Porphyrias are disorders caused by deficiency of enzymes in the biosynthesis pathway of heme and are classified by site of defect (erythroid versus hepatic) and acuity (cutaneous versus hepatic) (Figure). Erythroid porphyrias are encountered in the outpatient setting and arise due to an overproduction of porphyrins, which oxidize in light and cause cutaneous lesions.1 In contrast, hepatic porphyrias often present with acute illness due to an overproduction of porphyrin precursors triggered by physiological stress. These porphyrin precursors damage the peripheral and central nervous systems, resulting in a wide array of nonspecific neurovisceral manifestations, including abdominal pain, nausea and vomiting, muscle weakness, anxiety, hemodynamic instability, and seizures. The evolving and diverse symptomology adds to the difficulty of diagnosis, possibly contributing to a low recorded incidence of 0.2 per million.1,2 Due to the acute presentation, rapid progression of disease during stress, and unpredictability of symptoms, acute hepatic porphyrias are a great concern for the anesthesiologist who works in perisurgical and acute care realms.
Until recent decades, hospitalized porphyria patients carried a high morbidity and mortality rate. The turning point was in the 1940s, with avoidance of precipitating factors and the advent of heme analogs.3,4 However, not all precipitating factors are standard perioperative triggers, and we present a case of porphyria attack precipitated by prolonged cardiopulmonary bypass (CPB). We discuss the patient’s challenging and atypical presentation of delayed emergence, hemodynamic instability, and failure to wean from mechanical ventilation; we also discuss the mechanisms of CPB-related inflammation as a novel precipitant of acute porphyria and review the perioperative management of porphyria attacks. The patient’s family has provided authorization for the publication of this case report.
A 66-year-old woman with a possible history of acute porphyria was admitted for a redo mitral valve replacement and tricuspid valve annuloplasty. The patient had 1 questionable porphyria attack at 35 years of age involving episodes of abdominal pain and constipation after starting a migraine medication. Workup at that time showed borderline abnormalities, suggesting possible acute intermittent porphyria (AIP). Given this previous diagnosis, when the patient presented for her initial mitral valve replacement in 2011, several precautionary measures were taken, including listing of common drugs known to induce porphyria as allergies, control of anxiety and pain, and early timing of scheduled procedure. The surgical course was uncomplicated, with a CBP time of 109 minutes and an aortic cross-clamp time of 63 minutes. The patient was extubated and discharged from the intensive care unit on postoperative day 1.
The same perioperative precautions were taken for the repeat surgery 6 years later, including 5 mg midazolam given before and during induction to aid unease and 1000 µg fentanyl for pain. However, the surgical course was prolonged due to difficult dissection, resulting in a CPB time of 359 minutes and an aortic cross-clamp time of 184 minutes. Epinephrine, norepinephrine, and vasopressin infusions were initiated on weaning from CPB. Intraoperative transesophageal echocardiography showed ejection fraction of 55%. She received 5 units of packed red blood cells, 4 units of platelets, 6 units of fresh frozen plasma, 1 unit of cryoprecipitate, and 450 mL of Cell Saver. The patient was brought to the intensive care unit intubated with propofol for sedation, vasopressin at 0.04 U/min and epinephrine at 0.03 µg/kg/min for hemodynamic support, and dextrose and insulin for glycemic control.
Over the next several hours, despite cessation of sedation, the patient’s mentation varied between unconsciousness and agitation. During the next 48 hours, she developed hallucinations, hemodynamic instability, and inability to follow command. Pupils were reactive and accommodating, gag reflex was absent, and deep tendon reflexes were preserved. Tidal volumes were low on spontaneous ventilation (2–4 mL/kg). A full series of investigations looking for infective, inflammatory, and structural causes of her presentation were unrevealing. Head computerized tomography and magnetic resonance imaging were negative for intracranial abnormalities. Electroencephalogram (EEG) indicated nonconvulsive seizures, and the patient was started on levetiracetam. On postoperative day 2, plasma and urine porphyria studies were obtained, and an empiric 4-day course of intravenous dextrose and hemin at 3 mg/kg was initiated, which resulted in improvement of neuropsychiatric symptoms. However, inspiratory effort did not improve, and electromyography (EMG) demonstrated severe axonal sensorimotor neuropathy. On postoperative day 7, laboratory results returned to reveal elevated total plasma porphyrin at 2.6 µg/dL (normal <1 µg/dL) and borderline elevated urine aminolevulinic acid (ALA) at 16 nmol/mL (normal <15 nmol/mL). A second course of hemin infusion at 3 mg/kg lasting 14 days was initiated. Repeat porphyria studies obtained throughout the second course of hemin showed worsening increased total plasma porphyrins, peaking at 4.1 µg/dL. The patient required a tracheostomy and escalating hemodynamic support. Ultimately, the decision to withdraw care was made by the patient’s surrogate that was consistent with the patient’s living will.
Presentation of acute hepatic porphyria has classically been difficult to diagnose due to its vague symptomology, such as abdominal pain, anxiety, and fatigue. The postoperative phase presents an additional challenge, and in this case, delayed emergence was the first sign of devastating neurological injury.
The patient was protected in both her first and second cardiac surgeries from common precipitants of porphyria, including hypoglycemia, pain, and porphyria-inducing drugs. The variable in the second surgery was the prolonged CPB. In previous successful cases of cardiac surgery in porphyria patients, the average CPB time was 113.4 ± 45.8 minutes,5–9 which was similar to that of our patient’s first cardiac surgery (CPB time, 109 minutes) but not the second (CPB time, 359 minutes). Prolonged CBP correlates with high levels of inflammatory mediators10 that can activate gene transcription of structures that require heme, including hemoglobin, P450 enzymes, and nitric oxide synthase. The patient’s subtype of porphyria, AIP, is the most common type of acute hepatic porphyria and is due to the accumulation of porphobilinogen due to a deficiency in porphobilinogen deaminase. Like other types of acute hepatic porphyrias, patients with AIP lack the ability to produce heme, resulting in the accumulation of heme precursors, which lead to oxidative damage,11 inhibition of myelin formation, and damage of glial cells.2 Recently, a lack of nitrous oxide as an end product of NOS has also been postulated to be a culprit in porphyria symptoms due to a reduction of intestinal blood flow leading to abdominal pain and reduced cerebral blood flow leading to a neuropsychiatric phenomenon.12,13
Although CPB could not be avoided in our case, other perioperative risk factors were minimized. These risk factors included fasting, infection, pain, and medications, which are factors that modulate enzymes in the heme synthesis pathway. In our patient’s case, in addition to adequate control of anxiety and pain, early preoperative evaluation allowed drugs known to induce porphyria to be listed as allergies, and her procedure was listed as the first case of the day. Early timing of surgery is important given that perioperative fasting guidelines should be followed. However, some patients may still require dextrose infusions. This is true especially in patients with a history of gastric bypass.14 Antibiotic protocols should be followed closely; patients should also be given adequate pain control to prevent physiological stress, and, finally, all medications should be closely evaluated, especially inducers of the P450 system. The American Porphyria Foundation and the Nordic Drug Database offer a database on the safety profile of drugs in porphyria, and a revised list is categorized in the Table.
If prevention of acute porphyria fails, management should focus on supportive measures, including mechanical ventilation, control of seizure activity, and hemodynamic support. Mechanical ventilation with low tidal volumes of <4 mL/kg is related to bulbar palsy or motor neuron–related diaphragmatic weakness, which can be diagnosed as large axonal neuropathy on EMG.15 Muscle weakness other than diaphragmatic weakness may be present, although this can be difficult to assess in a patient who is unable to follow command. Seizures, which occur in 20% of acute porphyria cases,1 may be potentiated by a syndrome of inappropriate antidiuretic hormone secretion. Management of convulsions should exclude drugs that induce the P450 enzymes, which leaves few choices, such as levetiracetam, pregabalin, and gabapentin (Table). Given the sedating effects of the latter 2 agents, levetiracetam was the agent of choice in this case. In addition, as convulsions may be masked by sedatives, an EEG may be appropriate. Hemodynamic support may often be necessary because the autonomic nervous system can be similarly affected by porphyrin precursors.
Once supportive measures are in place, treatment should focus on halting the ALA pathway to prevent further damage. Given that the synthesis of heme in hemoglobin induces porphyria, transfusions in anemia may be necessary to prevent porphyria exacerbation, and the patient was given blood transfusions more liberally intraoperatively. Postoperatively, hemin (also known as hematin) infusions were initiated on suspicion of acute porphyria. Hemin is a form of exogenous heme and suppresses hepatic production of ALA and other porphyrin precursors by negative feedback (Figure). Hemin is available in the United States as Panhematin, which is approved for 1–4 mg/kg for up to 14 days. In our patient, hemin was given at 3 mg/kg for 4 days for the first course, followed by the same dose for 14 days. In Europe and South Africa, heme arginate as Normosang is available and is therapeutically equivalent. An early start of hemin has been associated with improved outcomes and a shorter duration of hospital stay.3
Porphyria patients present an additional challenge in the perioperative phase due to drug intolerances, metabolic demands, and the need for careful pain modulation. However, as this case illustrated, despite careful prophylactic planning, porphyria attacks can still occur due to major systemic inflammation caused by prolonged CPB. Objective data, such as EEGs or EMGs, aid to unmask etiologies of seizures or respiratory failure associated with neurological attacks when symptomology is nonspecific. Once a diagnosis is made and supportive measures are taken, treatment for all acute porphyrias should focus on stopping the heme feedback system with infusions of heme analogs to prevent further neurological damage.
Name: Yi Cai, MD.
Contribution: This author helped write the manuscript.
Name: Johnathan Ross Renew, MD.
Contribution: This author helped care for the patient and edit the manuscript.
Name: Robert Ratzlaff, MD.
Contribution: This author helped care for the patient and edit the manuscript.
This manuscript was handled by: BobbieJean Sweitzer, MD, FACP.
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