like photo-sensitivity and sometimes may also lead to the acute neuro-visceral crisis which is a life-threatening condition.

• Precipitating factors like anesthetic drugs cause hyperstimulation of the enzyme ALA synthetase (rate-limiting step) and accumulation of resulting porphyrins and because of lost negative feedback control of heme on ALA synthetase, leads to porphyric attacks in the operating room.

What Are the Various Types of Porphyria?

Clinically, porphyria has been classified into:

1. Acute porphyria.

2. Chronic porphyria.

Acute and chronic porphyria are further subdivided based on the location of the defective enzymes in the heme synthesis pathway and on the manifestations of subsequent clinical symptoms.

1. Acute porphyria is classified into:

• Acute intermittent porphyria (AIP) is the most common form, which is caused by a deficiency of porphobilinogen (PBG) deaminase.

• Variegate porphyria (VP) is caused by a deficiency of protoporphyrinogen oxidase.

• Hereditary coproporphyria (HCP) is caused by a deficiency of coproporphyrinogen oxidase.

• Plumboporphyria (PP) is a rare type, inherited as an autosomal recessive disease, whereas the other three are autosomal dominant conditions.

2. Chronic porphyria is classified into:

• Porphyria cutanea tarda (PCT) is caused due to deficient uroporphyrinogen decarboxylase enzymes.

• Congenital erythropoietic porphyria (CEP) is caused due to deficient uroporphyrinogen cosynthase enzymes.

• Erythropoietic protoporphyria (EPP) is caused due to deficient ferrochelatase enzymes.

What Are the Clinical Manifestations of Porphyria?

1. Abdominal pain can be recurrent, severe, and poorly localized, accompanied by nausea and vomiting.

2. Cardiovascular signs:

• Tachycardia.

• Tachyarrhythmia.

• Hypertension.

1. Weakness is more prevalent in the upper limbs than the lower, and up to 20 percent develop respiratory failure and may progress to bulbar paresis in severe cases.

2. Psychiatric disturbances include the following:

• Mood disturbance.

• Confusion.

• Psychosis.

1. Sensory neuropathy with extreme back and thigh pain.

2. CNS (central nervous system) manifestations like seizures.

3. Other autonomic features are the following.

• Constipation.

• Gastroparesis.

• Postural hypotension.

1. Cutaneous lesions like the following.

• Vesicular rash.

• Photosensitivity. Most commonly found in Variegate porphyria (VP) and Hereditary coproporphyria (HCP).

1. Hyponatremia and other electrolyte disturbances.

What Are the Risk Factors of Porphyria?

• Hunger.

• Dehydration.

• Hormonal imbalance.

• Stress. All the above-mentioned aspects are inevitable in patients prepared to go for elective surgeries, which increases the risk, along with the presence of triggering anesthetic agents leading to life-threatening complications.

• Pregnancy.

• Excessive alcohol consumption.

• Infections.

How Is Porphyria Diagnosed?

1. A urine test detects the presence of PBG (porphobilinogen) and ALA (aminolevulinic acid) in acute porphyrias.

2. Blood test.

3. Fecal analysis helps in differentiating AIP (acute intermittent porphyria), VP (variegate porphyria), and HCP (hereditary coproporphyria).

How Is Porphyria Treated?

Diagnosing acute crisis is crucial, and the management of the same includes,

1. Eliminate and treat potential triggering factors.

2. Avoid being led to a catabolic state.

3. Administration of IV (intravenous) Hemearginate 3 mg/kg daily for four days.

4. Supportive measures include,

• Large doses of Morphine to manage pain.

• Antiemetics like Prochlorperazine and Ondansetron are used.

• Tachycardia and hypertension are treated with β-blockers.

• Hyponatremia should be corrected.

• Seizures are to be avoided.

• Gabapentin, Vigabatrin, or Levetiracetam are commonly used.

• Propofol and Alfentanil are safe for sedation.

How to Manage Porphyria in Pregnancy?

• Epidural anesthesia is recommended.

• Propofol or Succinylcholine is used for RSI (rapid sequence induction). RSI is done to minimize the risk of pulmonary aspiration of stomach contents.

• Oxytocin and Hemabate are administered in case of postpartum hemorrhage.

What Are the Anesthetic Implications in Patients Suffering From Porphyria?

Acute porphyrias pose a high risk for patients undergoing anesthetic procedures during surgery to develop potentially life-threatening neurovisceral crises, which can be aggravated by a number of factors, including drugs. Anesthetics involved in the care of such patients undergoing surgery will have to take the following measures:

1.Manage acute crises, which include,

• Risk of aspiration (bulbar dysfunction).

• Seizures, peripheral neuropathy, quadriplegia.

• Respiratory failure from respiratory muscle weakness.

• Autonomic instability, tachycardia, hypertension.

• Electrolyte imbalances: especially hyponatremia (decreased sodium levels) but also hypomagnesemia (decreased magnesium in the blood) and hypokalemia (decreased potassium levels in the blood).

• Severe abdominal pain.

• Anxiety, restlessness, agitation, hallucinations, hysteria (unstable emotional status such as expressing extreme fear or anxiety), disorientation, delirium, apathy, depression, phobias, and altered consciousness, ranging from somnolence to coma.

2.Eliminate precipitating agents ( drugs used in anesthetic care), which include:

• Barbiturates or Etomidate.

• Ropivacaine (care to be taken in regional anesthesia), Lidocaine, and Bupivacaine are safe.

• Ketorolac.

• Anti-seizure medications like Phenytoin and Barbiturates.

3.Take supportive measures, which include,

• Large doses of morphine to manage pain.

• Antiemetics like Prochlorperazine and Ondansetron are used.

• Tachycardia and hypertension are treated with β-blockers.

• Hyponatremia should be corrected.

• Seizures are to be avoided.

• Gabapentin, Vigabatrin, or Levetiracetam are commonly used.

• Propofol and Alfentanil are safe for sedation.

How Are Anesthetic Implications Managed in Patients Suffering From Porphyria?

1. Preanesthetic Management:

• A team of experienced anesthesiologists, well-versed in managing the patient in acute crisis, and a physician with thorough knowledge in the management of porphyria play an important role in the pre-anesthetic evaluation of the patient.

• A detailed medical history, including familial history, general physical examination, and neurological assessment, should be carried out prior to surgery.

• Urine tests are to be advised to detect porphyria precursors.

• Stress and anxiety should be avoided as it can lead to acute attacks.

• Maintain fluids and carbohydrates (300g/day); minimize fasting periods. IV (intravenous) Dextrose saline should be given to avoid calorie deficit.

2. Intraoperative Management:

• Premedication with Midazolam should be done if necessary.

• Droperidol should be given instead of corticosteroids.

• Soft positioning of the patient is to be done to avoid stress.

• Morphine and Propofol are used for inducing anesthesia, and Vecuronium is used for relaxation.

• Desflurane is used to maintain anesthesia.

• Atropine and Neostigmine are given for the reversal of muscle relaxation.

• Morphine, Ibuprofen, or Bupivacaine as regional anesthesia is used for postoperative analgesia.

3. Postoperative Management:

• Additional care is to be given to ICU (intensive care unit) patients, and patients in the postoperative recovery room are to be given special care.

• Hydration with glucose-containing fluids (300g/day) is done continuously to inhibit ALA synthase-1 enzyme synthesis.

• IV Heme (3 mg/kg body weight/day) should be given for three to five days if necessary.

• Signs and symptoms of acute crises like hypothermia, psychotic symptoms, nausea, vomiting, diarrhea, and seizures should be checked regularly.

• Laboratory tests are to be advised to control serum sodium and magnesium levels. Also, urine tests should be done to check the porphyrin precursor levels.

Conclusion

Although porphyria is a rare condition, anesthesiologists should be aware of the perioperative factors that may trigger or worsen an acute crisis. Also, if the patient is vulnerable to encountering a porphyria crisis during the procedure, then the patient must be carefully examined and well-prepared for the surgery before entering the operating room.