Malignant hyperthermia

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Classification according to ICD-10
T88.3 Malignant hyperthermia
ICD-10 online (WHO version 2019)

The Malignant Hyperthermia (MH), outdated and malignant hyperpyrexia , anesthesia hyperthermia syndrome and Ombredanne syndrome , is a certain, especially after administering anesthetic infrequently occurring medical emergency. It is a rare pharmacogenetic disease of the skeletal muscles, which is based on a congenital defect in intracellular calcium regulation.

After administration of triggering agents ( triggers ) at the appropriate genetic predisposition by an uncontrolled release of calcium ions across functionally altered sarcoplasmic a life-threatening metabolic derangement in calcium channels skeletal muscle causes that requires rapid processing.

The Malignant hyperthermia is a rare, life-threatening complication of anesthesia and can also occur at the stage after the operation. The trigger substances (especially halogenated hydrocarbons used as volatile anesthetics and the muscle-relaxing succinylcholine ) are not only used in operations under general anesthesia, but also in intensive care units and in emergency medicine.

The symptoms are very variable (from only mild forms with only one or a few symptoms to a fulminant MH crisis) and include muscle stiffness , palpitations , increased production of carbon dioxide (CO 2 ) and a rise in temperature (from a slight rise in temperature to fever ) up to hyperacidity of the body as well as metabolic and organ failure (including acute kidney failure, functional disorders of the heart and lungs and neurological complications), which can ultimately lead to death. Malignant hyperthermia can be effectively treated by immediately interrupting the supply of anesthetics that may be a trigger and treating it as quickly as possible with the active ingredient dantrolene , which has been available for this purpose since 1979 . Its introduction has made it possible in the past to significantly reduce mortality (to below 3 percent).

If a predisposition to malignant hyperthermia is suspected, the in vitro contracture test and molecular biological methods are available to clarify this. In such cases, anesthesia can also be carried out without triggering substances.

In addition to humans, it is also known to occur in other mammals such as pigs, dogs and horses, which is why they are used as animal models in research .

Epidemiology

The frequency ( prevalence ) of the genetic disposition for malignant hyperthermia syndrome (MHS) is around 1: 2,600, or 1: 3,000 to 1: 2,000, regardless of ethnicity. The frequency of clinical occurrences varies from 1: 5,000 to 1: 100,000 anesthesia. Most authors assume about one case per 20,000 anesthetics, with fulminant MH crises being significantly less common at 1: 60,000 (1: 250,000 to 1: 10,000). MH cases can also occur in non-surgical specialist areas: Given that 430,452 intensive care patients were ventilated in Germany in 2017, for example, up to 165 cases of MH can be expected in intensive care units alone annually. Malignant hyperthermia occurs in every age group, but young patients are more frequently affected (around half of MH crises affect children and adolescents up to the age of twelve). The average age is around 18 years, and MH occurs more often for unknown reasons in men (2: 1). The majority of patients with malignant hyperthermia had already had previous anesthesia with an unremarkable course (in numerous cases MH only occurs after repeated trigger exposure). Due to the decreasing use of trigger substances (especially halothane and succinylcholine), the frequency is falling. The mortality rate ( lethality ) has historically been reduced from over 90% to under 5% through improved training and patient monitoring such as the development of dantrolene. On average, if the disease does occur, it is detected earlier today.

Malignant hyperthermia is most common in domestic pigs , especially in fast-growing breeds with high skeletal muscle attachments such as Pietrain . In some breeding lines, up to 95% of the animals can be affected. In pigs, stress can be enough to trigger the disease, which is called porcine stress syndrome (PSS). The meat quality of these animals is reduced (→ PSE meat ).

In domestic dogs , the prevalence is given as 1: 15,000, making the disease a very rare complication. A genetic predisposition has been demonstrated in greyhounds .

Causes and development mechanisms

Normal skeletal muscle contraction

→ Main article: Contractile mechanism

The physiological contraction of the skeletal muscle occurs through the release of calcium ions (Ca 2+ ) from the storage system of the cell, the sarcoplasmic reticulum . To trigger a muscle contraction, an electrical impulse ( action potential ) from a motor nerve is transferred to the muscle cell via the motor end plate . This leads to the activation of a voltage-controlled ion channel in protuberances in the cell membrane ( T tubules ) . This is in spatial contact with a calcium channel of the sarcoplasmic reticulum, the ryanodine receptor , which is subsequently opened. The calcium (Ca 2+ ) flowing into the cell interior ( cytosol ) enables the actin and myosin filaments to contract, and the muscle contracts. This connection of an action potential with the muscle contraction is called electromechanical coupling .

Processes in malignant hyperthermia

Malignant hyperthermia involves genetic changes ( mutations ) in the ryanodine or dihydropyridine receptors (i.e. the sarcoplasmic calcium ion channels). By administering trigger substances, a massive and uncontrolled release of calcium within the muscle cells is triggered in predisposed patients. This activates the muscle fibers. Since both the re-uptake of calcium in the sarcoplasmic reticulum and the dissolution of the contractile filaments after the contracting are energy-dependent processes that require ATP , the cell quickly becomes deficient in energy. The calcium ions lead to a strong increase in cell metabolism ( aerobic energy production, later also anaerobic metabolism ), which leads to increased oxygen turnover (and thus consumption) and increased carbon dioxide and heat production. These processes initially take place in isolation in the skeletal muscle. In the course of the process, muscle contractions up to rigidity , cell death and muscle breakdown ( rhabdomyolysis ), which lead to an oxygen deficiency ( hypoxia ), increased carbon dioxide accumulation ( hypercapnia ) and severe acidosis ( acidosis ) with lactic acidosis or lactataemia (due to anaerobic glycolysis ) and overheating ( hyperthermia ) of the entire body. This has a (secondary) damaging effect on other organs (see clinical picture ). It is unclear whether genetic changes also play a role in other organs in addition to the skeletal muscle and lead to disorders there. The heart muscles are not affected by the mutations in the ryanodine receptor.

genetics

Six different gene locations on different chromosomes have so far been associated with malignant hyperthermia. The most common cause is one of about 100 known point mutations of the ryanodine receptor- coding gene RYR1 on chromosome 19 , which can be detected in over 80% of MH patients ( MH susceptibility 1 ). In addition, mutations in the gene of the dihydropyridine receptor and other proteins can be the cause of malignant hyperthermia ( MH susceptibility 2–6 ). While point mutations cause the exchange of a single amino acid in most cases, deletions and insertions are also known. The inheritance of the mutations occurs in humans autosomal - dominant .

Patients with central core myopathy and multiminicore myopathy may have an MH disposition. These rare muscle diseases are also often based on mutations in the RYR1 gene. An MH disposition can also exist with other muscle diseases such as periodic hypokalemic paralysis , potassium-sensitive myotonia ( Myotonia fluctuans ), the rare King-Denborough syndrome . Even if no anesthetic problems were documented in the majority of patients with McArdle's disease (glycogenosis type V), malignant hyperthermia can also occur in this patient group.

There is evidence that a predisposition to exercise-induced heat stroke and MH are due to the same genetic makeup.

Malignant hyperthermia is passed on according to an autosomal dominant inheritance pattern .

Trigger substances

Vaporizer with inhalation anesthetics (sevoflurane, isoflurane)

Trigger substances are vapor or gaseous inhalation anesthetics such as B. sevoflurane , desflurane and isoflurane as well as depolarizing muscle relaxants ( succinylcholine ). Poisoning, drug use, physical exertion or fear can play a role as cofactors for the triggering, and in individual cases it can also be the sole cause. The other drugs used in anesthesia ( laughing gas , opioids , sleeping pills , benzodiazepines , non-depolarizing muscle relaxants) are safe and can also be used in cases of MH disposition.

In addition to halothane , caffeine , ryanodine and cresols can trigger malignant hyperthermia, which is used for diagnostic purposes in the laboratory (contracture test, see below). No risk is to be expected from the ingestion of caffeine with food or the administration of drugs containing cresol such as heparin or insulin .

Clinical picture and acute diagnosis

The extent of malignant hyperthermia is very variable, making the diagnosis, which must be confirmed by early blood gas analysis and laboratory diagnostics, difficult.

Early symptoms

Early signs are an increased carbon dioxide concentration ( hypercapnia ) in the exhaled air, an increase in the heart rate ( tachycardia or tachycardiac arrhythmia), an increased respiratory rate (tachypnea), muscle rigidity ( rigor , generalized muscle rigidity), a cramp of the muscle masseter (masseter spasm, "trismus “) Immediately after administration of succinylcholine, hyperacidity of the body (combined respiratory and metabolic acidosis with negative base excess ) as well as lactataemia (an excess of lactate in the blood) and an oxygen deficiency caused by increased oxygen consumption ( hypoxemia ). Other early symptoms are ventricular arrhythmias and unstable blood pressure behavior, and only rarely a rise in temperature.

Late symptoms

The eponymous rise in temperature ( hyperthermia ) is usually a late sign (late symptom), but it can also be the only clinical sign of an impending MH crisis. More late mark drop in blood pressure ( hypotension ), waste of oxygen saturation and cyanosis by extremely increased oxygen consumption at excessively enhanced muscle metabolism, potassium release from the cells ( hyperkalemia , conditioned by an increased cell membrane permeability), threatening cardiac arrhythmias , or even heart-circulatory arrest and muscle wasting ( rhabdomyolysis , with partly, in the later course after more than four hours occurring, extreme increase of creatine phosphokinase (CK) and myoglobin in the blood).

monitoring

In addition to the standard monitoring measures ( ECG , blood pressure measurement , pulse oximetry , capnometry to measure the end-tidal carbon dioxide concentration, assessment of muscle tone), early and repeated blood samples ( blood gas analysis , electrolytes such as potassium in the Serum, creatine phosphokinase (CK), transaminases , lactate and myoglobin) are necessary. The early onset of an increase in the carbon dioxide concentration in the exhaled air is often associated with a strong warming of the CO 2 absorber on the anesthesia machine.

Gradient forms

A distinction is made between the following forms of malignant hyperthermia:

  • The fulminant malignant hyperthermia develops rapidly in a crisis and is characterized by a broad spectrum of clinical symptoms. The first sign is a rapid, enormous increase in the CO 2 concentration measured in end-tidal expiration, combined with an increase in heart rate. A fulminant MH crisis occurs when the CO 2 - partial pressure in arterial blood than 8.0 kPa (60 mmHg) is (normal value to 6.0 kPa; 45 mm Hg), a base deficit > 8  mmol / l or mval / l (normal value up to 3 mmol / l) is a sign of severe metabolic acidosis and / or a rapid increase in temperature to over 38.8 ° C without any other cause can be measured (temperature increases of up to 1 ° C per 5 minutes have been measured) . In the further course there is an increasing impairment of the circulation with a reflex increase in the cardiac output , tachycardia, drop in blood pressure and damage to the heart muscle . If the crisis is not recognized and treated quickly, the metabolic disorders lead to organ damage such as kidney failure ( crush kidney ), damage to the brain ( cerebral edema ), blood clotting disorders ( consumption coagulopathy ), and cardiovascular failure, which ultimately lead to multi- organ failure and death . The training and development of a brilliant MH happens within minutes to a few hours.
  • The abortive malignant hyperthermia starts creeping, often only hours after the trigger exposure. This form of malignant hyperthermia is much more common, but often difficult to diagnose due to its very variable clinical picture. Lower values ​​of carbon dioxide partial pressure, base deficit and temperature than in a fulminant MH crisis do not reliably rule out an MH diagnosis. In the differential diagnosis , sepsis , a thyrotoxic crisis , a neuroleptic malignant syndrome or a pheochromocytoma come into question if the symptoms are appropriate . An abortive course can develop into a fulminant crisis ( exacerbation ) at any time .
  • A masseter spasm is a severe, acute spasm of the masseter muscle in the jaw, which typically occurs after the administration of succinylcholine and which is noticeable during endotracheal intubation because the mouth is difficult or impossible to open. While this symptom is often isolated, it can also herald a rapidly developing progression. Another manifestation that can occur without further symptoms is a dark discoloration of the urine due to myoglobinuria due to severe damage to the skeletal muscles ( rhabdomyolysis ) if trigger substances were used during anesthesia.

therapy

Malignant hyperthermia can usually be successfully treated with early suspected diagnosis, immediate interruption of the supply of triggering substances and immediate treatment (especially with the drug dantrolene ).

Immediate action

If there is a suspicion of a developing MH crisis after early symptoms have been identified and other causes have been excluded, therapy must be initiated immediately and consistently continued. The measures for the treatment of the fulminant MH are very personnel-intensive, additional support must be organized immediately. Recommendations for the treatment of malignant hyperthermia, including an algorithm, are provided in the S1 guideline on the therapy of malignant hyperthermia (as of March 2018). If the development of MH is suspected shortly before the start of an elective (non-emergency) operation, the surgeon must be informed and the operation postponed. If the operation has already started, a joint decision is made by the anesthetist and the surgeon on whether to continue the operation (quickly) or to stop.

The immediate termination and avoidance of further supply of MH trigger substances is a priority. When using inhalation anesthetics (usually sevoflurane, desflurane or isoflurane), the vaporizer is removed from the anesthesia machine and (to maintain or restore adequate oxygen saturation) controlled ventilation with a high fresh gas flow of 10 liters per minute (to minimize rebreathing of the vapors) and 100% oxygen (for the therapy of existing or threatened hypoxemia) carried out (changing the anesthesia machine is not indicated). If feasible - depending on the anesthesia machine - the CO 2 absorber volume (soda lime ) is significantly increased. The minute volume is also increased (approximately three to four times) in order to normalize the strongly increased CO 2 through exhalation (by means of hyperventilation ). The anesthesia is continued with intravenous drugs (sedatives such as propofol, opioids such as sufentanil, non-depolarizing muscle relaxants such as rocuronium) without triggering ( total intravenous anesthesia , TIVA).

Structural formula of dantrolene

Specific therapy through the fastest possible infusion of the active ingredient dantrolene with an initial dose of 2.5 mg / kg is crucial for the prognosis . This is a hydantoin derivative that inhibits the release of calcium from the sarcoplasmic reticulum. Dantrolene is the only active ingredient available that enables causal therapy. The active ingredient is therefore on the list of supply-relevant active ingredients of the Federal Institute for Drugs and Medical Devices (BfArM). According to the new S1 guideline (March 2018), emergency therapy in adults requires a stock of at least 10 mg / kg body weight of dantrolene; this corresponds to 36 to 48 injection bottles of dantrolene (one bottle of dantrolene contains 20 mg of dantrolene sodium). Since the emergency medication must be available within a few minutes, sufficient quantities should be stored immediately in the operating unit. In clinics with anesthesia locations that are further apart, the guideline recommends positioning in several predestined locations. Adequate stocks of dantrolene are also essential in practices that provide outpatient care under general anesthesia and using trigger substances for malignant hyperthermia. Falling below the minimum quantities can lead to dangerous delays in individual cases and possibly result in very serious harm to the patient.

Dantrolene is repeatedly and rapidly infused (as a bolus dose) at short intervals until a clinical effect occurs through normalization of the hypermetabolic metabolism ("hypermetabolic syndrome") and MH symptoms are no longer detectable, in order to continue to administer it subsequently. If this does not lead to success, even if more than 10 mg / kg dantrolene is administered, the diagnosis must be reconsidered. Dantrolene doses of up to 10 mg / kg / 24 hours may, depending on the clinical course, be necessary even after successful primary therapy. Dantrolene has a slightly relaxing effect on muscles . In most cases, however, sufficient spontaneous breathing is still possible after the anesthesia has ended.

The S1 guideline for the therapy of malignant hyperthermia recommends the established initial dose of initially 2.5 mg / kg body weight for immediate therapy. The administration may have to be repeated several times and at short intervals until a clinical effect sets in and MH symptoms are no longer detectable. In individual cases, doses of 10 mg / kg body weight must be exceeded.

In parallel, symptomatic therapy is carried out. This includes the stabilization of the circulatory system (if necessary by means of volume , vasopressors or inotropics ), and with a continuous flow of lactate from the cell, a balancing of the metabolic acidosis (with sodium hydrogen carbonate or possibly TRIS buffer according to the acid-base status in blood gas analysis) as well as electrolyte disorders , in particular those of a high potassium level ( hyperkalaemia ), an increase in urine production ( diuresis ) to flush out substances that are detrimental to kidney function and, if the previous measures have not yet improved, treatment of (caused by predominance of the sympathetic nervous system and with cardiac arrhythmias associated with the risk of cardiac insufficiency (with antiarrhythmics such as amiodarone or beta-blockers, but not with calcium antagonists contraindicated due to possible interactions with Dantrol).

Further measures

Since hyperthermia is a late symptom, active cooling (external measures to cool the surface of the patient, cold infusion solutions of around 4 ° C) is usually only necessary during the course of an increased body temperature or a fever. Such cooling is continued at least until the body temperature has dropped below 38.5 ° C. The forced diuresis (with an increase in urine production to 1 to 2 ml / kg / hour) with adequate hydration to avoid an acute kidney failure which may occur due to a shock symptoms and rhabdomyolysis, requires the monitoring of renal function a bladder indwelling catheter through which also cooling (hypothermic rinsing) can take place. If the hyperkalaemia or impaired renal function cannot be adequately treated with forced diuresis with loop diuretics and a glucose-insulin infusion, then dialysis should be considered, as with other therapy-refractory electrolyte imbalances. The administration of heparin can counteract the possible coagulation disorders ( disseminated intravascular coagulation ). The administration of calcium channel blockers is ineffective and can lead to damage to the heart muscle if dantrolene is administered at the same time. It is therefore not indicated ( contraindicated ).

Circulatory monitoring should be carried out (in addition to standard monitoring ) by means of invasive blood pressure measurement via an arterial access . In addition, a central venous catheter is placed and sufficient peripheral volume accesses are created. After the initial stabilization of the patient, monitoring and further treatment in an (anesthesiological) intensive care unit for at least 24 hours are necessary. Laboratory parameters in particular are checked there (blood gas analyzes, electrolytes, CK, kidney function values). In addition to hyperkalemia, there is also the risk of hypernatremia (from previous infusion and acidosis therapy). The extent of muscle damage is estimated by determining CK, transaminases and myoglobin (in serum and urine). For the prophylaxis of disseminated intravascular coagulation with consumption coagulopathy, the administration of low-dose heparin should be continued or started early and the coagulation parameters should be checked regularly.

Prevention

Diagnosis of MH disposition

The indication for clarifying diagnostics at an MH center is after an anesthetic incident or the suspicion of a familial disposition. Patients with a proven tendency to hyperthermia ( MH-susceptible MHS) are informed about the dangers of exposure to trigger substances for them and possibly also their blood relatives and receive an anesthesia ID as a certificate of MH disposition with a corresponding warning.

In vitro contracture test

The in vitro contracture test (IVKT, IVCT) is a sensitive and specific method ( sensitivity 94%, specificity 99%) and represents the gold standard of MH diagnostics.

Here, under regional anesthesia, a muscle biopsy is taken from the thigh ( vastus lateralis or vastus medialis muscle ) and halothane (increasing doses of 0.5; 1.0; 2.0; 3.0 and, if necessary, 4 , 0 percent by volume) and caffeine (increasing doses from 0.5 to 32 mmol / l). In patients with a predisposition to MH, a contraction occurs in the sample taken; these are referred to as MH-susceptible (MHS), in the event of a negative reaction as MH-nonsusceptible (MHN). The reaction to only one of the two agents occurs in 10% of patients ( MH-equivocal , MHE); these are also considered to be at risk, although a final scientific assessment of such cases is pending. In addition to this definition by the European Malignant Hyperthermia Group, there is a test variant by the North American Malignant Hyperthermia Group , according to which a positive reaction to only one of the two triggers is referred to as MH-susceptible .

The reliability of the IVCT is offset by the disadvantage of its invasiveness. The diagnosis should be carried out at the earliest three months after an incident, and due to a possible age-dependency, only after school age. Carrying out the in vitro contracture test is also logistically complex. The test result is only meaningful on the fresh muscle preparation, which is why a maximum of five hours may pass from the removal to the completion of the test.

The diagnostic value of the IVCT in the case of unclear muscular symptoms or an increased activity of the creatine kinase in the blood serum of unexplained cause is assessed inconsistently.

Molecular genetic diagnostics

If the IVCT is positive, molecular genetic diagnostics can be added to identify the underlying mutation. A blood sample sent in is sufficient, which makes it easy to carry out; there is no age limit. An initial genetic test (without a previous contraction test) does not make sense because of the heterogeneity of the MH disposition and the associated uncertainty about not recognizing those affected or misdiagnosing those who are not affected. If a mutation is identified, family members are also offered an examination. However, in about 5% the results of the genetic status and IVCT do not match, so that an IVCT is recommended for largely safe exclusion of people who tested negative.

Hotline for malignant hyperthermia

The SRH-Kliniken Landkreis Sigmaringen offer an information brochure for download on their website. a. Contains addresses of diagnostic and information centers. The Germany-wide MH hotline on 07571 / 100-2828 is available for further questions and for emergency advice on malignant hyperthermia .

Another Germany-wide 24-hour hotline for laypeople and medical professionals was set up in 2011: 08221-9600.

Performing anesthesia

For every facility or treatment unit that uses MH trigger substances, it makes sense to have procedural instructions or emergency checklists available for the treatment of malignant hyperthermia.

In the pre-medication interview, the history of the occurrence of MH in the patient's family is sought. If there is any suspicion, appropriate testing will be carried out prior to the planned intervention.

If suitable for the procedure, regional anesthesia procedures can usually be used safely in patients with MH risk (genetic predisposition, existing high-risk muscle disease). If general anesthesia is necessary, the trigger substances (succinylcholine, inhalation anesthetics) are dispensed with and total intravenous anesthesia (TIVA) is carried out. The anesthesia machine must first be flushed with pure oxygen, the anesthetic gas vaporizer is removed. A prophylactic administration of dantrolene is not displayed.

Legal Aspects

According to § 630e BGB, the doctor is obliged to inform the patient about the type and scope as well as about possible risks of the upcoming procedure. Alternative treatment methods must also be considered, as long as they lead to the same success of the procedure. The risk of MH and its frequency is pointed out in general anesthetic discussions. However, if the patient's anamnesis suggests that he or she has a family disposition, the patient must be informed about the possibility of an MH crisis and this information must be documented in writing. If there is a claim for damages after an operation, the documentation of proper information and consent of the patient can be decisive in the process. Due to the time-critical use of emergency medication, it is necessary to store the active ingredient in the operative unit. In clinics with operating units that are further apart, the emergency medication should also be stored in several places. Sufficient dantrolene must also be available in intensive care units and in anesthesiological practices. According to a ruling by the Federal Court of Justice in 1990, “the hospital owner's organizational fault may be that a drug […] is not available in good time before the operation.” National specialist societies and international expert groups recommend that in every anesthesia or intensive care unit, in the MH trigger substances are used, recommendations for action (SOPs) for prevention, detection and treatment of an MH crisis are to be kept available. It is the responsibility of the head of department to determine the amount of medication to be stocked, the stocking itself is in the care of the head of the clinic pharmacy.

history

Even in the early days of anesthesia, when ether and chloroform anesthesia were the rule, there were reports of "heat strokes" and "ether cramps", which were probably based on malignant hyperthermia. The first publications about such events in the international specialist literature go back to 1900. The pediatric surgeon Louis Ombrédanne (1871–1956), who, in addition to an ether vaporizer developed in 1908, also contributed to further improvements to anesthesia technology, gave the hyperpyrexia syndrome its name .

Malignant hyperthermia was first described as an independent clinical picture in 1960 by MA Denborough and RR Lovell. Michael Denborough described the connection between genetic disposition and the triggering by general anesthesia. 1962 in Australia. He had examined the case of a young student who had undergone an operation for a fractured lower leg and who had developed the symptoms of fulminant malignant hyperthermia after administration of halothane . The patient was chilled with ice and survived the crisis. It turned out that ten close relatives had previously died under anesthesia. Progress in pigs after administration of succinylcholine was published a little later. The effectiveness of dantrolene for the treatment of malignant hyperthermia was first proven in pigs in 1975, introduced clinically in 1979 for the treatment of malignant hyperthermia and confirmed in a clinical study in humans in 1982. In 1983 the European Malignant Hyperpyrexia Group was founded , an association of doctors from eight countries. In the same year, the contracture test to diagnose MH was introduced, which has been supplemented by genetic diagnostics since 2001. As early as 1990, two working groups had independently identified the locus of most MH-associated mutations.

literature

  • Werner Klingler (Ed.): Malignant hyperthermia and associated diseases in anesthesia and intensive care medicine. Thieme, Stuttgart 2016, ISBN 978-3-13-240868-5 .
  • German Society for Anaesthesiology and Intensive Care Medicine, German Interdisciplinary Association for Intensive Care and Emergency Medicine: S1 guideline: Therapy of malignant hyperthermia. Developed by Werner Klingler, Norbert Roewer, Frank Schuster and Frank Wappler. In: Anästh Intensivmed. Volume 59, 2018, pp. 204-208.
  • Frank Wappler: S1 guideline for malignant hyperthermia, Update 2018. In: Anaesthesist. Volume 67, 2018, pp. 529-532.
  • Werner Klingler, E. Pfenninger: Inhalative analgosedation in the intensive care unit. In: Medical Clinic - Intensive Care Medicine and Emergency Medicine. , doi : 10.1007 / s00063-018-0453-7 .
  • E. Pfenninger, M. Minde, S. Heiderich, Werner Klingler: SOPs and guidelines for malignant hyperthermia. In: Anästh Intensivmed. Volume 59, 2018, pp. 4-11.
  • H. Rosenberg, N. Pollock, A. Schiemann, T. Bulger, K. Stowell: Malignant hyperthermia: a review. In: Orphan J Rare Dis. Volume 10, 2015, p. 93.
  • Thomas Metterlein, Frank Schuster, BM Graf, Martin Anetseder: Malignant hyperthermia. In: Anaesthesiologist. Volume 63, 2014, pp. 908-918.
  • Martin Anetseder, N. Roewer: Malignant hyperthermia. In: Rossaint, Werner, Zwissler (ed.): Die Anästhesiologie. General and special anesthesiology, pain therapy and intensive care medicine. 2nd Edition. Springer, Berlin 2008, ISBN 978-3-540-76301-7 .
  • H. Rüffert, M. Wehner, C. Deutrich, D. Olthoff: Malignant Hyperthermia - The ugly. In: Anaesthesiologist. 2007 Sep; 56 (9), pp. 923-929. Review. PMID 17565473
  • H. Rosenberg, M. Davis, D. James, N. Pollock, K. Stowell: Malignant hyperthermia. In: Orphanet J Rare Dis. 2007 Apr 24; 2, p. 21. Review. PMID 17456235
  • H. Rosenberg, N. Sambuughin: Malignant Hyperthermia Susceptibility Gene Reviews. University of Washington, Seattle 2006.
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Web links

Individual evidence

  1. ↑ a b c d e f g h i j German Society for Anesthesiology and Intensive Care Medicine: S1 guideline: Therapy of malignant hyperthermia . In: Anästh Intensivmed . 2018, p. 204-208 .
  2. ↑ T. Girard, O. Bandschapp: Malignant hyperthermia. In: Anaesthesiology & Intensive Care Medicine. Volume 60, 2019, pp. 135-143. DOI: 10.19224 / ai2019.135 [1]
  3. ^ RS Litman, CD Flood, RF Kaplan, YL Kim, JR Tobin: Postoperative malignant hyperthermia. An analysis of cases from the North American Malignant Hyperthermia Registry. In: Anesthesiology. Volume 109, 2008, pp. 825-829.
  4. ^ A b Werner Klingler, E. Pfenninger: Inhalative analgosedation in the intensive care unit . In: Medical Clinic - Intensive Care Medicine and Emergency Medicine . August 3, 2018, ISSN  2193-6218 .
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  8. ↑ Frank Lehmann-Horn, Werner Klingler, Karin Jurkat-Rott: Nonanesthetic Malignant Hyperthermia . In: Anesthesiology: The Journal of the American Society of Anesthesiologists . tape 115 , no. 5 , November 1, 2011, ISSN  0003-3022 , p. 915-917 , doi : 10.1097 / ALN.0b013e318232008f ( asahq.org [accessed October 19, 2018]).
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  13. ^ W. Klingler, S. Heiderich u. a .: Functional and genetic characterization of clinical malignant hyperthermie crises: a multi-center study. In: Orphan J Rare Dis. Volume 9, 2014, p. 8.
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  19. ↑ German Society for Anesthesiology and Intensive Care Medicine: S1 guideline: Therapy of malignant hyperthermia. 2018, p. 204.
  20. ↑ German Society for Anesthesiology and Intensive Care Medicine: S1 guideline: Therapy of malignant hyperthermia. 2018, p. 206.
  21. ↑ Rüffert u. a. 2007, p. 923ff; Rosenberg et al. a. 2007.
  22. ↑ Online Mendelian Inheritance in Man - Malignant Hyperthermia Susceptibility (accessed July 5, 2019)
  23. ↑ Monnier et al. a .: A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. In: Hum Mol Genet . 2003; 12, pp. 1171-1178 PMID 12719381
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