Safety of exposure of malignant hyperthermia non-susceptible patients and their relatives to anaesthetic triggering agents.
Malignant hyperthermia (MH) is an uncommon, inherited, hypermetabolic disorder caused by dysfunctional calcium homeostasis in skeletal muscle. It is triggered almost exclusively by potent anaesthetic inhalational agents and depolarising muscle relaxants. The consistent presence of extreme hyperthermia and high mortality (>70%) in the earlier years led to the name (1).
The gold standard for testing potentially susceptible patients is the in vitro contracture test (IVCT) of a muscle biopsy (2-4). The test is invasive, requiring excision of a segment of muscle from the lateral quadriceps and can cause some morbidity (5). Current anaesthetic agents are relatively free of side-effects and so administration of trigger-free anaesthesia is more straightforward than previously. Therefore, there must be good reasons to test for MH susceptibility. Testing is necessary as a wider pool of possible MH susceptible individuals will develop rapidly if testing is abandoned. This will mean an increasing number of patients will not have the full range of anaesthesia available to them. Volatile anaesthetics are particularly useful in some situations such as inhalational induction in an infant when difficulty with intravenous access is encountered, repeat anaesthetics in young children, radiology procedures in young children and epiglottitis management. The use of suxamethonium may also be strongly indicated in the event of laryngospasm. However, while rocuronium does not give as good intubating conditions as suxamethonium, the problem with reversal has been bypassed by the introduction of sugammadex (6).
Many patients want to know if they are affected by this disorder. They do not want lifelong attachment to a MedicAlert[R] (MedicAlert[R] Foundation New Zealand Inc., Upper Hutt, New Zealand) emblem and their careers may be affected, e.g. army personnel may be limited in the scope of their employment. Travellers in a developing country may be affected by inadequate supplies of currently used anaesthetics. Marriage prospects may also be affected in individuals with a genetic disorder, particularly in some Asian countries (7). These factors may all affect the lifestyle of the patient.
Trigger-free anaesthetics are more expensive than normal anaesthetics. For instance, 'cleaning' an anaesthetic machine (Aestiva, Aisys, GE Healthcare, Chalfont St Giles, Buckinghamshire, UK) (8) requires a flushing time of 55 minutes and a subsequent constant flow of oxygen at 10 l/minute for the duration of the operation, as well as fresh soda lime, charcoal filters if used and increased theatre preparation time and staffing.
A negative or normal test (MHN) however, confirms that the individual is not susceptible to MH. The reliability of the MHN result has been questioned and there have been reports of false negative results. On the other hand, there have been no reports, anecdotal or otherwise, of false negative IVCT results in New Zealand. This study set out to determine the reliability of MHN results in New Zealand by retrospective analysis.
MATERIALS AND METHODS
Ethics approval for this study was obtained from the Multi-region Ethics Committee, Ministry of Health, Wellington.
Palmerston North is the New Zealand national testing centre for patients suspected of malignant hyperthermia. A database was established in 1991 which contains all known families affected by MH in New Zealand. From this database, MHN individuals and their relatives and descendants were contacted and hospital records were obtained to document anaesthetic data. Children, grandchildren and more distant generations of MHN individuals are regarded as immediate relatives and are considered not susceptible to MH.
If an MHN individual or immediate relative had received a triggering agent, the following data were recorded.
1. Duration of anaesthesia, location, type of operation, MH status (MHN or relative), patient demographics and anaesthesia drugs used.
2. Intraoperative data--anaesthetic triggering agent (suxamethonium and inhalational agent), heart rate, respiratory rate (RR), blood pressure, temperature (T[degrees]), end-tidal carbon dioxide (ETC[O.sub.2]), oxygen saturation (Sp[O.sub.2]). At Palmerston North hospital temperature was recorded using an infrared emission detector thermometer (Braun-Thermoscan, Welch Allyn Inc., Skaneateles Falls, NY, USA) which measures infrared heat generated by the tympanic membrane and auditory canal (accuracy [+ or -] 0.53[degrees]C) or a thermistor sensor (a temperature probe measuring nasal core temperature). Also, in earlier years, a digital thermometer was used to measure axillary temperature.
3. MH Clinical Grading Scale (MHCGS) ranking was determined for each anaesthetic.
4. Any intraoperative complications were documented and other clinical abnormalities such as increased creatine kinase, increased potassium ([K.sup.+]), bigeminy or ventricular ectopic beats.
5. Arterial blood gases analysis when performed.
6. Post-anaesthesia care unit (PACU) data included duration of stay, PACU MHCGS ranking, drugs used, complications and prevalence ratio, RR, temperature, blood pressure, Sp[O.sub.2] and ETC[O.sub.2].
7. Where available, data in the first four hours after leaving PACU were documented: heart rate, RR, blood pressure, temperature, Sp[O.sub.2] and any complications.
In vitro contracture test and DNA testing
The IVCT is conducted according to the European MH group protocol (3). Results are divided into three categories--MHS (susceptible), MHN (normal) and MHE (equivocal) (3).
Analysis of DNA was undertaken at Massey University, Palmerston North. Blood samples were taken after obtaining informed consent. Ethical approval was obtained from the Central Region Human Ethics committee. DNA was extracted from whole blood using the Promega Wizard[TM] (Promega Corp., Madison, Wisconsin, USA) genomic DNA purification kit according to the manufacturer's instructions. Familial mutations were identified by polymerase chain reaction-amplification of RYR1 sequences from genomic DNA using allele-specific assays with hybridisation probes and real-time polymerase chain reaction on the Roche Lightcycler 1.2. Primer and probe sequences are available from the authors (KS) on request.
Malignant Hyperthermia Clinical Grading Scale
The MHCGS was developed in 1994 and ranks the likelihood that an adverse anaesthetic event represents MH9. Signs of an MH reaction are non-specific and the lack of a precise clinical definition has led to poor prediction of MH susceptibility by clinical criteria alone. To improve prediction, a group of MH experts created a multifactorial MH scale using standardised clinical criteria (Tables 1 and 2). Points are assigned to specific abnormal signs and laboratory findings (clinical indicators) and then summed to produce a score which translates to an MH rank designating the likelihood that this adverse event was MH. This ranges from 1 (almost never) to 6 (almost certain). Each anaesthetic was ranked using the MHCGS.
Descriptive statistics (mean and range) of intraoperative, PACU and ward data are presented. Age range, mean age and intraoperative time are also presented.
Confidence intervals for zero numerator proportions were derived using the following link--http://statpages.org/confint.html. This computes exact confidence intervals from binomial distributions and calculates 95% confidence intervals.
A negative IVCT result was documented in only 37 of the 51 known MH susceptible families in New Zealand. In nine of these 37 families, MHN patients or immediate relatives had not been administered triggering agents or family members could not be contacted. Therefore, members of 28 families are represented in this MHN study. Consent forms were sent to 348 MHN individuals and replies were received from 172 (49.4%). All MHN parents contacted regarding anaesthetics in their children received a consent form, and verbal consent was obtained to review the child's anaesthetic records for 69 individuals.
A total of 329 anaesthetics with known triggering agents were administered to 165 MHN patients or their immediate relatives. The 165 patients were subdivided into 116 MHN patients and 49 immediate relatives. All anaesthetics were undertaken between 1979 and early 2008. Approximately 8% of anaesthetics were undertaken before 1991. Of the total 329 anaesthetics, 241 were administered to MHN patients and 88 to immediate relatives. The anaesthetics in immediate relatives were further subdivided into 68 children and 20 grandchildren or great-grandchildren of MHN patients.
Triggering agents used are shown in Table 3. Sevoflurane was the most commonly used volatile agent (41%). Halothane was used in 71 cases (22%), but usage of this agent declined from the early 1990s. Isoflurane was used in 87 cases (27%), but has decreased in use since the early 2000s. Only 47 anaesthetics included a combination of suxamethonium plus an inhalational agent (15%), of which 15 included halothane, 12 sevoflurane and 16 isoflurane. In two anaesthetics suxamethonium was the only triggering agent used. The longest duration of anaesthesia with a combination of suxamethonium and an inhalational agent was 3 hours and 45 minutes. Triggering agents were recorded in another 20 anaesthetic records, but these were so inadequate that they have not been included in this study.
Of the 165 patients, 98 received one triggering anaesthetic (59%), 34 had two exposures (21%) and 33 (20%) three or more exposures. One patient received eight exposures to triggering agents. This patient was an adult with negative DNA analysis who received a combination of suxamethonium and three different potent inhalational agents.
Anaesthesia duration ranged from 10 minutes to 10.5 hours (mean 69 minutes). Ages ranged from three months and 23 days to 79 years (mean 27 years). A standard range of surgical procedures was undertaken including orthopaedic, gynaecologic, ear nose and throat, dental, general surgical, obstetric and ophthalmologic procedures. A few specialised procedures, including radiologic, cardiac and neurosurgical procedures were also performed.
The creatine kinase was measured in two cases. Reported creatine kinase results were 319 IU (n=20-215) in a patient who had suxamethonium during induction for an open reduction internal fixation of mandible and 147 IU for a patient having an appendicectomy. Potassium was measured in 13 cases. Measurements ranged from 2.9 to 5.0 mmol/l. Arterial blood gases were measured in 11 cases. The maximum base deficit recorded was 1.8 mmol/l.
Intraoperative recordings are shown in Table 4. Peak recordings of each variable were noted except for Sp[O.sub.2] where the lowest recording was documented. Many anaesthetic records were incomplete, particularly the older records.
Complete records, i.e. with six variables recorded (or five with ward recordings as ETC[O.sub.2] were not included there), were present in 56 intraoperative records. There were 85 records with one variable omitted, and 184 with more than one omitted. Similar data were obtained from PACU and following discharge from PACU (day of surgery or ward) groups.
Intraoperatively, 33 adult patients had an abnormal heart rate at some point during anaesthesia. Respiratory rate was >26 /minute in nine paediatric patients (<15 years age) and >20 /minute in two adult patients. These two patients had a thoracotomy and bilateral venting tubes. T[degrees] was increased (>38[degrees]C) in five adults (all had appendicetomies) and two children. In one child, the temperature increase was during an ophthalmic procedure and the other during a laparoscopic appendicectomy. Five of the seven patients had a T[degrees] >38.8[degrees]C. The ETC[O.sub.2] was >55 mmHg in nine children breathing spontaneously and in seven adults. Six of the seven adults were breathing spontaneously during the procedure. There were no other signs of MH. An Sp[O.sub.2] <95% was recorded in eight adult patients.
Similar analysis was undertaken for PACU data. Abnormal recordings were obtained in individuals but overall no evidence of MH was noted (Table 5). Similar results were obtained for day of surgery unit or ward data.
Malignant Hyperthermia Clinical Grading Scale
Each anaesthetic was ranked using the MHCGS: 235 ranked 1 indicating an 'almost never' likelihood of an MH reaction, 66 ranked 2 indicating an MH reaction was unlikely and 28 ranked 3, 'somewhat less than likely' risk of MH (Figure 1). The majority of rank 2 scored points on the basis of an inappropriate tachycardia, usually at induction. An increase in RR and occasionally increased ETC[O.sub.2] unrelated to hypermetabolism resulted in a rank of 3 in 28 anaesthetics.
Similar recordings were analysed from PACU observations (Figure 2). Some abnormal individual variables were found: 243 ranked 1, 54 ranked 2, 31 ranked 3 and one ranked 4. The increased ranking in these patients was mainly on the basis of tachycardia and either pyrexia or increased RR. One three-year-old patient ranked 4 but there were other explanations for the abnormal signs.
Nine different causative RYR1 mutations had been identified in families of patients who had been administered the 329 triggering anaesthetics. DNA analysis was available for 179 (55%) triggering anaesthetics. DNA negative results were obtained in all patients. There was no discordance between IVCT and DNA analysis.
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
Thirty-three percent or 111 anaesthetics were undertaken in Palmerston North Hospital. In the region around that hospital a large susceptible MH family is based. The larger New Zealand centres provided the remainder of the anaesthetics. Only 31 anaesthetic records were obtained from private hospitals.
Using binomial distributions, if 329 trigger anaesthetics were administered, 95% confidence intervals for the probability of MH are 0 to 1.12%. However the anaesthetics were administered to 165 patients so the confidence interval may be as wide as 0 to 2.2%. This analysis indicates that the risk is most likely zero, but might be as high as 2%.
In this study, 329 triggering anaesthetics were analysed in 116 MHN patients and 49 immediate relatives with no evidence of an MH reaction. These observations support those of smaller previous studies, and more importantly, confirm the diagnostic accuracy of a negative contracture test. The data suggest that it is safe to administer triggering agents to patients tested MHN.
There have been five similar but smaller previous studies. Ording (10) used a questionnaire method and contacted the first 371 patients investigated on the Danish MH Register. From this questionnaire, it was found that 35 MHN patients subsequent to their IVCT received 64 anaesthetics. Of these, 13 received a total of 26 anaesthetics with triggering agents, all with no signs of an MH reaction. Scala et al (11) documented nine MHN patients who received 16 triggering anaesthetics and Gronert (12) 15 patients who received 15 triggering anaesthetics. Both studies reported no evidence of an MH reaction. Allen et al (13) found similar results in 16 patients who received 26 triggering anaesthetics and in another Scandinavian study, 17 triggering anaesthetics were administered to seven MHN patients and seven immediate relatives (children), without evidence of MH (14). These prior studies therefore document a total of 67 MHN patients or immediate relatives receiving 100 triggering anaesthetics with no demonstrable MH reactions.
When this data is pooled with the present study, 232 patients have received 429 anaesthetics with triggering agents. (Statistical analysis, 95% confidence intervals using binomial distributions calculate the probability of an MH reaction as 0 to 1.56% and 0 to 0.87% in patients and anaesthetics respectively).
Early signs of MH are indistinguishable from the normal physiological response to surgery. Patients, especially children will have a tachycardia or increased respiratory rate in response to pain. Fever around the time of surgery is common, especially for appendicectomy (15). An increase in ETC[O.sub.2] will occur if there is inadequate ventilation or as a result of drug-induced respiratory depression, secondary to opioid drugs. It is to be expected that some patients will show abnormal signs during surgery, as documented in Tables 4 and 5. Peak findings included intraoperative heart rate 176 bpm, RR 60/minute, T[degrees] 39.3[degrees]C and ETC[O.sub.2] 69 mmHg in individual patients (Table 4).
When patients were ranked using the MHCGS, 72% ranked 1 indicating an 'almost never' likelihood of an MH reaction. A further 20% ranked 2, usually on the basis of a tachycardia (usually at induction) or an increased RR (especially in children). These findings were similar in PACU and both probably resulted from anxiety. A ranking of 2 gives an 'unlikely' likelihood of an MH reaction (9). Of the remainder, 8% ranked 3 with a 'somewhat less than likely' likelihood of a reaction and this was usually on the basis of increased temperature, particularly in children, and tachycardia or tachypnoea, again likely related to anxiety. Several patients had an increased ETC[O.sub.2], mainly caused by hypoventilation and there was no other evidence of hypermetabolism.
One child achieved a ranking of 4 indicating 'a somewhat greater than likely risk of MH' with sepsis as the most likely diagnosis. This child had a tonsillectomy and was found to have otitis media with bilateral ear infections. She had a temperature of 39.3[degrees]C, with tachycardia and tachypnoea (RR 60 /minute). She was treated with paracetamol and antibiotics and her signs settled after a few hours. Dantrolene was not administered to any patient.
Measurement of ETC[O.sub.2] is difficult to record in PACU but was documented for a few patients in Palmerston North Hospital. Temperatures were measured for the first four hours after return to the ward. Two studies found no evidence that an MH reaction can develop after the patient has been assessed as stable and discharged from PACU (16,17). The postoperative data in this study provides further confirmation of this.
All potent inhalational anaesthetics have triggered MH reactions (18). Halothane is the most potent trigger of an MH reaction in vivo (19,20) and in vitro (22) and in this study 22% were exposed to this agent. A study by Horbaschek et al (21) found that sevoflurane in vitro produced weaker contractures than halothane and isoflurane, but Yuge et al (22) found more potent effects in vivo. The mean anaesthetic time for patients in this study was 69 minutes, with exposure of the study group to eight different triggering agents. The mean time for triggering an MH reaction (23) (from induction to initial sign of a reaction) is 48 minutes (unpublished data, N. Pollock). This is less than the mean time of 69 minutes for the 329 procedures indicating adequate exposure to trigger an MH reaction.
Uncertainty regarding the reliability of MHN diagnoses has developed from reports of false negative IVCT diagnoses and discordance. The anaesthetic literature contains 10 reports of false negative IVCT results although all but one or two can be explained by alternative diagnoses. Isaacs et al (24) reported four patients, exposed to triggering anaesthetics after normal muscle biopsies, who developed clinical evidence of MH but the specimens were not tested according to a standard protocol. Wedel and Nelson25 reported four children 10 years of age and younger with clinical MH who had muscle biopsies which were positive only to a combined halothane caffeine test but not caffeine or halothane alone. This combined test is no longer part of the North American MH group protocol. The children were aged six to 10 years. Ellis et al reported inconsistent responses in children less than 10 years of age because of muscle immaturity (26). The muscle biopsy result can be questioned on this basis. All New Zealand muscle biopsies are carried out after 10 years of age.
Ording et al (27) found one of 105 patients with rank 5 or 6 using the MHCGS tested MHN, but this patient also had a concurrent myopathy that may have resulted in a clinical presentation similar to MH. In a smaller study, Allen et al (28) noted one of 32 patients with a similar finding. The IVCT results have been found to be abnormal in certain neuromuscular disorders (29,30). Therefore, in all but one of these reports an alternative diagnosis is possible, while clinical details are not available for the remaining report. The alternative diagnoses however, do not appear to have been fully accepted as in some countries the majority of anaesthetists accept only those IVCT results that demonstrate that the patient is MH susceptible (i.e. they do not accept MHN IVCT results). Subsequent trigger-free anaesthesia may be administered regardless of the IVCT outcome. A review of New Zealand anaesthetic records demonstrated 32% of anaesthetics administered to MHN patients and their immediate relatives were trigger-free (unpublished data, N. Pollock, K. Hor). This study should help increase confidence to administer triggering agents to MHN patients.
Ording et al found a specificity of 93% for IVCT (27) and Larach et al 78% for the caffeine halothane contracture test (North American protocol) (31). This indicates that a minority of IVCT results may be false positive and this is a limitation of this biological test--increased sensitivity to reduce false negative test results may lead to an increased false positive rate.
MHN individuals with positive DNA tests (discordant) are potentially at risk. Although there are no known reports of MH reactions in patients with this diagnostic scenario (32), these patients must be regarded as susceptible to MH. False negative diagnoses are more likely to have potentially fatal consequences under anaesthesia than false positive diagnoses (33). Possible reasons for discordance include multiple mutations and the presence of a modifying gene. Other factors in the aetiology of discordance include mistaken identity of blood samples and environmental factors. Bona fide false negative IVCT, though apparently extremely rare, may also contribute to discordance (33).
Four hundred and ninety-four DNA tests have been performed in New Zealand in patients receiving an IVCT. Thirteen percent (38/291) of MHS individuals have had a negative DNA test for the known family mutation (unpublished data, K. Stowell). Also 180 MHN patients have had negative DNA tests and 23 MHE individuals tested negative for the known family mutation. These findings indicate significant MHS/negative DNA discordance; however MHN/positive DNA discordance has not been reported. No positive DNA tests have been recorded in MHE individuals in New Zealand families (unpublished data, N. Pollock). This may suggest that diagnostic criteria are conservative in New Zealand minimising false negative MHN results at the expense of false positive results, but it does give increased confidence in administering triggering agents to MHN patients and their offspring.
The MHCGS was used to estimate the likelihood that abnormal observations were the result of developing MH. The MHCGS has limitations, especially in the absence of complete monitoring data as discussed above. There were however, no further developments to suggest MH even when patients were followed for four hours postoperatively. Offspring of MHN individuals are considered not susceptible to MH. In general, only one parent is tested, leaving the possibility that the other parent could be MH susceptible. This would make unexpected MH reactions more likely in the descendants of MHN individuals. This, however, has not occurred and there has been no evidence in New Zealand that the non-tested parent may be susceptible.
Another scenario that should be mentioned is the extremely unlikely possibility of a false negative test result. As inheritance is autosomal dominant, there would be a 50% chance that the child of the affected individual would be MH susceptible and a 25% chance that a grandchild would be susceptible. As has been discussed above, there is no evidence of this in New Zealand.
Larach et al published a paper in which a patient had 30 anaesthetics before triggering (34). This patient had a hypermetabolic reaction with isoflurane as the trigger but there is no record of muscle biopsy or DNA analysis. This would appear to be an exceptional scenario as Larach et al also found that in 152 patients the mean number of anaesthetics before triggering was two (34), a result similar to the study of Strazis et al (35). In this current MHN study, 41% had multiple anaesthetics with triggering agents, without evidence of an MH reaction.
In conclusion, both the findings of this study and previous experience with MHN patients indicate that these patients can be safely given triggering agents in subsequent anaesthetics without risk of developing MH.
The authors wish to thank Jeanine Willink, Dr Roz Machon and Dr Mark Waddington for editorial assistance. In addition, the authors thank Mr Ben Marshall for his statistical guidance.
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N. POLLOCK *, E. E. LANGTON ([dagger]), K. M. STOWELL ([double dagger]), T. F. BULGER *
Department of Anaesthesia, Palmerston North Hospital, Palmerston North, New Zealand
* F.A.N.Z.C.A., Specialist Anaesthetist.
([dagger]) F.A.N.Z.C.A., Specialist Anaesthetist, Wellington Hospital, Wellington.
([double dagger]) B.Sc. (Hons), Ph.D., Associate Professor, Institute of Biomedical Sciences, Massey University.
Address for correspondence: Dr N. Pollock, email: firstname.lastname@example.org
Accepted for publication on May 22, 2011.
TABLE 1 MH Clinical Grading Scale--clinical indicators Process Points Rigidity 15 Muscle breakdown 3-15 Respiratory acidosis 15 Temperature increase 10-15 Cardiac involvement 3 Family history 5-15 MH=malignant hyperthermia. TABLE 2 MH rank and qualitative likelihood Raw score MH range rank Likelihood 0 1 Almost never 3-9 2 Unlikely 10-19 3 Somewhat less than likely 20-34 4 Somewhat greater than likely 35-49 5 Very likely 50+ 6 Almost certain MH=malignant hyperthermia. TABLE 3 Triggering agents Agent Anaesthetics (total=329) Sevoflurane 134 Isoflurane 87 Halothane 71 Desflurane 20 Enflurane 7 Trichloroethylene 2 Cyclopropane 6 Suxamethonium 2 Suxamethonium + inhalational 47 TABLE 4 Intraoperative recordings No. anaesthetics where parameter Recording Range (mean) recorded PR,bpm 49-176 (78) 327 Systolic BP, mmHg 90-200 (115) 295 RR, rate 10-60 (13) 149 Temperature, [degrees]C 35.2-39.3 (36.6) 75 Sp[O.sub.2], % 93-100 (98) 247 ETC[O.sub.2], mmHg 31-69 (41) 181 Total no. anaesthetics=329. PR=pulse rate, BP=blood pressure, RR=respiratory rate, ETCO2=end-tidal carbon dioxide. TABLE 5 PACU recordings No. anaesthetics where parameter Recording Range (mean) recorded PR,bpm 49-180 (78) 327 Systolic BP, mmHg 106-200 (122) 288 RR, rate 12-35 (19) 240 Temperature, [degrees]C 35.5-39.3 (36.5) 160 Sp[O.sub.2], % 92-100 (98) 255 ETC[O.sub.2], mmHg 41-50 (45) 6 Total no. anaesthetics=329. PACU=post-anaesthesia care unit, PR=pulse rate, BP=blood pressure, RR=respiratory rate, ETC[O.sub.2]=end-tidal carbon dioxide.