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Anesth Analg 1999;88:1292
© 1999 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

Patients with Malignant Osteopetrosis Are at High Risk of Anesthetic Morbidity and Mortality

Napoleon Burt, MD, Gary R. Haynes, PhD, MD, and Melinda K. Bailey, MD

Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, Charleston, South Carolina

Address correspondence and reprint requests to Napoleon Burt, MD, Medical University of South Carolina, Department of Anesthesia and Perioperative Medicine, 165 Ashley Ave., Suite 525, PO Box 250912, Charleston, SC 29425. Address e-mail to burtn{at}musc.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The anesthetic literature contains no focused discussion of the perioperative management and risks of children with malignant autosomal recessive osteopetrosis (osteopetrosis). We retrospectively analyzed the perioperative morbidity and mortality rates encountered in the anesthetic management of children with osteopetrosis. We compared the perioperative mortality rate for this patient population with that for other pediatric patients in our institution and that reported in the literature for children and other high-risk patients. We also investigated the inability to intubate the tracheas of children with osteopetrosis compared with other pediatric patients in our institution. Using Fisher's exact test, patients with osteopetrosis were found to have a higher likelihood of perioperative mortality compared with other children or all ASA physical status III, but not ASA physical status IV, patients (P < 0.05). Finally, we discovered that children with osteopetrosis were more likely to have tracheas that could not be intubated than other pediatric patients in our institution. We conclude that children with osteopetrosis are at risk of adverse respiratory events and mortality associated with these adverse events.

Implications: Osteopetrosis is a rare disease that increases perioperative morbidity and mortality. By performing a retrospective chart review, we found that this increased perioperative morbidity and mortality is primarily related to airway and respiratory factors. Anesthetic management strategies should consider the factors that cause the high frequency of adverse airway events in this patient population.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Morbidity and mortality rates in anesthesia have improved dramatically over the decades (1–3). In 1954, Beecher and Todd (1) documented an anesthesia related mortality rate of 1:1560. Accepted adult mortality rates now range from 1:10,000 (2) to 1:200,000 (3) anesthetics. The risk may be increased by a factor of 3 to 5 in pediatric patients compared with adults (1,4). Airway and respiratory problems account for more perioperative morbidity and mortality in pediatric patients than any other factor (5–8). Within the pediatric patient population, risk can be stratified by age groups, with younger children showing a more frequent risk of adverse airway events and perioperative complications than older children (5,7). Additionally, co-existing disease states may contribute to greater perioperative risk in pediatric patients, as they do with adult patients (9).

Osteopetrosis is a rare co-existing disease state with multiple associated anatomic and physiologic abnormalities. The primary problem in all forms of osteopetrosis is an inability to effectively resorb and remodel bone. The bony and radiologic features of osteopetrosis were first described as Albers-Schönberg disease in 1904 (10). The name "osteopetrosis" was introduced in 1922 as further information was accumulated about the disease (10). Osteopetrosis is also referenced as "osteosclerosis" and "marble bone disease."

The several forms of osteopetrosis that have been identified may be distinguished by different inheritance patterns. An autosomal dominant transmission pattern has been identified in some osteopetrosis patients. This form of osteopetrosis may be subdivided into two types. Type I autosomal dominant osteopetrosis is characterized by a markedly reduced number and size of osteoclasts (11). Type II autosomal dominant osteopetrosis is characterized by the proliferation of large, highly multinucleated osteoclasts (11). Pathologic fractures occur with both types of autosomal dominant osteopetrosis but are more common with Type II (12). A wide range of other clinical manifestations is associated with autosomal dominant osteopetrosis. Generally, however, autosomal dominant osteopetrosis is clinically mild and is not diagnosed until adulthood.

An autosomal recessive inheritance pattern has also been described (13). This variant of osteopetrosis is also subdivided into two groups. Whyte et al. (14) described a benign autosomal recessive osteopetrosis syndrome characterized by bony sclerosis, renal tubular acidosis, and cerebral calcifications. Our experience has been primarily with the classic malignant autosomal recessive form of osteopetrosis that is characterized by multiple significant, if not severe, clinical complications. This variant of osteopetrosis only affects infants and children.

The most significant clinical manifestation of osteopetrosis is the predisposition to pathologic fractures. Patients with the malignant autosomal recessive form of osteopetrosis have additional complications due to bony encroachment on surrounding spaces and tissues. Pathophysiologic changes in this form of osteopetrosis affect the respiratory, neurologic, and hematologic systems, in addition to increasing the risk of pathologic fractures seen in the benign forms of osteopetrosis. Moreover, systemic metabolic abnormalities, such as hypocalcemia, may occur in children with malignant autosomal recessive osteopetrosis (13).

Upper respiratory tract function may be drastically altered in children with malignant autosomal recessive osteopetrosis. Children with malignant autosomal recessive osteopetrosis may have head and neck abnormalities that include proptosis, a high-arched palate, broad facies, hypertelorism, frontal bossing, mandibular enlargement, or mandibular hypoplasia (15). In the osteopetrotic patient, the risk of airway obstruction may be further increased by gross widening and sclerosis of the mandible (16). In addition to these mandibular changes, diminished temporomandibular joint movement may make oral intubation difficult. Bony encroachment on the nasal turbinates may make nasotracheal intubation difficult or impossible (16). Thrombocytopenia may lead to profuse bleeding after minor trauma associated with airway instrumentation in these children. Finally, the functional residual capacity may be diminished due to cephalad displacement of the diaphragm secondary to hepatosplenomegaly, which often occurs in children with osteopetrosis (13,17,18). This constellation of factors increases the risk of airway obstruction (19), makes difficult intubation more likely, and results in a greater propensity for profound arterial desaturation during airway management.

Neurologic complications are not uncommon in children with malignant autosomal recessive osteopetrosis. These complications result from bony encroachment on neurologic spaces and tissues. Increased intracranial pressure may occur as a result of encroachment on the cranial vault space (17). Neurologic abnormalities, including cranial nerve entrapment causing compression and ischemia of nerve roots, may result in visual impairment (including blindness) in up to 75% of these children (13,20). Deafness, facial nerve palsies, and mental retardation have been described (17,21–25). Brainstem impaction in the foramen magnum is a potential complication (26).

The failure of osteoclasts to resorb old bone results in encroachment of bone on the marrow space. There are hematologic complications in up to 75% of children with malignant autosomal recessive osteopetrosis (13). Anemia, thrombocytopenia, and leukocyte and macrophage dysfunction are notable hematologic problems associated with the malignant autosomal recessive form of osteopetrosis (17,18,27). Compensatory extramedullary hematopoiesis results in hepatosplenomegaly and hypersplenism. Hepatosplenomegaly may cause significant cephalad displacement of the diaphragm, leading to atelectasis and respiratory distress. Immunologic compromise and predisposition to infection may be other risk factors (28,29).

Various therapeutic interventions for children with malignant autosomal recessive osteopetrosis have been tried. Medical management alternatives include dietary manipulations (17), large-dose calcitriol (30), interferon (31), and bone marrow transplantation (32). Despite advances in the medical management of children with malignant autosomal recessive osteopetrosis, the mortality rate remains 70% before 7 yr of age (13,21).

A relatively large number of children with osteopetrosis receive experimental therapy at our institution in a protocol sponsored by the National Institutes of Health. These patients require surgical intervention for complications related to osteopetrosis, and the experimental therapy protocols often require bone biopsies. The anesthesia literature contains little discussion and few recommendations for the management of these patients. Furthermore, we have noted several complications in the anesthetic management of these patients. Patients with osteopetrosis have several abnormalities that might contribute to increased morbidity and mortality compared with the general population. We reviewed our experience with perioperative complications in patients with osteopetrosis and made comparisons with those of other pediatric cases performed during the same time period. In this article, we propose recommendations for the anesthetic management of patients with osteopetrosis based on our clinical experience and knowledge of the disease process.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
We performed a retrospective chart analysis of 42 patients with osteopetrosis presenting for 65 surgical procedures. A group of 2400 consecutive pediatric patients requiring general anesthesia (single anesthesia provider) served as a control group. Chart data were analyzed for patient characteristics, anesthetic techniques, and complications and outcomes associated with general anesthesia. Patients receiving general anesthesia were evaluated for method of airway management, including mask or laryngeal mask airway (LMA), intubation, or the use of a preexisting tracheostomy. Complications associated with general anesthesia were assigned to the categories of airway difficulty, inability to intubate, and postoperative mortality. Osteopetrosis patients were compared with a group of 2400 pediatric patients presenting for a variety of surgical procedures. Both patient groups were compared with the currently accepted morbidity and mortality rates. Fisher's exact test was used for all comparisons, with a P value <0.05 considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
We identified 65 anesthetics in 42 patients with osteopetrosis, with an equal distribution of male and female patients. Patient age ranged from 3.5 mo to 18 yr (Table 1). Approximately 32% of these cases involved patients <1 yr of age. Of the patients, 71% were <5 yr old. Half the group presented with blindness, severe orthopedic pathology, or both; 30% of the patients had anemia. Other common complications included neurologic sequelae, hypocalcemia, and hepatosplenomegaly. Half the patients were medically managed with {gamma}-interferon alone or in combination with prednisone. None of the patients receiving steroids had Cushing's syndrome. Ten patients presented with severe thrombocytopenia requiring platelet transfusion in the perioperative period. The most common surgical procedure was an iliac crest bone biopsy to assess the efficacy of interferon therapy. All procedures were elective.


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  		Table 1. Patient Characteristics and Anesthetic Techniques
 
Sixty-five surgical procedures were performed on the 42 patients with osteopetrosis. Anesthetic management for three cases consisted of IV sedation with ketamine, midazolam, or propofol. In those cases, spontaneous ventilation was maintained without tracheal intubation, and there were no anesthetic complications. Of the 65 surgical procedures, 62 were performed under general inhaled anesthesia. Within the group receiving general anesthesia, 32% were tracheally intubated, 65% were managed with a face mask or LMA, and 3% had airway management accomplished through an existing tracheostomy. We experienced airway difficulties in 17.7% and intubation difficulties in 14.5% of the general anesthetics performed on osteopetrosis patients in our institution. Neither the airway difficulty nor the intubation difficulty rates were significantly higher than the rates reported by Morray et al. (6) for routine general anesthetics in pediatric patients (Table 2). The tracheal intubation difficulty rate for children with osteopetrosis was higher than that associated with other pediatric anesthetics in our institution (0.13%; P < 0.0001). There were two deaths among the 62 general anesthetics performed on children with osteopetrosis (3.2%). This rate is significantly higher than the 0.04% perioperative mortality rate in patients <=18 yr of age receiving general anesthesia from the primary pediatric anesthesiologist at our institution (P < 0.0001). It is also higher than the 0.21% rate (P < 0.0001) for children <=13 yr of age reported by Tiret et al. (5). Furthermore, the perioperative mortality rate for children with osteopetrosis is higher than that reported for patients classified as ASA physical status III (0.28%; P < 0.001). The perioperative mortality rate for children with osteopetrosis was not significantly different from that reported by Marx et al. (33) for ASA physical status IV patients. Both deceased osteopetrosis patients died from pulmonary complications during hospitalization in which they underwent general anesthesia and surgery. Another patient developed severe negative pulmonary pressure pulmonary edema but recovered. The single noncardiac perioperative death in our general pediatric patient population occurred in an infant with end-stage liver disease, coagulopathy, and an ASA physical status of IVE.


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  		Table 2. Perioperative Major Morbidity and Mortality Data
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The malignant autosomal recessive form of osteopetrosis is associated with multiple pathophysiologic changes. The numerous organ system effects associated with the malignant autosomal recessive form of osteopetrosis create several clinical issues for the anesthetic management of these patients. Because we could find no focused discussion of the perioperative management and risks of anesthesia in children with malignant autosomal recessive osteopetrosis in the current anesthesia literature, we retrospectively evaluated the risks and offer recommendations for management. Anesthetic plans should be constructed in consideration of the known pathophysiologic changes and the greatly increased incidence of critical perioperative events noted in patients with malignant autosomal recessive osteopetrosis.

Two case reports recommended using IV anesthetic techniques instead of volatile anesthetics (16,34). Our experience, which is the only reported series detailing the anesthetic management of children with malignant autosomal recessive osteopetrosis, suggests that the perioperative complications that occur in patients with osteopetrosis are mainly airway-related and are probably independent of the use or avoidance of volatile anesthetics. We have used volatile anesthetics, narcotics, ketamine, propofol via infusion or bolus, and both depolarizing and nondepolarizing muscle relaxants successfully in the anesthetic management of these patients.

Meticulous airway management should be the focal point of anesthetic planning for children with malignant osteopetrosis. Airway management via a mask or LMA may be desirable because they minimize airway manipulation in these difficult airway cases. However, the craniofacial deformities that occur in osteopetrosis may alter airway maintenance dynamics when performing face mask or LMA anesthetics. Because of the inherent challenges to intubating children with osteopetrosis, one should consider the merits of allowing the patient to breathe spontaneously without intubation to minimize airway manipulation for short surgical cases that can be concluded quickly (i.e., the bone biopsy procedure often performed in children with osteopetrosis). For surgical procedures that require endotracheal intubation (i.e., splenectomy or craniofacial reconstruction), conservative intubation techniques that allow the patient to maintain spontaneous respiratory efforts until the vocal cords are visualized or the airway is secured may be prudent. When substantial hepatosplenomegaly results in encroachment on diaphragmatic mobility and decreased pulmonary compliance, maintaining spontaneous ventilation until the airway is secured becomes increasingly important. Preanesthetic planning should consider several airway management alternatives and include plans for emergency airway management contingencies. The airway management of these children becomes an even more critical issue when the bleeding disorders, small nasal passages, and hepatosplenomegaly with rapid desaturation are considered in combination with the potential difficulties of securing the airway.

The current rate of anesthesia-related morbidity and mortality is low (2,3). Several factors may increase anesthesia-related mortality among patients with malignant autosomal recessive osteopetrosis compared with the general surgical patient population. Among these factors are age (1,4,5,7), poor preoperative physical status (9), and co-existing disease characteristics. The impact of age and physical status has been elucidated in the literature (1,4,5,7,9). However, the characteristic abnormalities associated with malignant autosomal recessive osteopetrosis may further contribute to the higher morbidity and mortality that we noted in retrospectively comparing these patients with other pediatric patients at our institution and with data reported in the literature.

Authors have previously noted that airway or respiratory factors are the foremost causes of adverse events in pediatric patients undergoing general anesthesia (6). Airway obstruction accounts for 10.6% of the damaging events that occur during pediatric anesthesia (6), whereas difficult intubation occurs in 8.7% of children undergoing general anesthesia (Table 2). The difficult tracheal intubation rate for children with osteopetrosis was higher than that associated with other pediatric anesthetics at our institution. Moreover, respiratory events were the inciting events for the perioperative mortality that occurred in the two children with osteopetrosis who died. Hence, at our institution, children with malignant autosomal recessive osteopetrosis have a greater risk of airway problems than other pediatric patients. Furthermore, adverse airway events are more likely to be associated with perioperative mortality in children with osteopetrosis than in other pediatric patients.

In conclusion, the incidence of critical perioperative events is high in the pediatric osteopetrosis patient population. The primary risks are respiratory. Preparation for aggressive airway management should be made preoperatively because securing the airway often proves challenging. Other risks should also be considered in the preoperative planning of the anesthetic course (Table 3).


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  		Table 3. Anesthetic Implications of Osteopetrosis
 

   Acknowledgments
 
We thank Phillip F. Rust, PhD, for assistance with statistical analysis of the data.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 25, 1999.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press