Information about Malignant Hyperthermia specialities such as Malignant Hyperthermia in childbirth.
Childbirth and Malignant Hyperthermia
Childbirth is always an unpredictable time of life. Most babies are born normally, without any problems, but even after a normal pregnancy, things can go wrong during labour. Women who have had several normal deliveries, sometimes need emergency caesarean section for another baby. The type of general anaesthetic used for emergency caesarean sections or other emergency surgery requires the use of the very drugs most likely to trigger malignant hyperthermia. These drugs can cross the placenta to the unborn baby.
It is therefore important that everyone caring for a woman at risk of malignant hyperthermia, or the partner of a man susceptible to malignant hyperthermia, knows that the risk is there. Sometimes things happen so fast that there is no time to prepare.
Malignant hyperthermia susceptibility is genetically transmitted. This means that a baby has a 50% chance of being susceptible to malignant hyperthermia if either of his parents is susceptible. Therefore the woman who has no risk herself, but whose partner, the father of her baby, is susceptible, must be looked after to protect the unborn child.
The safest anaesthetic for a woman or baby at risk of malignant hyperthermia, is a regional anaesthetic. By that is meant the use of an epidural, spinal, or combined spinal epidural to make the lower half of the body numb. Surgery can then be carried out without pain, and without the risk of triggering malignant hyperthermia. Regional anaesthesia takes longer to take effect than does a general anaesthetic, when the woman can be put to sleep very rapidly. It is therefore important to have more warning, and more preparation time, if a woman or baby is susceptible to malignant hyperthermia.
This is one of the reasons why it is strongly recommended that these women have their baby delivered at a base hospital. If things unexpectedly go wrong, there is time to provide the safest anaesthetic.
Stress has sometimes been thought to be a cause of malignant hyperthermia. There is a lot of work for the body in a normal labour, and a lot of stress. It has been postulated that the work and stress of labour may itself precipitate malignant hyperthermia. No such event has ever been documented. However, it is thought to be important to reduce the stress to the body during labour for women and babies at risk of malignant hyperthermia. Epidural analgesia is the best form of analgesia for reducing stress in labour to both mother and baby. There is no indication to avoid pushing in second stage - spontaneous vaginal delivery is fine.
This is one of the reasons why it is strongly recommended that these women have their baby delivered at a base hospital. Epidural analgesia in labour can reduce the stress to mother and baby.
The woman and her baby should be closely monitored during labour and for four hours after delivery. This is to ensure that any problems with labour are acted on promptly, so reducing the need for emergency general anaesthesia. At our hospital we monitor mother's temperature, pulse and blood pressure hourly throughout labour and for four hours postpartum. Fetal heart rate monitoring is carried out during labour, and the baby's temperature, heart rate and respiratory rate are monitored hourly for four hours after birth. Close monitoring after delivery ensures a rise in temperature or other signs of stress response are acted on immediately. Discharge home or to a low dependency unit is possible after four hours.
Even if baby is delivered at a base hospital, mother and baby can return home or to a smaller birthing unit four hours after delivery.
Assessment in early pregnancy is important for women or babies at risk of malignant hyperthermia. Early referral allows time for family trees to be examined, and information to be obtained from other hospitals. Relationships can be clarified and the true nature of adverse anaesthetic events assessed. This is much easier than at 2am with a woman in labour. Antenatal assessment by an anaesthetist also involves examination of the airway to give more information about the risk of emergency general anaesthesia. It is an opportunity to discuss epidural analgesia and other questions the woman may have.
Specialist Anaesthetist assessment is important early in pregnancy.
DNA testing is carried out in some centres to test for malignant hyperthermia. Different families have different DNA abnormalities, so a negative test still requires further follow up. DNA testing can be done on cord blood to allow earlier diagnosis of malignant hyperthermia susceptibility in the baby. This should be discussed with an anaesthetist antenatally so that arrangements can be made for DNA testing.
Management of emergency surgery is best done under regional anaesthesia. However, on rare occasions there is no time for this. Therefore it is important that the theatre staff are prepared ahead of time. When a woman susceptible to malignant hyperthermia starts in labour, her lead maternity carer should notify the operating theatre and the on-call specialist anaesthetist. Even if surgery is carried out under regional anaesthesia, the correct equipment needs to be available for general anaesthesia if complications occur.
There are now general anaesthetic techniques available that are quite safe for people susceptible to malignant hyperthermia, including intravenous infusions of propofol, and intubation using remifentanil. An anaesthetic machine free of volatile anaesthetic agents needs to be used. Dantrolene and equipment for rapid cooling need to be immediately available to the theatre team.
This is one of the reasons why it is strongly recommended that these women have their baby delivered at a base hospital. The special anaesthetic requirement are more likely to be available at short notice.
Central Core Disease
Central Core Disease (CCD) is a rare non progressive myopathy with autosomal dominant inheritance presenting in infancy and characterised by hypotonia and proximal muscle weakness. Histological examination tion of affected muscles shows a predominance or type I fibres containing clearly defined areas (cores) lacking oxidative enzyme activity (Quinlivan et al 2003).
An important feature is its close association with MH susceptibility. CCD patients are often susceptible to MH by IVC testing but MH and CCD phenotypes do not always co-segregate within families. Patients with MH may present with cores despite being clinically asymptomatic and some RYR1 mutations, specifically some of those in the 3’transmembrane domain of the gene, may be specific to CCD. Although RYR1 mutations are the most common identified cause of CCD it does show genetic heterogeneity, with several rare susceptibility loci known (the ACTA1 gene, in association with nemaline myopathy, and the MYH7 gene, in association with hypertrophic cardiomyopathy), with further loci yet to be identified (Shepherd et al 2004).
At least 44 mutations have been reported in the RYR1 gene in association with CCD (Shepherd et al 2004). In general terms single point RYR1 mutations can cause (a) CCD only (b) MH only (c) MH with variable CCD penetrance. In this latter case all individuals with the mutation should be MH susceptible while they may or may not have CCD. If a mutation is specific to CCD is identified in a family, MH is not automatically excluded as a second mutation may be present and MH susceptibility needs to be assessed by IVCT (Robinson et al 2002). If the mutation has no functional studies performed it is of no use clinically. An MHN parent eliminates susceptibility in the children.
Quinlivan RM, Muller CR, Davis M, Laing NG, Evans GA, Dwyer J et al. Central core disease: clinical, pathological and genetic features. Arch Dis Child 2003;88: 1051-1055
Shepherd S, Ellis F, Halsall J, Hopkins P, Robinson R. RYR1 mutations in UK central core disease patients; more than just the C-terminal transmembrane region of the RYR1 gene. J Med Genet 2004;41: e33
Robinson RL, Brooks C, Brown SL, Ellis FR, Halsall PJ, Quinnell RJ et al. RYR1 Mutations causing Central Core Disease are associated with more severe malignant hyperthermia In Vitro Contracture Test Phenotypes. Human Mutation 2002;20: 88-97
Rhabdomyolysis
Rhabdomyolysis refers to the breakdown of skeletal muscle which is associated with excretion of myoglobin in the urine. Classically MH presents with hypercarbia, tachycardia, cardiac arrhythmias, pyrexia rigidity and metabolic acidosis and rhabdomyolysis as a late sign.
Several reports of isolated rhabdomyolysis apparent immediately following anaesthesia or developing up to 24 hours post anaesthesia have been published (Fieroche et al 1998).Increased creatine kinase (CK) measurement and a positive IVCT have been obtained in these patients indicating MH susceptibility. However MH like muscle responses can represent false positive diagnoses and an underlying myopathic process may produce a positive IVCT (Lehmann-Horn et al 1990) so there must remain some doubt on the validity of this feature i.e. rhabdomyolysis as an expression of MH. Burns et al however state that MH should be considered in all patients presenting with rhabdomyolysis where the degree of muscle necrosis exceeds that expected for the severity of the accompanying disorder.
Burns AP, Hopkins PM, Hall G, Pusey CD. Rhabdomyolysis and acute renal failure in unsuspected malignant hyperthermia. Q J Med 1993; 86;431-34
Fieroche MD, Nivoche Y, Mantz J, Younes E, Veber B, Desmonts J-M. Perioperative severe rhabdomyolysis revealing susceptibility to malignant hyperthermia. Anesthesiology 1998; 88;263-5
Harwood TN, Nelson TE. Massive Postoperative Rhabdomyolysis after uneventful surgery.: A case report of subclinical malignant hyperthermia. Anesthesiology 1998; 88:265-8
Lehmann-Horn F, Iaizzo P. Are myotonias and periodic paralyses associated with susceptibility to malignant hyperthermia. Br J Anaesth 1990; 65: 692-97
Stress Induced Malignant Hyperthermia
In 1954 the Porcine Stress Syndrome was first described affecting several strains of pigs. It was of great concern to the meat industry because these pigs would die while waiting to be slaughtered.
Other stresses such as fighting, transportation, will produce the same symptoms, namely tachycardia, dyspnoea, rigidity and pyrexia, with death within 10 minutes. It was noted that the muscle had a high acid content and was unpalatable.
Hall, L.W., an English Veterinarian in 1966 reported three pigs from the same litter that were given a halothane followed by suxamethonium anaesthetic, became rigid, very difficult to intubate, pyrexic and the soda lime they were using exhausted very rapidly. These pigs also died very rapidly. The muscle had a similar acid content to the Porcine Stress Syndrome. It was soon recognised that both syndromes were manifestations of the same underlying myopathy.
It was quickly realised that this syndrome, because of its clinical and biochemical abnormalities, was almost identical to the human form of MH. This demonstrated that some susceptible pigs, when exposed to stress, can develop fatal MH reactions.
In 1974 Wingard described an MH susceptible family in North America, with heat, exercise and emotional induced pyrexia, and other signs suggestive of MH. There are a number of sudden deaths in this family, which had no relationship to surgery, but appeared to be stress related, and he considered that MH was part of a “human stress syndrome”.
There was some scepticism about Wingard’s report, but subsequently there have been a variety of reports of stress-induced MH reactions, which can be loosely summarised into three groups.
Anaesthetic Incidents:
There have been a number of reports of MH reactions in patients given trigger-free anaesthetics. None of these are totally convincing, but there are sufficient features in some to suggested that they cannot be completely discounted. For example Ranklev reported an anxious MH patient with increased CO2 production, and Hodges et al described a patient with pyrexia, hypercapnoea, metabolic acidosis, and a CK of 15,000 I.U. Both had been given trigger-free anaesthetics suggesting some form of stress had triggered these reactions. There are several other similar examples.
Exercise and emotional induced incidents:
Gronert reported a patient in 1980 with recurrent fever, joint pains, and malaise induced by emotional or exercise stress that responded to oral dantrolene, and in 1982 Denborough described a patient with exercise induced heat stroke, and clinical findings similar to that of an MH reaction who responded to IV dantrolene. Both these patients had positive muscle biopsies.
American footballers:
Several have been reported to have problems. In general they presented with pyrexia, dyspnoea, muscle aches, and in one case, mild neurological symptoms. Some had a personal or family history of MH and all but one were non-fatal.
Rosenberg recently described a very unfortunate 13 year old male with a previous MH reaction, who collapsed and developed a fatal pyrexia after a football match. The CK was 9000. His father had a positive muscle biopsy and a causative RYR1 mutation was identified in both the father and the 13 year old boy.
Although these are anecdotal reports there are some consistent findings – stress related events, e.g. surgery, exercise, heat, emotion; a positive muscle biopsy, a response to dantrolene when used sometimes a family, and in one case a causative mutation was identified.
Physiological Studies:
MHS vs control groups looking at metabolism, temperature responses, etc, have been criticised because of methodology. Other interesting findings:
- the sympathetic system is not primarily involved in MH.
- MH muscle responds normally to sympathomimetics.
5HT agonists can cause an MH-like syndrome in MH susceptible pigs, and these agents can also cause MHS contractures in susceptible muscle. So, serotonin may have a role in stress-induced episodes.
In the human form of MH, genetic heterogeneity may lay the foundation for possible MH stress-induced episodes.
In January 2000 Wappler et al. described a 34yr old male with recurrent fever, fatigue, muscle cramping and aching with mild exercise and emotional stress. A controlled exercise study demonstrated that temperature increased 1.5c, lactate and CK increased substantially, although ETCO2 did not change. Muscle biopsy was reported as MHS, and a causative RYR1 mutation was identified.
A year later he published a report of 12 individuals with exercise induced rhabdomyolysis (EIR) with positive muscle biopsies and RYR1 mutations identified in 3 of this group.
Davis et al in 2002 published a report of 2 patients who again developed EIR and were MHS with muscle biopsy. A novel mutation was identified in these 2 unrelated individuals. The same novel mutation was identified in a New Zealand male who had had a previous MH reaction and was found MHS on contracture testing. Three consistent factors stress induced symptoms and signs, positive muscle biopsy and a RYR1 mutation.
Possible conclusion – It is suggested that a small subset of MH patients may display muscle damage and perhaps other more ominous signs with the stress of exercise and perhaps other stresses.