Anesthetic Considerations in PorphyriasPorphyrias present special anesthetic challenges, including preoperative assessment of a patient with acute abdominal pain, intraoperative management of known porphyria, and respiratory and cardiovascular management of acute porphyric crisis. To meet these challenges, a current and thorough understanding of porphyria is essential. Several years have elapsed since there has been a comprehensive review of the spectrum of issues related to porphyria of concern to the anesthesiologist: presentation, pathophysiology, monitoring, and relevant pharmacology. The last significant review of this subject provided a pharmacologic perspective, but much relevant anesthetic information was not addressed, such as new methods of detection and the evolving role of hematin and heme arginate in treatment [1]. Deoxyribonucleic acid analysis of suspected porphyric patients promises earlier, definitive diagnosis of the disease and thereby the opportunity for safer anesthetic management. This management may soon include heme arginate, the most stable form of heme, which currently lacks approval by the Food and Drug Administration but is soon to be tested in clinical trials in the United States. Safe anesthetic management of porphyria demands far more today than an understanding of appropriate pharmacologic therapy. It demands a thorough, current understanding of many other aspects of the disease. Pathophysiology The porphyrias are a group of inherited or acquired enzymatic defects of heme biosynthesis. 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 Figure 1Figure 1: Enzymatic defects in the acute porphyrias. The porphyrias are a group of inherited or acquired enzymatic defects of heme biosynthesis. Each type of porphyria has a characteristic pattern of overproduction and accumulation of heme precursors based upon the location of the dysfunctional enzyme in the heme synthetic pathway. Modified from Moore et al. [4].The rate-limiting step in heme synthesis is the condensation of succinyl coenzyme A and glycine to form delta-amino levulinic acid (ALA) [2,3], catalyzed by the mitochondrial enzyme ALA synthetase. The basal activity of ALA synthetase is substantially lower than that of subsequent enzymes in the synthetic pathway, and therefore changes in ALA synthetase activity are rate-limiting, controlling the rate of heme synthesis. Heme, the end-product of the synthetic pathway, exerts negative feedback regulation on ALA synthetase activity [4-6]. The specific enzyme deficit in each type of porphyria results in a partial block in heme biosynthesis and lower intramitochondrial heme levels Figure 1. Decreased negative feedback from heme contributes to the increased "baseline" ALA synthetase activity which is characteristic of the porphyrias [4-6]. 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 [4-6]. The increased ALA synthetase activity results in increased levels of heme precursors proximal to the site of the specific enzyme deficiency. These precursors are colorless and nonfluorescent porphyrinogens. Irreversible oxidation of these porphyrinogens causes the formation of porphyrins, which have no known physiologic function but are highly reactive oxidants. The accumulation of porphyrins in the epidermal skin layers lead to cutaneous photosensitivity. [7] 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 [6,8-12]. Neuronal damage and axonal degeneration may be the primary pathologic lesions, with later axonal changes leading to secondary demyelination [4,6]. Many hypotheses have been porposed to explain the mechanism of porphyric neuropathy [4,9]. Two of the most plausible attribute the neuronal dysfunction to direct neurotoxicity of ALA (not porphobilinogen [PBG]), or to diminished intraneuronal heme level or both [4,6,11]. In addition, there may be a significant relationship between tryptophan metabolites and/or folate deficiency and clinical expression of the disease [13,14]. Recent reviews provide additional detail [4,6,9]. Classification and Incidence The porphyrias may be classified according to three characteristics: 1. The major site of abnormal porphyrin production (hepatic versus erythropoietic); 2. Acute or nonacute presentation; 3. Pattern of enzyme deficiency in heme production Table 1[4].Table 1: Classification of PorphyriasHeme is a component of microsomal and mitochondrial cytochrome systems and is synthesized and used in all cells. The two major quantitative sites of heme synthesis are erythropoeitic and hepatic cells where heme is incorporated into hemoglobin and hepatic cytochromes. Erythropoeitic porphyrias cause extreme skin sensitivity buy lack neurologic involvement and are not associated with drug-precipitated crises. Porphyria cutanea tarda is the only hepatic porphyria without neurologic sequelae. Porphyria cutanea tarda is usually associated with hepatic disease but not acute neurologic crisis. Other hepatic porphyrias are associated with abdominal pain, peripheral neuropathy, and mental status changes, with crisis frequently precipitated by "triggering" drugs. Barbituates are the most frequent "trigger" [9,15]. There is little difference in the neurologic syndrome exhibited during an attack among the four acute hepatic porphyrias. Hereditary coproporphyria (HCP) and variegate porphyria (VP) manifest skin photosensitivity and extreme skin fragility, whereas acute intermittent porphyria (AIP) does not [4-6]. Once diagnosed, AIP is associated with a relatively good prognosis. Symptoms occur in less than one-third of genetically susceptible patients but rarely before puberty. Acute attacks are associated with a significant risk of mortality, particularly if the diagnosis is delayed and neurologic involvement progresses. Although autosomal dominant, clinical expression is more common in females [16]. Most patients with HCP are asymptomatic and clinical onset may be associated with intercurrent hepatic disease. Presentation has occurred between the ages of 7 and 75 yr. Prognosis is generally good [17]. VP has a prognosis as good as acute intermittent porphyria. Systemic effects are more common in women, while cutaneous manifestations are more common in men [17]. Treatment of known hepatic porphyria consists of prophylaxis and treatment of the acute attack. Factors known to precipitate acute porphyric crisis include fasting/dehydration, infection, psychologic stress, physiologic hormone variation, excessive alcohol intake, and administration of specific drugs. Many drugs cause porphyric crisis Table 2. Most do so by decreasing heme levels, thus decreasing negative feedback and thereby increasing ALA synthetase activity [4-6].Table 2: Porphyria and Anesthetic DrugsMany commonly used drugs trigger porphyric crisis by decreasing heme [2]. Barbiturates induce the cytochrome P450 system; this incorporates more heme into the new cytochromes, thereby decreasing heme levels. Oral contraceptives cause destruction of the heme group in cytochromes, requiring new heme for incorporation into cytochromes. Griseofulvin converts heme into N-methylated derivatives, which further inhibit heme synthesis. Some endogenous steroid hormones are thought to trigger porphyria by increasing the synthesis of new ALA synthetase enzyme [2]. Factors known to decrease synthetase activity include high carbohydrate (glucose) loading, propranolol, and and increased negative feedback from heme [3-6,18]. Propranolol is used during the acute porphyric attack to control hypertension and tachycardia. This drug increases heme synthesis in vitro, which exerts an inhibitory effort upon ALA synthetase activity through negative feedback [19]. The acute porphyrias are associated with hereditary enzyme deficits [20-24]. AIP, HCP, and VP exhibit autosomal dominant transmission with variable expression. The frequency of AIP is estimated to be 1/20,000 in Europe, with a high of 1/10,000 in Northern Sweden [4,25]. ALA dehydratase deficiency porphyria, also known as plumboporphyria (PLP), has an autosomal dominant pattern. Since PLP has been described only recently, no estimate of prevalence has been established [26-28]. The frequency of HCP is also difficult to estimate since greater than half of affected individuals are asymptomatic (variable expression) and the number of reported cases is small [4]. VP is particularly common in certain populations groups, such as white South Africans, where prevalence has been estimated at 1/250-500 [4,29]. Pregnancy may exacerbate or provoke an acute attack. Avoidance of planned pregnancy until 1-yr latent period has elapsed is recommended. The mortality rate from acute attack among pregnant patients hs been reported to be as high as 42% [30]. Clinical Features: Acute Attack Acute attacks occur in only four types of porphyria: AIP, HCP, VP, and PLP [7]. The signs and symptoms of acute porphyric crisis are well known and quite consistent: severe abdominal pain, vomiting, anxiety, confusion, autonomic instability manifested by hypertension and tachycardia, dehydration and electrolyte disturbances such as hyponatremia, hypokalemia, and hypocalcemia [22,24,31]Table 3.Table 3: Features of the Acute Porphyric AttackAIP, HCP, and VP may be clinically indistinguishable during acute attacks [32]. Central to each is neurologic dysfunction Table 3[9,29], with significant impairment of both sympathetic and parasympathetic nervous systems occurring during an acute attack [33]. During remissions function improves but parasympathetic dysfunction can persist [33]. Tachycardia is often an indicator of disease state progression [25,34,35]. As heart rate increases, the patient's condition generally worsens and with clinical improvement tachycardia usually resolves. Most of the clinical features subside within the approximate time course of the acute crises, but residual paresis may persist for years in the absence of further attacks [34]. The paresis, per se, does not have specific implications for the use of neuromuscular relaxants. The use of muscle relaxants in the setting of porphyria is discussed below. Recovery of mental function often lags behind physical recovery, and some patients report anxiety, emotional instability, or other functional disturbances indefinitely [29]. Electrolyte abnormalities occur secondary to dehydration, vomiting, and diarrhea and may entail serious hyponatremia and hypochloremia [6]. Stein et al. [35] performed radioisotope studies to measure blood volume in nine AIP patients. All had low blood volumes, ranging from 67% to 97% of normal, despite normal electrolytes in some patients. Although the syndrome of inappropriate secretion of antidiuretic hormone is well described in acute porphyrias, presumably due to hypothalamic involvement, hyponatremia with appropriate antidiuretic hormone levels occurs more often [34-36]. Laboratory diagnosis of porphyric crisis can involve fecal analysis [32] but most frequently involves quantification of urinary porphyrin and porphyrinogen precursors [37]. These can be markedly increased during an attack, but may return to normal during remission. This normality can create a difficulty in early and accurate diagnosis in high-risk groups, such as in patients with a strong family history of porphyria. Many carriers of the trait can thus remain asymptomatic unless exposed to precipitants. One technique known as gene linkage analysis offers a new approach to the diagnosis of acute intermittent porphyria and relies on direct complementary deoxyribonucleic acid sequencing [20,22]. It does not depend on urinalysis, but rather on polymorphic markers within the porphobilingen deaminase gene [21]. This permits unequivocal and early detection of carriers. Early and accurate detection of the disease in high-risk patients is of obvious benefit to safer anesthetic management of those affected and constitutes a major breakthrough in terms of perioperative anesthetic management. Preoperative Evaluation Acute Abdomen and Porphyria The following symptoms should raise suspicion of porphyria in patients with acute abdominal pain: mental status changes (confusion, hysteria), peripheral neuropathy (motor > sensory), dark-colored (red to purple) urine, and known family history of porphyria [38]. Of special concern is the parturient with acute abdominal pain. Greater than 50% of pregnant women who have porphyria will experience a crisis during pregnancy. If the patient with an acute abdomen, pregnant or not, does not have suggestive symptoms of porphyria, anesthetic drugs and therapies should not be modified [40]. Known Acute Porphyria In the setting of known acute porphyria, perhaps the most difficult situation is when an acute attack is caused by and is concurrent with a disease process which mandates surgical intervention; i.e., the infection, pyrexia, and anorexia of acute appendicitis inducing ALA synthetase and precipitating crisis. Neurologic evaluation should focus on mental status and peripheral neuropathy. If an acute crisis is suspected, attention to cranial dysfunction and bulbar symptomatology may predict impending respiratory failure. Premedication is important, as pyschologic stress alone has been reported to precipitate crises [18,34,36]. Many reports have implicated benzodiazepines [4,41,42], and their use is discussed below. Narcotics are safe in porphyria, with the exception of pentazocine, a partial agonist. Scoplamine and atropine are considered safe. Acceptable nonnarcotic sedatives include droperidol, promethazine, chloral hydrate, and diphenhydramine. Intraoperative Management Regional Anesthesia Acute porphyria is not an absolute contraindication to regional anesthesia but in the setting of peripheral neuropathy, detailed preoperative exmination and documentation is essential. Potential mental status changes and patient cooperation is especially important in this setting. 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 after the administration of ester or amide local anesthetics [1,43]. Procaine decreases ALA synthase activity in the rat liver experimental model [43]. Regional anesthesia should probably be avoided in the setting of acute porphyric crisis. Associated neuropathy may be rapid in onset, clouding the differentiation between regional anesthetic onset and progressive porphyric neuropathy. In addition, mental status changes often make porphyric patients uncooperative. Finally, hypovolemia and a labile autonomic response, characteristic of acute porphyric crisis, increase the risk of hemodynamic instability in the setting of a sympathectomy. In fact, there are no studies specific to this issue--probably secondary to the ethical and medicolegal issues surrounding the institution of regional anesthesia while acute neurologic deterioration is occurring. Induction of Anesthesia Thiopental has accounted for the majority of drugprecipitated attacks [15,35] but the multifactorial nature of porphyric crisis makes interpretation of isolated cases difficult [18]. Since dehydration, infection, fever, and endogonous steroid hormones themselves induce ALA synthetase, virtually any drug administered to a patient entering a porphyric crisis implicates that drug as a "trigger" [18]. Interestingly, even a known trigger may not induce an attack [5,44]. For example, Ward [40] cases of of anesthesia in patients with porphyria. had a porphyric crisis. In was administered to patients with an acute porphyria but not in crisis of these patients an attack Of patients who in acute crisis to anesthetic with had of porphyric symptoms These results that administration of drugs does not, by an attack will Administration of such drugs is therefore probably only that may precipitate crisis. will not precipitate crisis, are in known porphyric patients in their has been implicated as a as have and has been used during porphyric crises has been used for of anesthesia in patients with VP, as has is in animal One has been reported of use for in a latent porphyria patient with an clincial but at porphyric crises has been reported after use has been implicated as porphyric crisis [18]. Laboratory of tissue culture results are as to be at but not at clinical levels The of such in or in animal studies to the clinical setting is Many to be safe in porphyrias has been as an drug to induce anesthesia. Many porphyric patients have with no clinical evidence of acute crisis ALA synthetase is not in animal A clinical of VP patients no evidence of when was used for the of anesthesia [7]. A report of a patient with VP increases of urinary porphyrins after a [33]. as was by et al. and et [7] this increase occurred after the anesthetic and was not by any symptoms is therefore considered for after anesthesia is [1]. of Anesthesia anesthetics are generally considered safe in porphyric patients. of a of with crises both experimental and clinical experience exacerbate porphyric crisis in has been classified as based on animal and are considered safe and have been used and are safe there is any of to is not has been used and is considered safe in Other muscle relaxants reported as safe include and It is to that some are considered in porphyria. and a steroid but only the has been as based on from experience and definitive are Treatment of and tachycardia are common features of an acute attack and are the most appropriate Propranolol decreases ALA synthetase activity and increases heme levels in tissue culture [19]. It is not known these effects occur with other such as or but a is safe [6]. is both clinical and reports in porphyric crisis is also associated with evidence of Since of patients in porphyric crisis safe is including and are safe are treatment for management but are not for acute management. has been for acute despite reports of porphyria crises after administration is in porphyria patients and autonomic neuropathy with labile hypertension suggests the of blood during an acute crisis. Central may be in the setting of clinical with heart and where excessive blood or are There is no documentation of a primary associated with this disease. The cardiovascular manifestations are secondary to autonomic nervous manifestations by electrolyte disturbances described These may have greater implications in the of disease. Management for the onset of porphyric crisis should be for to since onset may be The onset of crisis may be by neurologic signs or autonomic nervous [16]. In such appropriate cardiovascular may include as well as a to function and in the diagnosis and treatment of failure. in the setting of an acute attack should be by clinical The of after acute porphyric attack is The institution of of volume status should be by the and of and blood and the clinical status of the patient Neurologic status should be frequently If is probably should be but promethazine, droperidol, or are [6]. Acute Management of acute porphyric crisis involves specific to which increase ALA synthetase activity, of treatment of symptoms with appropriate and appropriate patient treatment at the disease process electrolyte monitoring, administration of may decrease enzyme activity as well as control treatment of and increases negative feedback to ALA synthetase [4-6]. the used most often in the treatment of porphyria, is but probably not the has clinical with decreases in urinary acid and Associated with are significant and include and These negative effects are secondary to the instability of the in the The of hematin is only These and this instability has to the of heme heme arginate is more stable in has a of and does not the effects of hematin The to heme usually occurs within after the of endogenous heme synthesis and decreases the of ALA and The only in the United is at a is to that this was the drug through the Drug to of treatment without hematin has been by use for or cases Recent information suggests that the early administration of heme arginate and improves this heme arginate, the most stable form of the lacks approval by the Food and Drug Administration and is not for in the United States. Clinical trials are to at the of at in the may have a role in the treatment of acute intermittent porphyria by heme activity, decreasing heme and ALA synthetase through a negative feedback mechanism This to the that may be as a and of remission. and animal but studies have not been Although does not the clinical course and can be used as an in patients with AIP, does not to be associated with an acute attack may therapy. and should be with or rather than which is [6]. bulbar symptoms frequent for respiratory should be blood analysis and are often important In patients with a history of tachycardia and hypertension characteristic of the acute crisis increase and should be in crises is with current treatment and is due to two and respiratory secondary to of respiratory or respiratory muscle [4]. has been reported in affected patients with and bulbar symptoms [18]. The of severe may clinical studies on the use of and anesthetics are clinical reports to the of these clinical of the use of or in porphyria is The lack of significant hemodynamic with these drugs makes their particularly in this group of patients. hereditary types of porphyria are classified as acute porphyrias. Enzymatic defects in accumulation of porphyrin precursors ALA and The of these precursors may be normal or increased in latent but increase to levels during a porphyric crisis. of ALA synthetase by administration of certain is only of which to porphyric crisis. and symptoms of acute porphyric attack of neurologic which occurs secondary to neurotoxicity of ALA or diminished intraneuronal heme levels. anesthetic management of porphyria of the type of porphyria assessment of latent versus of clinical features of porphyric attack, and of safe pharmacologic