Mastocytosis is a rare disorder of mast cell proliferation that occurs in both cutaneous (urticaria pigmentosa) and, in approximately 10% of cases, systemic forms . In the systemic form, the mast cells proliferate in all organs, such as bone, liver, and spleen, but not in the central nervous system . A peculiar and rare form of systemic mastocytosis, known as malignant aggressive systemic mastocytosis, is characterized by diffuse mast cell proliferation in parenchymal organs. Degranulation of mast cells with release of histamine, heparin, prostaglandin, and numerous enzymes (tryptases, hydrolases) may occur spontaneously or be triggered by nonimmune factors, including physical or psychological stimuli, alcohol, and drugs known to release histamine [3,4].
The anesthetic management of patients with systemic mastocytosis may be challenging. Some case reports have outlined the risk, complications, and recommendations to prevent these potentially life-threatening complications [5,6]. Serious problems, such as cardiovascular collapse, bronchospasm, and death, have been documented during general anesthesia [7-9]. We report on the successful use of total IV anesthesia with propofol in a patient with malignant systemic mastocytosis undergoing an elective splenectomy.
A 30-yr-old, 49-kg woman with systemic mastocytosis was admitted for an elective splenectomy and associated thrombocytopenia. The diagnosis of systemic mastocytosis was confirmed by a bone marrow, splenic, and liver biopsy, which showed a massive infiltration of immature and atypical mast cells. The specimens were consistent with the aggressive and progressive malignant form of the disease .
The patient's medical history was remarkable for recurrent flushes, urticarial weals, episodes of wheezing, severe pruritus, bouts of diarrhea, chronic peptic ulcer and gastroesophageal reflux disease, as well as several pathologic bone fractures during the last 10 yr. Her physical examination on admission was remarkable for liver and spleen enlargement. A generalized brownish cutaneous discoloration was noted. Darier's sign (dermographism) was positive with a weal and flare after scratching the skin. During the week preceding surgery, a treatment consisting of ranitidine (2 x 150 mg per os), paracetamol (3 x 500 mg per os), and disodium cromoglycate (3 nebulisations of 20 mg/d) was undertaken. The three drugs likely to be used during anesthesia-propofol, vecuronium, and fentanyl-were intradermally skin tested. All results were negative for a drug concentration of 10-3. Preoperative laboratory investigations were normal, except for moderate anemia (hemoglobin 99 g/L), increased alkaline phosphatase (196 U/L, normal 36-108 U/L), and decreased platelet count (38 g/L).
The patient was premedicated with midazolam 7.5 mg per os, ranitidine 100 mg per os, paracetamol 500 mg per os, methylprednisolone 100 mg IV, and disodium cromoglycate 20 mg by nebulisation. One hour before arrival in the anesthetic room, 6 U of platelets were given. A 14-gauge IV cannula, a radial artery cannula, and a pulmonary catheter via the right internal jugular vein were inserted. Continuous monitoring of arterial pressure and electrocardiogram was started.
The patient was placed on a warming matress and all IV fluids were warmed. Anesthesia was slowly induced with a bolus of propofol <or=to140 mg until the loss of eyelid reflex. Fentanyl 5 micro g/kg IV was given, and tracheal intubation was facilitated by 0.1 mg/kg of vecuronium. Anesthesia was maintained by propofol 8-10 mg [center dot] kg-1 [center dot] h-1, and fentanyl was added as necessary to keep the heart rate and blood pressure within 20% of the preinduction values. Ventilation was adjusted to maintain normocapnia; the fraction of inspired oxygen was 0.5 in a mixture of air. A nerve stimulator was placed over the right ulnar nerve, and vecuronium was given according to the train-of-four response. A nasopharyngeal temperature probe and a urinary catheter were inserted.
Blood samples were drawn throughout the surgical procedure to allow monitoring of histamine and tryptase blood levels and measurement of thrombin time. Plasma and whole blood histamine levels were measured by using a radioimmunoassay (Immunotech S.A., Marseille, France) . Plasma tryptase was also measured by using a radioimmunoassay (Pharmacia, Uppsala, Sweden). Figure 1 shows the profile of whole blood and plasma histamine levels during the operation. The plasma levels of tryptase did not vary during the surgical procedure and remained stable between 9.9 U/L (preinduction) and 10.2 U/L (postextubation). Thrombin time remained stable between 20 s (preinduction) to a maximal value of 23 s (after removal of the spleen).
Laparotomy was performed, and a large (2950 g) spleen was carefully liberated. The splenic veins were first ligatured to avoid a release of mediators during manipulation. The spleen was then removed. A blood specimen taken from the splenic vein at this time showed an increase in plasmatic (236 nmol/L, normal <10 nmol/L) and whole blood (3166 nmol/L, normal 200-2000 nmol/L) histamine levels, as well as a slight increase in plasmatic tryptase levels (15 U/L, normal 5-13 U/L), (Table 1). There were no episodes of flushing, bronchospasm, or hypotension during the operation, and clinically significant alterations in hemodynamic parameters were not observed. Neuromuscular blockade was not reversed, the trachea was extubated, and the patient was transferred to the surgical intensive care unit.
In the postoperative period, analgesia was achieved by a continuous infusion of fentanyl (0.5-2 micro g [center dot] kg-1 [center dot] h-1); the administration of paracetamol and ranitidine was continued. The recovery was uneventful and the patient was transferred to the ward on the fifth postoperative day.
Systemic mastocytosis often involves the skin, bone, gastrointestinal tract, liver, spleen, and lymph nodes. Systemic mastocytosis is considered malignant when parenchymal organs are not only surrounded by "nests," but also massively infiltrated by mast cells. The numerous organs infiltrated by the mast cells important to the anesthetist because anemia, thrombocytopenia, osteoporosis, pathological fractures, and bleeding diathesis are direct consequences of the disease process. Moreover, mast-cell degranulation releases different mediators-histamine, leukotrienes, 5-hydroxytryptamine, platelet-activating factor, prostaglandin, and others [4,11]-that may cause severe peri- or postoperative hypotension, tachycardia, bronchospasm, and coagulopathy.
Preoperatively, therapy consisting of sodium cromoglycate, a mast-cell stabilizer, ranitine to block the H2 receptor, and paracetamol was begun. Although paracetamol is a weak prostaglandin inhibitor, we preferred not to give acetylsalicylic acid because it may have deleterious effects on the bleeding tendency. Propofol, vecuronium, and fentanyl were chosen as anesthetic drugs because previous reports have shown their safety in this clinical context . The three drugs were preoperatively skin tested, and all returned negative results. On the contrary, lidocaine, morphine, oxymorphone, codeine, d-tubocurarine, metocurine, acetylsalicylic acid, etomidate, thiopental, succinylcholine, enflurane, and isoflurane were each directly or indirectly associated with mast-cell degranulation [8,9,12]. Under this anesthetic regimen, the surgical procedure was well tolerated, as evidenced by peroperative histamine and tryptase monitoring. No untoward events were observed during the surgical procedure or during the postoperative recovery phase.
Histamine is one of several mast-cell mediators implicated in the pathogenesis of diseases that result, at least in part, from mast-cell degranulation. Friedman et al.  have shown that patients with mastocytosis have increased plasma histamine levels, whereas patients with idiopathic anaphylaxis have increased plasma histamine levels only during reaction, with normal levels between episodes. This is in accordance with our patient, who had preoperatively a 10-fold increase in plasma histamine levels, whereas the total blood histamine was within normal range, as described in the case report of Smith et al. . Graneras et al.  found that the urinary excretion of the main histamine metabolite, methylimidazoleacetic acid, was correlated to widespread mast-cell infiltration and also to the intensity of pruritus. Although they did not find a correlation between the extent of the disease and histamine excretion, the preoperative histamine excretion of our patient, which was more than 15 times the normal value, may indirectly reflect the severity of the disease. Desborough et al.  measured plasma histamine concentrations in a patient with systemic mastocytosis and reported a >or=to1000-fold increase of histamine blood levels during an episode of intraoperative profound hypotension; otherwise, the patient had preoperative normal histamine blood values. The preoperative excretion of histamine and its metabolites was not described. This is in contrast with our patient, who had a 10-fold increase in preoperative plasma histamine concentrations.
Two interesting aspects in the present case deserve to be mentioned. First, plasma basal histamine levels were 10 times the normal value, in contrast with the patient of Desborough , although the patient reported by Desborough et al. histologically had only nests of mast-cell infiltration of the parenchymal organs compatible with the nonaggressive form of systemic mastocytosis. Second, samples taken at the same time from the splenic vein and the mixed venous blood showed whole blood histamine levels >or=to5 times greater in the splenic vein compared with the basal levels found in the mixed venous blood, although during the whole procedure, the whole blood histamine was always within the normal range, in contrast to plasma levels, which were consistently increased (Figure 1). This is compatible with the increased basal turnover of mast cells. The increase of whole blood histamine may be explained by the release of mast cells stocked in this heavily infiltrated spleen after, and despite, gentle surgical manipulation. According to the huge reserve of available histamine, we may surmise the disastrous clinical consequences if a mast-cell degranulation had occurred.
Tryptase, a neutral protease selectively concentrated in the secretory granules of human mast cells, but not basophils, is released by mast cells, together with histamine, and therefore serves as a specific marker of mast-cell activation . Monitoring of the tryptase plasma levels during the whole surgical procedure revealed that the anesthetic technique used did not stimulate mast-cell degranulation. The only value that was slightly outside the normal range was that in the splenic vein after the spleen had been manipulated.
We report the safe use of total IV anesthetic technique in a patient with malignant systemic mastocytosis undergoing general anesthesia. Histamine and tryptase blood levels confirmed the absence of mast-cell degranulation during surgery. However, whole blood and plasma histamine levels, particularly in the splenic vein, reflect the huge reserve of histamine available in this patient. It is therefore mandatory to take all measures to prevent mast-cell degranulation in patients with malignant systemic mastocytosis, and we recommend that the usual recommendations (preoperative control of symptoms and anxiety; avoidance of precipitating factors such as trauma, hypothermia, and hyperthermia) be closely followed . In this context, we believe that an intradermal skin test of drugs likely to be used during anesthesia is particularly indicated.
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