Abstract
Objectives and Aims
The primary aim was to determine the frequency of anesthetic-related complications for patients with malignant infantile osteopetrosis (MIOP) before and after hematopoietic stem cell transplant (HSCT). The secondary aims were to describe the types of complications that occurred, to determine whether the risk of anesthetic complications was altered by HSCT, and to determine the frequency of difficult intubation.
Background
Patients with MIOP undergo HSCT, often in infancy, and anesthesia is frequently required for investigations and procedures associated with transplantation. Although MIOP has adverse implications for anesthetic management, the literature describing anesthetic management of MIOP patients is limited.
Methods/Materials
A retrospective review of medical and anesthetic records was undertaken between November 2000 and March 2008.
Results
Eleven patients underwent 127 anesthetics. The overall complication rate was 11%. Before HSCT, there were 12 complications in 62 anesthetics (19.3%). After HSCT, there were 2 complications in 65 anesthetics (3.2%). This difference was not statistically significant. All of the complications were airway or respiratory events. Of the 26 intubations associated with anesthesia, 23 (88.5%) were easy, 1 (3.8%) was moderately difficult, and 2 (7.7%) were difficult.
Conclusion
Complications associated with anesthesia for infants and children with MIOP having HSCT are fairly common and are usually airway or respiratory related. Difficult endotracheal intubation is also common.
Introduction
Osteopetrosis is a group of rare heritable disorders caused by defects in osteoclasts, the large multinucleated cells that line the endosteal surface of the bone and are principally responsible for bone resorption. Dysfunctional osteoclasts cause the process of resorption and remodeling of immature bone to be impaired, which leads to numerous anatomic and physiologic abnormalities related to skeletal tissue (1).
Several variants of the disease have been identified, but clinical experience at St. Jude Children’s Research Hospital has primarily been with the autosomal recessive malignant infantile osteopetrosis (MIOP), which is the most severe subtype of the disease (2). The exact incidence of MIOP is unknown, but it has been estimated to be 1:200,000 (1). Osteoclast dysfunction, in addition to normal osteoblast function, results in a disproportionate increase in mineralized bone and abnormal hematopoiesis. Consequently, bones are homogeneously dense, sclerotic, and radiopaque (3). Additionally, there is excess bone and mineralized cartilage leading to encroachment of medullary cavities and a subsequent decrease in medullary spaces (4). There are many serious clinical manifestations of the disease, and their variability may reflect different underlying genetic abnormalities (5).
Patients present to St. Jude, usually in infancy, for hematopoietic stem cell transplantation (HSCT), because it is the only treatment that can alter the mortality rate of approximately 70% before 6 years of age (1). Several researchers have reported potential reversal of the adverse manifestations of MIOP upon HSCT treatment, including noticeable weight gain, growth, and resolution of abnormal facial appearance (6, 7). If the grafts are from human leukocyte antigen-identical siblings, the patients have a 5-year disease-free survival rate of 73%, and grafts from unrelated or mismatched donors result in a disease-free survival rate of up to 45% (8).
Before HSCT, patients receive anesthesia for procedures such as permanent central venous catheter placement, bone marrow aspiration, tracheostomy, and total body irradiation. Afterward, there are bone marrow biopsies to determine the success of HSCT and monitor for the development of graft-versus-host disease, radiological studies, and treatment of any surgical complications that arise (9). Although MIOP has adverse implications for anesthetic management (10), the literature describing anesthetic management of MIOP patients is limited. Furthermore, there has been no report in the medical literature regarding how HSCT changes anesthesia risk.
The primary aim of this study was to describe our recent experience with anesthesia for patients with MIOP before and after HSCT and determine the frequency of anesthetic-related complications. Secondary aims were to describe the types of complications that occurred, to determine whether the risk of anesthetic complications was altered by HSCT, and to determine the frequency of difficult intubation.
Materials and Methods
This retrospective study was approved by the institutional review board of St. Jude Children’s Research Hospital. Patients with MIOP who had undergone HSCT between November 2000 and March 2008 were identified from the hospital database. Medical records of these patients were reviewed to obtain patient age, sex, weight, age at diagnosis, comorbid conditions, physical examination findings, and results of laboratory and radiological studies. All anesthesia records for these patients were examined to determine the procedures performed under anesthesia before and after HSCT. Details of the anesthetic technique and any anesthesia-related complications were recorded. The anesthetic record has a section in which the practitioner notes the ease of intubation. This section was examined in cases where intubation took place.
The complication rate was defined as the number of anesthesia-related complications divided by the number of procedures performed for each patient before and after HSCT. The pre- and post-HSCT complication rates were compared using an exact Wilcoxon signed rank test.
Results
Eleven patients were identified in the database and included in the study. There were 8 boys and 3 girls. Most patients were diagnosed at birth (N=7); the other patients ranged in age at diagnosis from 1.7 to 8.1 months. Comorbid conditions present before HSCT are listed in Table 1. The median age at first HSCT was 8.4 months (range, 5.2–63.4 months). One patient (#3) had 2 HSCTs, and another patient (#11) had 4. Only data from anesthetics conducted before a second HSCT were included in the analysis. Post HSCT anesthetics included in the study occurred between 1 and 42 months after HSCT (mean, 10.5 months; median, 4 months).
Table 1.
Comorbid conditions present before HSCT
| Patient number |
Sex | Nasal congestion |
High arched palate/changes in mandibular size/osteomyelitis |
Macrocephaly/frontal bossing/ hydrocephalus |
Hepatosplenomegaly | Thrombocytopenia/ anemia |
Fractures | Vision impairment |
Obstructive sleep apnea |
|---|---|---|---|---|---|---|---|---|---|
| 1 | F | + | +/+/− | +/+/− | + | +/+ | + | + | + |
| 2 | M | + | +/−/− | +/+/− | − | −/− | − | + | + |
| 3 | M | + | −/−/− | +/+/+ | + | −/+ | + | + | − |
| 4 | M | + | −/−/− | −/+/− | + | −/+ | − | + | − |
| 5 | M | + | +/−/− | +/+/+ | − | +/+ | − | + | + |
| 6 | M | + | +/−/− | −/+/− | − | −/− | − | + | + |
| 7 | F | + | −/+/− | +/+/− | − | +/+ | − | + | + |
| 8 | M | + | +/−/− | +/−/− | + | −/− | − | + | + |
| 9 | M | + | +/−/− | +/+/+ | + | −/− | + | − | + |
| 10 | M | − | ◇ | +/−/+ | + | +/+ | − | + | − |
| 11 | F | ◇ | −/−/+ | −/−/+ | + | +/+ | − | + | + |
Plus sign indicates presence of condition; Minus sign indicates absence of condition; ◇ indicates not mentioned on history or physical examination
Of the 127 procedures requiring anesthesia, 62 were done before HSCT, and 65 were done afterward. Airway management for the 62 pre-HSCT procedures included face mask (FM; n=22; 35.5%), tracheostomy (n=16; 25.8%), endotracheal tube (ETT; n=18; 29%), and laryngeal mask airway (LMA; n=6; 9.7%). Airway management for the 65 post-HSCT procedures included FM (n=27; 41.5%), tracheostomy (n=26; 40%), ETT (n=11; 16.9%), and LMA (n=1; 1.5%).
There were 26 oral endotracheal intubations (20.5%) out of 127 procedures. For another 3 procedures, the patient had already been intubated in the intensive care unit. Of the intubations associated with anesthesia, 23 (88.5%) were easy, 1 (3.8%) was moderately difficult, and 2 (7.7%) were difficult. All 11 patients were intubated at least once. Eight patients were intubated one or more times and were easy every time. One patient was intubated once and was moderately difficult, and another patient was intubated once and was difficult. One final patient was intubated 7 times and was noted to be difficult on one occasion but easy the other 6 times.
A total of 14 anesthetic complications in 8 patients were observed. The overall rate of anesthetic complications was 11%. Ten of 11 patients had at least one procedure both before and after HSCT. The other patient (#3) had procedures done only before HSCT. Before HSCT, there were 12 complications in 62 anesthetics (19.4%). After HSCT, there were 2 complications in 65 anesthetics (3%). The numbers of complications per patient before and after HSCT are shown in Table 2. The complications are described in Table 3.
Table 2.
The numbers of complications per patient before and after HSCT
| Before HSCT | After HSCT | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Pt # | Age at first HSCT (months) | # of procedures | # of complications | Complication Rate^ | Months from diagnosis to first HSCT | # of procedures | # of complications | Complication Rate^ | Months from first HSCT to death or last contact |
| 1 | 8 | 6 | 1 | 17% | 8.0 | 4 | 0 | 0% | 4.5 |
| 2 | 8.4 | 6 | 2 | 33% | 6.7 | 2 | 1 | 50% | 3.1 |
| 3 | 18.5 | 4 | 2 | 50% | 18.5 | 0 | 0 | . | 2.0 |
| 4 | 5.2 | 4 | 0 | 0% | 1.9 | 1 | 0 | 0% | 0.9 |
| 5 | 10.8 | 3 | 0 | 0% | 6.7 | 2 | 0 | 0% | 3.8 |
| 6 | 7.4 | 6 | 3 | 50% | 7.4 | 4 | 0 | 0% | 4.1 |
| 7 | 14 | 3 | 1 | 33% | 6.0 | 7 | 0 | 0% | 42.1 |
| 8 | 8 | 6 | 1 | 17% | 8.0 | 10 | 0 | 0% | 6.6 |
| 9 | 6.5 | 6 | 0 | 0% | 6.5 | 27 | 1 | 4% | 36.2 |
| 10 | 13.3 | 7 | 0 | 0% | 13.3 | 3 | 0 | 0% | 4.1 |
| 11 | 63.4 | 11 | 2 | 18% | 63.4 | 5 | 0 | 0% | 9.3 |
| TOTAL | 62 | 12 | 19% | 65 | 2 | 3% | |||
HSCT = hematopoietic stem cell transplantation
Number of anesthesia-related complications divided by the number of procedures performed
Table 3.
Description of recorded complications
| Complication # | Patient # | Age | Procedure | Airway device | Complication | Pre or post |
|---|---|---|---|---|---|---|
| 1 | 1 | 7 months | MRI | Tracheostomy | Propofol TIVA and spontaneous ventilation. Desaturation during the MRI. Patient removed from scanner and manually ventilated via tracheostomy. Event possibly due to tracheostomy being inadvertently kinked. | Pre HSCT |
| 2 | 2 | 6 months | Femoral line insertion | FM | Propofol TIVA and spontaneous ventilation in the ICU. Several brief episodes of oxygen desaturation responding to airway repositioning. | Pre HSCT |
| 3 | 2 | 7 months | CT | Tracheostomy | Propofol TIVA and spontaneous ventilation. Several brief episodes of oxygen desaturation responding to repositioning and suction of the tracheostomy. | Pre HSCT |
| 4 | 2 | 9 months | BMA and biopsy | Tracheostomy | Propofol TIVA and spontaneous ventilation. Several episodes of desaturation responding to manual ventilation, suctioning and repositioning. | Post HSCT |
| 5 | 3 | 14 months | VER | FM/LMA | Propofol TIVA and spontaneous ventilation planned. Airway obstruction and desaturation not responding to LMA insertion, procedure cancelled. | Pre HSCT |
| 6 | 3 | 18 months | VER | ETT | Moderately difficult to intubate with some desaturation. Airway bleeding and upper body petechiae noted after procedure. | Pre HSCT |
| 7 | 6 | 5 months | DLHL insertion | ETT | Difficult to intubate. During central line tunnelling patient became difficult to ventilate. Desaturation with bradycardia. High airway pressures required with manual ventilation. | Pre HSCT |
| 8 | 6 | 6 months | ABR and echo/EKG | FM | Propofol TIVA and spontaneous ventilation. Airway obstruction, desaturation responding to oral airway insertion and repositioning. | Pre HSCT |
| 9 | 6 | 6 months | Adenotonsillectomy | ETT | IV induction followed by intubation. Bronchospasm and desaturation to 70% noted. Patient recovered slowly. Procedure cancelled. | Pre HSCT |
| 10 | 7 | 8 months | BMA and biopsy | FM | Propofol TIVA and spontaneous ventilation. Patient had decreased respiratory effort and desaturated. Did not respond rapidly to bag mask ventilation. Intubated emergently. Slow to emerge from anesthesia. | Pre HSCT |
| 11 | 8 | 7 months | CT and echo/EKG | FM | Propofol TIVA and spontaneous ventilation. Mild desaturation during transport that responded to airway positioning and bag mask ventilation. Echo cancelled. | Pre HSCT |
| 12 | 9 | 6 months | Emergency intubation in OR | ETT | Intubation attempted during deep sevoflurane anesthesia. Failed intubation with presumed laryngospasm. Paralysed and intubated successfully. | Post HSCT |
| 13 | 11 | 5 years | Emergency head CT | FM | Propofol TIVA and spontaneous ventilation. Short episodes of apnea which recovered without intervention. | Pre HSCT |
| 14 | 11 | 5 years | Bone scan | Tracheostomy | Propofol TIVA and spontaneous ventilation. Transient apnea during induction which responded rapidly to manual ventilation via tracheostomy. | Pre HSCT |
MRI = magnetic resonance imaging, CT = computed tomography, BMA = bone marrow aspiration, VER = visual evoked responses, DLHL = double lumen Hickman Line, ABR = auditory evoked brainstem responses, Echo = echocardiogram, EKG = electrocardiogram, FM = face mask, LMA = laryngeal mask airway, ETT = endotracheal tube, HSCT = hematopoietic stem cell transplantation
The data were considered paired observations, and an exact Wilcoxon signed rank test was used to compare them. Ten patients were used in the analysis; patient #3 was excluded (no procedures performed after HSCT). There was no evidence of a difference in the pre- and post-HSCT complication rates as defined above (p=0.125; exact Wilcoxon signed rank test).
Discussion
In our study, the overall rate of anesthesia-related complications was 11%. To place the results in the context of general pediatric surgical patients, one large study reported a 3% rate of intraoperative anesthesia-related complications in patients younger than 17 years (11). The only other study of anesthesia for patients with MIOP reported an even higher rate of anesthesia complications, with airway difficulties in 17.7% of patients (10). In our cohort however, there were no anesthetic-related deaths, compared with a 3.2% death rate in the previously reported study (10). A possible explanation for their higher mortality is that the patients in that study were older (65% were 5 years or older versus only 9% in our study), which may tend to worsen anesthetic outcome in this degenerating condition (10).
Not only were the anesthesia-related complications in this group of patients fairly common, but they were all airway or respiratory in nature. In the aforementioned study of pediatric surgical patients, only 2% of children younger than 8 years had adverse respiratory events (11), compared with 11% in this study. This propensity in the osteopetrotic patient for airway obstruction and oxygen desaturation is probably multifactorial. Patients commonly have mandibular abnormalities, with hypoplasia reported in younger patients (12) and narrowing of the area between the base of the tongue and the posterior pharyngeal wall (6). A high and narrow hard palate is believed to contribute to airway obstruction (5), and nasal obstruction and congestion is almost universal in infants with MIOP (12). Thrombocytopenia is common and may increase the possibility of bleeding during airway manipulation (1). Episodes of oxygen desaturation are undoubtedly made more frequent due to multiple coexistent respiratory abnormalities. Patients with MIOP usually have a small and poorly compliant chest wall (5), and extra medullary hematopoiesis causes hepatosplenomegaly (13), which reduces functional residual capacity even further (10). Primary pulmonary hypertension has been reported, and patients have an increased incidence of persistent pulmonary infections (14). The common observance of obstructive sleep apnea and chronic hypoxemia in patients with MIOP (6, 15) suggests that anesthesia is not necessarily required for these issues to become a problem.
We found that the rate of complications was higher before HSCT (19.4%) than afterward (3%); however this difference was not statistically significant. There are several factors to consider when interpreting these proportions. This study included a small number of patients and follow-up times varied widely among patients. Follow-up may have been of an insufficient duration to alter the pathophysiological features of MIOP that affect anesthetic outcome. During the study, patients obviously got older, and the incidence of anesthetic complications may be influenced by the aging of the patient (11). Another possible factor is the institutional “learning” that occurs for a well known patient. Complications may tend to become less likely as practitioners become familiar with patients and anticipate their anesthetic problems. Only a randomized controlled trial can truly address all these problems, but such a study would be challenging to conduct due to the small numbers of these patients.
In this study 11.5% of oral endotracheal intubations were described as difficult or moderately difficult. This rate is similar to that found in the only other study of anesthesia for patients with MIOP which reported intubation difficulty in 14.5% of patients (10). In the general pediatric population, a large study conducted at a tertiary referral center reported 0.2% of patients had unanticipated difficult intubation, although that included patients up to 16 years of age (11). Difficult oral intubation in patients with MIOP may be due to the mandibular and facial abnormalities that are frequently present (16).
There were several limitations to this study. The study design was retrospective, so we relied on accurate record keeping. It is therefore possible that we have underreported the frequency of complications in this cohort of patients. The description of the ease of intubation was taken from the anesthesia record and did not meet any accepted definition other than the opinion of an experienced pediatric anesthesia provider. The number of patients was small, and they were a select group who had all been referred to a tertiary center. They may not be representative of patients with MIOP in general. The anesthetics were frequently provided for minor and noninvasive procedures, and often did not require instrumentation of the airway. Our results therefore may not be generalizable to typical operating room situations.
We have examined our experience anesthetizing infants and children with MIOP before and after HSCT and found that anesthetic complications were common, and were usually due to airway obstruction and arterial oxygen desaturation.. The incidence of difficult or moderately difficult oral endotracheal intubation was high, and probably due to the same structural airway abnormalities that lead to airway obstruction. Although HSCT may reverse the anatomic abnormalities of MIOP, our numbers were too small to confirm a reduction in the risk of anesthetic-related complications.
Acknowledgments
The Authors wish to thank Angela Norris, RN, BSN, for data collection and David Galloway, ELS, for scientific editing of this manuscript. This work was supported in part by grant 5R25CA023944 from the National Cancer Institute (to A. Kaur). St. Jude Children’s Research Hospital is funded by the American Lebanese Syrian Associated Charities.
Contributor Information
Laura L. Burgoyne, Division of Anesthesiology, St. Jude Children’s Research Hospital, Memphis, TN.
Amanpreet Kaur, Northeastern Ohio Universities College of Medicine, Rootstown, OH.
Catherine A. Billups, Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN.
Mary Edna Parish, Division of Anesthesiology, St. Jude Children’s Research Hospital, Memphis, TN.
Roland N. Kaddoum, Division of Anesthesiology, St. Jude Children’s Research Hospital, Memphis, TN.
George B. Bikhazi, Division of Anesthesiology, St. Jude Children’s Research Hospital, Memphis, TN.
Lilia A. Pereiras, Division of Anesthesiology, St. Jude Children’s Research Hospital, Memphis, TN.
References
- 1.Gerritsen EJ, Vossen JM, van Loo IH, et al. Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course. Pediatrics. 1994;93:247–253. [PubMed] [Google Scholar]
- 2.Askmyr MK, Fasth A, Richter J. Towards a better understanding and new therapeutics of osteopetrosis. Br J Haematol. 2008;140:597–609. doi: 10.1111/j.1365-2141.2008.06983.x. [DOI] [PubMed] [Google Scholar]
- 3.Fasth A, Porras O. Human malignant osteopetrosis: pathophysiology, management and the role of bone marrow transplantation. Pediatr Transplant. 1999;3 (Suppl 1):102–107. doi: 10.1034/j.1399-3046.1999.00063.x. [DOI] [PubMed] [Google Scholar]
- 4.Wilson CJ, Vellodi A. Autosomal recessive osteopetrosis: diagnosis, management, and outcome. Arch Dis Child. 2000;83:449–452. doi: 10.1136/adc.83.5.449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Mazzolari E, Forino C, Razza A, et al. A single-center experience in 20 patients with infantile malignant osteopetrosis. Am J Hematol. 2009;84:473–479. doi: 10.1002/ajh.21447. [DOI] [PubMed] [Google Scholar]
- 6.Stocks RM, Wang WC, Thompson JW, et al. Malignant infantile osteopetrosis: otolaryngological complications and management. Arch Otolaryngol Head Neck Surg. 1998;124:689–694. doi: 10.1001/archotol.124.6.689. [DOI] [PubMed] [Google Scholar]
- 7.Sieff CA, Chessells JM, Levinsky RJ, et al. Allogeneic bone-marrow transplantation in infantile malignant osteopetrosis. Lancet. 1983;1:437–441. doi: 10.1016/s0140-6736(83)91438-1. [DOI] [PubMed] [Google Scholar]
- 8.Driessen GJ, Gerritsen EJ, Fischer A, et al. Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant. 2003;32:657–663. doi: 10.1038/sj.bmt.1704194. [DOI] [PubMed] [Google Scholar]
- 9.Beebe DS, Urban M, Belani KG. Anaesthetic management of bone marrow transplant recipients less than two years of age. Paediatr Anaesth. 1995;5:107–114. doi: 10.1111/j.1460-9592.1995.tb00254.x. [DOI] [PubMed] [Google Scholar]
- 10.Burt N, Haynes GR, Bailey MK. Patients with malignant osteopetrosis are at high risk of anesthetic morbidity and mortality. Anesth Analg. 1999;88:1292–1297. doi: 10.1097/00000539-199906000-00017. [DOI] [PubMed] [Google Scholar]
- 11.Murat I, Constant I, Maud’huy H. Perioperative anaesthetic morbidity in children: a database of 24,165 anaesthetics over a 30-month period. Paediatr Anaesth. 2004;14:158–166. doi: 10.1111/j.1460-9592.2004.01167.x. [DOI] [PubMed] [Google Scholar]
- 12.Wong ML, Balkany TJ, Reeves J, et al. Head and neck manifestations of malignant osteopetrosis. Otolaryngology. 1978;86:ORL-585–594. doi: 10.1177/01945998780860s410. [DOI] [PubMed] [Google Scholar]
- 13.Del Fattore A, Peruzzi B, Rucci N, et al. Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment. J Med Genet. 2006;43:315–325. doi: 10.1136/jmg.2005.036673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Kasow KA, Bonfim C, Asch J, et al. Malignant infantile osteopetrosis and primary pulmonary hypertension: a new combination? Pediatr Blood Cancer. 2004;42:190–194. doi: 10.1002/pbc.10455. [DOI] [PubMed] [Google Scholar]
- 15.Kasow KA, Stocks RM, Kaste SC, et al. Airway evaluation and management in 7 children with malignant infantile osteopetrosis before hematopoietic stem cell transplantation. J Pediatr Hematol Oncol. 2008;30:225–229. doi: 10.1097/MPH.0b013e318162c463. [DOI] [PubMed] [Google Scholar]
- 16.Elster AD, Theros EG, Key LL, et al. Cranial imaging in autosomal recessive osteopetrosis. Part I. Facial bones and calvarium. Radiology. 1992;183:129–135. doi: 10.1148/radiology.183.1.1549658. [DOI] [PubMed] [Google Scholar]