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FACTORS THAT CAN EVOKE THE RELEASE OF MAST
SPECIFIC PROTOCOLS IN RISK SITUATIONS IN PATIENTS
Mast Cell Research Institute (CLMast)
Spanish Network on Mastocytosis (REMA)
Hospital Virgen del Valle
Complejo Hospitalario de Toledo
Servicio de Salud de Castilla la Mancha (SESCAM)
Luis Escribano, MD, PhD
Director of the Mast Cell Research Institute
Coordinator of the Spanish Network on Mastocytosis
Iván Álvarez Twose, MD
Laura Sánchez Muñoz, MD, PhD
Almudena Matito, MD
José Mario Morgado, Msc
Grants: Ministerio de Ciencia e Innovación, Fondo de Investigación Sanitaria, ETS PI09/90871
FACTORS THAT CAN EVOKE THE RELEASE OF MAST CELL
1. PHYSICAL AGENTS
a. Heat: Use mildly warm water for bath or shower. Do not rub briskly
with towel to dry off. When drying hair, use hair dryer only on warm heat.
b. Coldc. Pressure: Traumas to scalp in patients with skin lesions in this area.
Avoid Darier’s sign (friction of skin lesions), this procedure can evoke a massive mast cell mediators release, especially in large lesions (mastocytomas).
d. Endoscopies (panendoscopy, rectoscopy, colonscopy)e. Manipulation of GI system/intestines during surgery
2. EMOTIONAL FACTORS
a. Stress (frequent)b. Anxiety (frequent)
3.1. Infections or Fevers of any etiology (frequent)3.2. Teething in children (frequent)3.3. Vaccination in children (infrequent)
4. DRUGS & MEDICATION
4.1. Non-steroidal antiinflammatory drugs (NSAIDs)*, are used as analgesic
and antipyretic medication. This group includes: Aspirin (acetylsalicylic acid), mefanamic acid, butibufen, diclofenac, fenbufen, fenilbutazone, flurbiprofen, ibuprofen, indometacine, ketoprofen, ketorolac, meclofenamate, metamizole, nabumetone, naproxen, propifenazone. among others.
Acetaminophen is usually well tolerated in mastocytosis, in this sense it is not initially restricited.
4.2. Opioids and morphine derivatives. These drugs are used in anaesthesia,
analgesic and cough therapy. This group includes: morphine, codeine, buprenorphine, meperidine, dextromethorphan, dimemorphan, fentanyl, tramadol. among others.
4.3. Alcohol: Rare <0.5% (REMA, unpublished data, 1984 – 2006).
4.4. Muscle relaxants and inductors used in general anesthesia.‡4.5. Beta-blockers are restricted during general anesthesia, and in cases who suffered previous anaphylactic episodes.
4.6. Local anesthetics¶: Exceptional using amide-derivatives.
4.7. Contrast Media used for diverse radiological studies: Rare.
4.8. Interferon Alpha 2b#:
4.9. Clorodeoxiadenosine or Cladribine (2-Cda): Rare. Only one case was reported (J. Sheik, Beth Israel Hospital, Harvard Medical School, personal communication, September 2002).
4.10. Hydroxyurea: Rare. It was reported in only one case (L Escribano, personal communication, June 2007).
4.11. Colloids: Substances with high molecular weight used to treat hypotension or hypovolemia, such as dextran (infrequent).
The frequency of mast-cell mediators release related to the NSAIDs, is 2% in
pediatric mastocytosis and 14% in adults. (Sánchez-Matas I, XXVIII Congress of the
‡According to the data recorded by REMA´s physicians, among 73 adult patients who underwent general anaesthesia, 3 suffered severe mast-cell mediators release symptoms (2 cardiorrespiratory arrests, and 1 coagulopathy with hypovolemic shock), the specific protocols in risk situations in mastocytosis were not followed in these cases (Matito A, 29th Congress of the EAACI). In pediatric mastocytosis, 17 children underwent general anaesthesia, and no severe mast-cell mediators release episodes were reported (CLMast, unpublished data, September 2010).
No adverse reactions were recorded in 850 bone marrow biopsies and 1,235
cutaneous biopsies. In these cases, adequate premedication was used (REMA,
unpublished data, 1984 – 2006). In 8 cases with previous history of anaphylaxis
induced by stress, the bone marrow biopsies were performed in the ICU with pre-
medication, local anaesthesia and sedation (CLMast, unpublished data, September
#Mast-cell mediators related symptoms were not reported in 23 cases who underwent of interferon therapy. In all cases antimediator premedication was used according to the REMA´s specific protocols, and the 3 initial doses were given in the ICU (Escribano L, unpublished data, 1995 – 2006).
SPECIFIC PROTOCOLS IN RISK SITUATIONS IN PATIENTS WITH
A. Protocol in general anesthesia
Some medications used in pre-anesthesia, induction and maintenance phase or during the post-anesthesia period can evoke anaphylactic/anaphylactoid reactions, and alterations in blood coagulation. These reactions are due to the release of mast-cell mediators, some of them are stored in the mast-cells such as histamine, heparine or tryptase; while others are synthesized during the process of mast-cell activation (PGD2, LTC4). The capacity of some of these drugs to induce mast-cell degranulation was reported in vitro
; furthermore, several case reports about life-threatening crisis related to anesthesia in patients with mastocytosis, can be found in the medical literature. In our series, the frequency of these severe episodes in adult patients who underwent general anesthesia is 4.1% (Matito A, 29th Congress of the EAACI).
Mast-cell activation can be triggered through cross-linking of high-affinity Fc receptors for IgE (FcεRI), Fcγ receptors for IgG, or complement proteins among others. The mediators released target at tissues and organs such as the heart, the blood vessels, the skin, the lungs, among others, resulting in cardiovascular, hemodynamic and metabolic disorders similar to those observed in anaphylactic reactions or serious coagulation disorders.
General anesthesia is an obvious risk for patients who suffer from mastocytosis or systemic mast cell activation disorders (SMCAD).
These protocols are supported on the experience of the Spanish Network on Mastocytosis, and an exhaustive review of the literature.
NOTE. The doses of drugs must be adjusted according to the body weight, comorbidities and drug-interaction.
A.1. GENERAL PREPARATION (ANTIMEDIATOR PREMEDICATION)
A.1.1. Corticosteroids (i.e. prednisone, methylprednisolone) 8 hours, and 1
hour before the anesthesia (optional
A.1.2. Dexchlorpheniramine (Polaramine®): IV one hour before the
anesthesia, (other H1- antihistamines can be used)
A.1.3. Ranitidine: one hour before the anesthesia
A.1.4. Montelukast (Singulair®): 24 and 1 hour before anesthesia (Castells
M, Brigham and Women’s Hospital, Harvard Medical School, personal communication, September 2003)
A.2.1. Sedation is important to avoid anxiety. Benzodazepines can be used.
A.3.2. Propofol A.3.3. Ketamine A.3.4. Inhalants of the “flurane” family
During the maintenance phase, these drugs must be used in enough concentration to gaurantee a deep anesthesia.
A.4.1. VecuroniumThere are no data about the safety of other muscle relaxants
A.5.1. Opioids and morphine derivatives must not be used in mastocytosis. In our series, 24 anesthetic procedures (18 under general anesthesia, 4 under epidural anesthesia, and 2 sedations) were performed using pethidine, fentanyl or remifentanil; one of them, who was not given antimediator therapy before the general anesthesia (with anesthetic drugs different to the recommended in this protocol) suffered a severe mast-cell mediators release episode. (CLMast, unpublished data, June 2009). Nevertheless, in our experience fentanyl and remifentanil can be safely used if they were tolerated before in the patient suffering from mastocytosis.
A.5.2. The colloids can evoke anaphylactic reactions in mastocytosis and must not be used.
A.5.3. Do not use beta-adrenergic or alpha-adrenergic blockers.
A.5.4. Tryptase serum levels before, during and after surgery should be analyzed.
The medications previously tolerated by the patient are allowed. Each patient should have a medical report from a Specialized Center in this sense.
If the analgesic drugs tolerated by the patients are unknown, provocation tests should be performed with the corresponding medications at a Specialized Unit under strict and monitored supervision.
TREATMENT OF EPISODES OF ACUTE MEDIATOR RELEASE DURING ANESTHESIA
A.7.1. Anaphylactic shock: Epinephrine, Corticosteroids, H1 and H2 antihistamines; and Glucagon (if the patient is under the effect of beta-blocker). A.7.2. Hypotension: Fluid thearpy (avoid colloids), Dopamine, Dobutamine.
A.7.3. Hemorrhagic syndorme. Treatment according to the coagulation alterations.
See specific protocols available in different countries.
B. Protocol in local anesthesia
The techniques of local anesthesia (including epidural) must be considered as the
first choice in patients with mastocytosis, therefore, they must be used instead of
general anesthesia when feasible.
The use of antimediator premedication (see above) can be useful to avoid mast cell-mediator release induced by stress.
B.1. Oral premedication should be used for skin or other tissue biopsies (bone
marrow), dental interventions or minor surgery.
B.2. Amide derivatives such as bupivacaine, lidocaine or mepivacaine should be
C. Radiological exams with a contrast media
Clinical experience as well as in vitro
research studies, have shown that most of intravenous contrast agents used for radiologic procedures can evoke mast-cell mediators release. In this sense, these agents should be be avoided; however if they are strictly necessary, the nonionic (low molecular weight) contrast agents must be chosen, since they decrease the risk of mast-cell degranulation. This group of agents includes: iohexol, iopamidol, iopromida, ioxilan, ioversol, idolatran and iodixanol.
The procedure must be carried out under strict supervision with adequate monitorization.
In addition, every patient must be given antimediator premedication previous to the intravenous contrast agent*:
C.1. H1-antihistamines (Dexchlorphenaramine: Polaramine®): one hour
before the radiologic contrast.
C.2. Ranitidine: one hour before the pradiologic contrast.
C.3. Corticosteroids: 13, 7 and 1 hour before the radiologic contrast. Optional,
these doses can be modified according to any practitioner criteria.
C.4. Montelukast (Singulair®): 24 and 1 hour before the radiologic contrast.
Recommended only in cases with previous mast-cell mediators release
episodes related to contrast agents.
* An allergic work-up must be performed in patients who suffered an allergic reaction or a mast-cell mediators release episode related to contrast agents, in order to detect specific sensitizations (IgE mediated mechanism) to the contrast agents, and to avoid their use.
*These medications should be adapted according to the avalability in each country.
D. Labor and delivery
This procedure can be carried out with epidural or general anesthesia, following the protocols recommended in this text.
Antimediator premedication is mandatory, since both the labor and the stress can evoke a mast-cell mediators release episode.
Delivery inductors as oxytocine can be used.
Fentanyl or remifentanil in epidural anesthesia, can be used only in patients who tolerated them after the onset of mastocytosis.
In our series (REMA), a total of 45 deliveries were recorded in women with mastocytosis; 32 epidural, 2 general and 1 local anesthesia were used, and no life-threatening release crisis were reported. (Matito A, Int Arch Allergy Immunol 2011).
Antimediator premedication (at the beginning of labor and/or 1 hour before the anesthesia)
D.1. *H1 anithistamines D.2. RanitidineD.3. Corticosteroids before the anesthesia (optional)
*These medications should be adapted according to the avalability in each country.
E. Protocol in mast-cell mediators related symptoms triggered by hymenoptera
sting (bee, wasp or red-ant).
Sporadic cases after sting or bite of other insects
E.1. Mild symptoms without hypotension or cardiovascular compromise: H1 antihistamines, ranitidine and corticosteroids.
E.2. Anaphylacitc shock
Immediately LIE ON ONE´S BACK
E.2.1. Injection of intramuscular epinephrine 1 in 1000 solution; or auto-
injectable epinephrine devices (Altellus, EpiPen, Anapen, Twinject.) 0,3 in adults and 0,15 in children. The patients and their relatives must be trained to use the device.
E.2.2. Go to the emergency room, to complete evaluation and treatment.
Tryptase must be measured in the following 1-3 hours after the anaphylaxis.
*Epinephrine must be used only in systemic reactions with severe
hypotension, laryngeal/uvular angioedema, or syncope/presyncope.
*Epinephrine must be used whenever there is a strong suspicion of an
anaphylactic shock is going on.
*These medications should be adapted according to the avalability in each country.
Insituto de Estudios de Mastocitosis de Castilla a Mancha (CLMast)Hospital Virgen del ValleRed Española de Mastocitosis (REMA)Carretera de Cobisa s/nToledo 45071, Spain
Phones: Dr. Escribano +34 925269335 +34 638226228
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Stellato C, De Paulis A, Cirillo R, Mastronardi P, Mazzarella B, Marone G. Heterogeneity of human mast cells and basophils in response to muscle relaxants. Anesthesiology 1991;74:1078-1086.
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Stellato C, Marone G. Mast cells and basophils in adverse reactions to drugs used during general anesthesia. Chem Immunol 1995;62:108-131.
Borgeat A, Ruetsch YA. Anesthesia in a patient with malignant systemic mastocytosis using a total intravenous anesthetic technique. Anesth Analg 1998;86:442-444.
Fisher MM, Baldo BA. Mast cell tryptase in anaesthetic anaphylactoid reactions. Br J Anaesth 1998;80:26-29.
Vaughan STA, Jones GN. Systemic mastocytosis presenting as profound cardiovascular collapse during anaesthesia. Anaesthesia 1998;53:804-807.
Worobec AS, Akin C, Scott LM, Metcalfe DD. Mastocytosis complicating pregnancy. Obstet Gynecol 2000;95:391-395
Auvray L, Letourneau B, Freysz M. Mastocytosis: general anesthesia with remifentanil and sevoflurane. Ann Fr Anesth Reanim 2001;20:635-638.
Tirel O, Chaumont A, Ecoffey C. Circulatory arrest in the course of anesthesia for a child with mastocytosis. Ann Fr Anesth Reanim 2001;20:874-875.
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Escribano L, Akin C, Castells M, Schwartz LB. Current options in the treatment of mast cell mediator-related symptoms in mastocytosis. Inflamm Allergy Drug Targets 2006;5:61-77.
Carter MC, Uzzaman A, Scott LM, Metcalfe DD, Quezado Z. Pediatric mastocytosis: routine anesthetic management for a complex disease. Anesth Analg 2008;107:422-427
Ahmad N, Evans P, Lloyd-Thomas AR. Anesthesia in children with mastocytosis-a case based review. Paediatr Anaesth 2009;19:97-107.
Matito A, Álvarez-Twose I, Sánchez-Muñoz L, Morgado JM, Orfao A, Escribano L. Clinical impact of pregnancy in mastocytosis: a study of the Spanish Network on Mastocytosis (REMA) in 45 cases. Int Arch Allergy Immunol 2011;156(1):104-111.
Escribano L, González de Olano D, de la Hoz Caballer B, Esteban López I, Sánchez
Fernández I. Mastocitosis: guías para su diagnóstico y tratamiento In: Peláez-Hernández A, Dávila-González IJ eds. Tratado de Alergología. 1 ed. Madrid: Ergon; 2007. p. 1241-1262.
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