Osteogenesis imperfecta is a rare genetic disorder caused by mutations that code for proteins that form type I collagen.1 Patients with osteogenesis imperfecta express heterogeneous disease characteristics and present with various phenotypes affecting skeletal and extraskeletal structures. Presentation can range from mild expression to pre-natal death. Clinically, osteogenesis imperfecta is characterised by low bone mass and increased bone fragility.2,3
A frequently cited concern regarding the anaesthetic management of these patients is the development of intraoperative hypermetabolism manifested with hyperpyrexia,4–7 raising concerns that osteogenesis imperfecta may be associated with risk for malignant hyperthermia.4,8 Evidence supporting development of hyperpyrexia during anaesthesia consists of case reports9,10 and case series that lack controls,7,11–13 and all were reported decades ago. The report of the use of more contemporary anaesthetic agents on intraoperative temperature does not exist. Patients with osteogenesis imperfecta may also have increased risk for anaesthesia-related complications such as injuries during positioning, airway management difficulties and/or tendency for bleeding.
Because the concern of intraoperative hyperpyrexia has persisted in the literature, the main aim of our study was to evaluate intraoperative temperature in patients with osteogenesis imperfecta undergoing non-cardiac surgery. A secondary aim was to describe perioperative complications in a large series of osteogenesis imperfecta patients in a contemporary anaesthesia practice.
Methods and patients
Ethics approval for this study (Ethics Committee No. IRB 08-002787) was provided by the Mayo Clinic Institutional Review Board, Rochester, Minnesota, USA (President Joseph Rubin, MD) on 21 May 2008.
Pre-operative co-morbidities and clinical outcomes
A computerised search of the Mayo Clinic Rochester medical records database (Mayo Clinic medical index) from 1 June 1998 to 31 June 2010 was conducted to identify patients who had been diagnosed with osteogenesis imperfecta and underwent surgery requiring anaesthetic care at Mayo Clinic, Rochester, Minnesota, USA. Using the above methods, a total of 49 osteogenesis imperfecta patients undergoing 180 procedures or surgeries with anaesthesia attendance were identified. Anaesthetic records were reviewed by three of the authors (K.B., C.G. and J.E.K.). Data were entered into standardised data collection form and all questionable entries were discussed with the senior authors (T.N.W. and J.S.). We reviewed demographics (age, sex and type of osteogenesis imperfecta), co-morbidities (structural heart abnormalities, hypertension, cardiac function including ejection fraction, pulmonary hypertension, lung function, obstructive sleep apnea, diabetes mellitus and hyperthyroidism), type of anaesthesia (general, regional or monitored anaesthesia care), type and length of procedure, anaesthetic agents used (type of induction drug, inhalation agents, type of neuromuscular blocking drugs: succinylcholine vs. non-depolarising agents and use of anti-cholinesterase and anti-cholinergic drugs), perioperative injuries, blood transfusions and airway management difficulties. We also reviewed the post-operative recovery course for anaesthesia-related complications.
Analyses of temperature, end-tidal carbon dioxide and minute ventilation
To assess whether intraoperative temperature increased in osteogenesis imperfecta patients, a matched design was performed. Of 49 osteogenesis imperfecta patients, seven undergoing cardiac operations were excluded because they underwent deliberate hypothermia during cardiopulmonary bypass. Osteogenesis imperfecta patients who received monitored anaesthesia care or who underwent short procedures for which intraoperative temperatures were not recorded were also excluded (n = 11). Thus, a total of 31 osteogenesis imperfecta patients were included in temperature and ventilatory variables analyses. If the patient had multiple surgeries, only the first surgery was taken into consideration. Each osteogenesis imperfecta patient was matched with two patients without osteogenesis imperfecta (controls) based on age (±2 years), sex, type of surgery [according to the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM codes)]. For each osteogenesis imperfecta patient, the pool of all potential controls was identified and the two controls with surgery dates closest to osteogenesis imperfecta patient were selected.
From anaesthesia records, we recorded method of temperature measurement (skin or oesophageal probes), end-tidal carbon dioxide and minute ventilation. For both osteogenesis imperfecta patients and controls, we noted the first temperature recorded under anaesthesia and then temperatures every 30 min up to 180 min of surgery. Within each 30-min interval, we recorded the highest achieved temperature. End-tidal carbon dioxide and minute ventilation were analysed at the same intervals as temperature.
Unless otherwise specified, data are presented as mean ± SD for continuous variables and frequency percentages for nominal variables. Perioperative complications were summarised using descriptive statistics. As multiple temperature measurements were obtained for each individual, these data were analysed using a mixed linear model. For this analysis, temperature was the dependent variable and group (osteogenesis imperfecta vs. control) and time (modelled as a continuous variable) were included as explanatory variables. The group-by-time interaction effect was included in the model to assess whether intraoperative temperatures changed differentially for osteogenesis imperfecta patients vs. controls. To supplement this analysis, temperature was also compared between groups at each time point using analysis of variance. Similar analyses were performed to assess changes in end-tidal carbon dioxide and minute ventilation. As younger age has been associated with more prominent metabolic response in osteogenesis imperfecta patients,14 a post-hoc analysis of the temperature data was performed with age (≤17 and ≥18 years) included as an additional explanatory variable in the model. For this model, the age-by-time-by-group interaction was assessed to determine whether differences in temperature over time between osteogenesis imperfecta patients and controls were dependent on age. In addition, as succinylcholine is a trigger agent in patients susceptible to malignant hyperthermia, we performed a similar analysis with succinylcholine use (yes or no) included as an explanatory variable in the model. Descriptive statistics only were used to provide a description of perioperative complications. In all cases, two-tailed P-values less than 0.05 were considered to be statistically significant. Analyses were performed using SAS statistical software (version 8.2, SAS Institute Inc., Cary, North Carolina, USA).
Patients and co-morbidities
Demographic information of 49 patients undergoing 180 operations is shown in Table 1. In 45% of these patients, the type of osteogenesis imperfecta was not specified; of those with specified type of osteogenesis imperfecta, the majority (63%) had type I. A total of 92 procedures were performed on children (0–18 years), with median age of 8 years (range 0.1–18), and 88 procedures on adults with median age of 43 years (range 19–72). The most prevalent co-morbidity was hypertension (35%) followed by restrictive lung disease (24%). The most common surgical procedures were orthopaedic (70%). Cardiac operations (n = 7) included replacement of mitral and aortic valves.
Characteristics of anaesthetics (n = 180)
Most (94%) operations were performed under general anaesthesia (Table 2), and there were no anaesthesia-related complications noted. The prevalent method of airway management was endotracheal intubation (75.3%), whereas five patients received elective fiberoptic intubation. Anaesthetic induction in adults was mostly achieved with sodium thiopental or propofol and in children with inhalational induction. Usually, anaesthesia was maintained with isoflurane and nitrous oxide. Succinylcholine was used uneventfully in 19 patients on 34 occasions. In addition, other non-depolarising muscle relaxants were used, also uneventfully. There were no recorded complications during anaesthetic induction and tracheal intubation (i.e. aspiration, dental trauma, etc.). Seven patients received neuraxial blocks, and there were no indications of difficulties. Three patients underwent monitored anaesthesia care. No patients suffered perioperative bone fractures. None of the osteogenesis imperfecta patients who underwent non-cardiac operations had excessive blood loss or excessive transfusion requirements. Of the seven patients undergoing cardiac surgery, four required six or more blood units.
Intraoperative temperatures were analysed for 31 osteogenesis imperfecta patients undergoing non-cardiac surgery and 62 matched controls. Intraoperatively, temperatures were measured with an oesophageal probe in all patients who were tracheally intubated. In the few cases in which a laryngeal mask airway was used (osteogenesis imperfecta patients, n = 6; controls, n = 6), temperature was measured with axillary skin probes. Body temperature and end-tidal carbon dioxide over the first 180 min of anaesthesia are summarised in Table 3. From an overall repeated measures analysis, temperature was found to increase over time in both patients with osteogenesis imperfecta and the matched controls (main effect of time, P < 0.001), but no overall difference was observed between the two groups (main effect of group, P = 0.589). Also, changes in temperature did not differ between groups at any measured intervals (time-by-group interaction, P = 0.938). For end-tidal carbon dioxide, no significant differences were detected (main effect of time, P = 0.747; main effect of group, P = 0.545; and time-by-group interaction, P = 0.800). Similarly, no group or time effects were detected in set minute ventilations (main effect of time, P = 0.631; main effect of group, P = 0.254; and time-by-group interaction, P = 0.406).
No group differences were found in supplemental analyses which compared temperature between osteogenesis imperfecta patients and controls at each time point (Table 3). A total of 25.8 and 34.4% of osteogenesis imperfecta and control patients, respectively, exceeded 37.0°C at some time point during the course of the anaesthetic. Only one patient exceeded 38.0°C, and this patient was a control patient (his initial temperature was 37.9°C and the last intraoperative was 38.1°C). Intraoperative temperatures did not exceed 37.9°C in any patient with osteogenesis imperfecta that had multiple surgeries; in only three patients, temperature was between 37.0 and 37.4°C, and in two between 37.5 and 37.9°C. From post-hoc analysis that also included age (≤17 and ≥18 years), we again found no evidence that increases in intraoperative temperature differed between osteogenesis imperfecta patients and controls (time-by-group interaction, P = 0.989) and no evidence that this finding was dependent on age (age-by-time-by-group interaction, P = 0.886). Similar findings were observed when the use of succinylcholine was included in the model (time-by-group interaction, P = 0.715; succinylcholine-by-time-by-group interaction, P = 0.275).
The main finding of our study is that our osteogenesis imperfecta patients undergoing surgery under general anaesthesia did not exhibit intraoperative hyperpyrexia or signs of hypermetabolism (increased carbon dioxide production). Furthermore, we did not identify any intraoperative complications that could be attributed to anaesthetic management.
Osteogenesis imperfecta and intraoperative temperature
Development of intraoperative hyperpyrexia in patients with osteogenesis imperfecta has been reported.7,10,15 An association of osteogenesis imperfecta and malignant hyperthermia has also been considered,4–7,9,10 albeit without the firm evidence for its presence. Ghert et al.15 demonstrated post-operative febrile response in the absence of infectious complications in 22 osteogenesis imperfecta children (the osteogenesis imperfecta patients were compared with the ‘historical’ controls). Hall et al.11 reported intraoperative temperature increases in 39 patients (out of 100), less than 1°C in 32 anaesthetics and between 1 and 3°C in seven patients. Others showed that temperatures in osteogenesis imperfecta patients either remained unchanged or slightly increased with enflurane, whereas they decreased with total intravenous anaesthesia.12 Peluso and Cerullo7 reviewed 214 anaesthetics in 24 patients and reported ‘many’ temperature elevations above 37°C. Finally, ‘mild pyrexia’ was common in a series of 63 patients with osteogenesis imperfecta undergoing 266 operations.13 The conclusions from all these reports, that is that osteogenesis imperfecta is associated with hyperpyrexia7,11–13 are somewhat questionable owing to the lack of control group of patients. A proposed mechanism of hyperpyrexia in pre-pubertal patients with osteogenesis imperfecta was elevation of thyroxin levels;14 however, in our cohort only one patient was treated for hyperthyroidism. In addition, we did not identify increase in end-tidal carbon dioxide in our osteogenesis imperfecta patients which would, if present, suggest an increased intraoperative metabolic rate. Also, a secondary analysis did not show association between younger age and propensity for differential rise in intraoperative temperature when compared with either patients with osteogenesis imperfecta or with control patients. Similarly to previous reports,7,11–13 we found that our osteogenesis imperfecta patients have a mild increase in intraoperative temperatures; however, this increase did not differ from that observed in control patients. Therefore, our data do not support the presence of clinically significant hypermetabolism which could lead to intraoperative hyperpyrexia. However, we cannot exclude the possibility that intraoperative hyperpyrexia could have been detected in a larger cohort than ours. Therefore, the anaesthesiologist should follow standard anaesthetic practice and carefully monitor patients with osteogenesis imperfecta for possible signs of hypermetabolism associated with hyperpyrexia.
Osteogenesis imperfecta and anaesthesia-related considerations
Disease characteristics of osteogenesis imperfecta patients result in several additional perioperative concerns. The defect of type I collagen results in the extreme bone fragility and joint laxity2,3 leading to the potential for bone injury. Oliverio 16 described a humerus fracture from the intraoperative use of a non-invasive blood pressure cuff. Due to fear of fractures with muscle fasciculations, some suggested avoiding the use of succinylcholine.5 This concern has never been clinically documented. Succinylcholine has been previously used in these patients uneventfully.11 In our osteogenesis imperfecta series, succinylcholine was used in 34 procedures without complication. Extra care with positioning is of importance during surgery to avoid bone fractures. In our patient series, we did not identify perioperative fractures or other type of positioning injuries.
Patients with osteogenesis imperfecta are prone to head and neck abnormalities that may complicate airway management. These include megalocephaly, macroglossia, short neck,5,16 mid-face and mandibular deformities,11 limited range of motion of the cervical spine5 and abnormal tooth formation. Difficulties with airway management in osteogenesis imperfecta patients have been reported.5,11,17–19 In our series of mostly type I patients, airway management was uncomplicated and there were no unanticipated difficult airways nor were there cases of dental trauma with tracheal intubation. However, the number of patients who received elective fiberoptic intubation is relatively high (five of 49), consistent with previous observations suggesting that airway abnormalities may occur more frequently in these patients.
The best anaesthetic choice for patients with osteogenesis imperfecta has been debated. In fear of airway difficulties, some proposed the use of neuraxial anaesthesia, but spinal abnormalities coupled with frequent spinal instrumentation may make this task challenging. Laryngeal mask airway,20,21 including intubating laryngeal mask,22,23 was successfully used in osteogenesis imperfecta patients. Because temperature may increase more during inhalational anaesthetic than during the use of intravenous agents,12 some considered using total intravenous anaesthesia.24,25 Neuraxial anaesthesia was successfully used in obstetrical practice,26–29 but occasional technical difficulties may exist due to deformities in the vertebral column.30,31 Further, as the vertebral column may be shortened from repeated compression fractures, the conus medullaris can extend caudad to the level usually used for spinal puncture;32 however, this concern for neural injury has never been substantiated. In our cohort, standard induction agents and inhalational anaesthetics in conjunction with depolarising and non-depolarising agents were used without noted complications.
Limitations of the study
This is a retrospective study and the accuracy of ascertained information is subject to the completeness of medical records. In both our groups, modest increases in body temperature occurred and we cannot comment on a cause, as the specifics of individual's intraoperative temperature management is frequently absent from anaesthesia records. Typically, during the study period patients' intraoperative temperature is maintained using a forced air warming blanket and/or increasing the ambient temperature. Our study time frame is 12 years and changes in anaesthetic management could have influenced our results. However, our matched control group was chosen from the same time frame; therefore, the limitations related to practice management should have been equally distributed between the two groups.
In conclusion, in contemporary anaesthetic practice, patients with osteogenesis imperfecta do not exhibit hyperpyrexia or other signs of hypermetabolism (increased carbon dioxide production) when compared with matched surgical patients without osteogenesis imperfecta. Further, no anaesthesia-related complications were noted which suggests that with careful attention, these patients may undergo anaesthesia safely.
This work was entirely supported by the Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA. The authors have no commercial or non-commercial affiliations or other associations that present or could be construed to present a conflict of interest.
We are grateful to Darrell Schroeder (statistician) and Andy Hanson (data analyst) for statistical help.
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