- Email: [email protected]
BRIDGING THE GAP
1101
the human body itself or are produced by techniques of molecular biology will be single isomers. However, about 90% of
that are derived from plants
or
synthetic chiral compounds, including many common drugs such as labetalol, propranolol, mexiletine, terbutaline, and warfarin, are supplied only as racemic mixtures. Consequently, half the drug given to the patient will not produce the effect that had been observed in animal pharmacology tests, for which pure stereoisomers are used. Pharmaceutical companies have long been aware of these difficulties, but the second stereoisomer has been regarded as inactive harmless ballast. Because of the high purification costs, it has seldom been judged worthwhile to produce large quantities of single stereoisomers.33 However, evidence has been accumulating slowly, especially over the past decade, that these "inactive" stereoisomers, in addition to exerting different effects, may also produce unwanted side-effects. For example, propoxyphene is a chiral compound whose two stereoisomers have very different properties--dextropropoxyphene is an established analgesic, whereas levopropoxyphene is an antitussive. (The chirality of the two products is even reflected in their trade names, ’Darvon’ and
’Novrad’.) Thalidomide provides a dramatic illustration of the side-effects of stereoisomers. German researchers showed that, in mice, although the two stereoisomers were sedative only one was responsible for the teratogenicity.4 Although this example has been used to support the case for the supply of single pure isomers as drug substances, further work showed that both isomers were teratogenic in rabbits,and we shall probably never determine what happened in pregnant women.
Advances in analytical chemistry have simplified the separation of stereoisomers, and we now know that they have different pharmacokinetic properties, particularly with respect to distribution and elimination.6 Some non-steroidal anti-inflammatory agents have been shown to convert from one stereoisomer to the other in the body.7 Such differences are especially important for drugs with a low therapeutic index. This knowledge is of little help to prescribing doctors, who are entirely dependent on what the companies choose to supply. Pharmaceutical companies have been severely criticised for not being quicker to act and also for not making clear in much of their promotional material that their chiral products are supplied only as racemic mixtures.8 However, things are changing—eg, the racemic product, fenfluramine, has already been relicensed by one company as the active stereoisomer, dexfenfluramine. Some companies who have taken racemic mixtures off the market because of sideeffects may even decide to re-examine the single isomers. Regulatory authorities are now starting to ask for more detailed information about the relative
pharmacokinetics of stereoisomers.9 Since January, 1989, the US Food and Drug Administration Center for Drug Evaluation and Research has had a stereoisomer committee, and from 1992 the FDA will insist that US companies show that the active stereoisomer of their chiral drugs is safe and effective and that the other isomer is harmless. Those companies who are already producing single stereoisomers may well start to emphasise this fact
when
promoting their products. Nevertheless, separation of individual stereoisomers from racemic industrial scale is not easy and stereospecific synthesis still has a long way to go, although progress is being made. 10 Single stereoisomers will be more expensive to produce than racemic mixtures. A wider issue that concerns us all and that probably poses a greater threat is the fact that several pesticides and fungicides are chiral. These agents are used in large quantities and it is unsettling to think that only half of what is used is doing what it is intended to do. A review1 lately used the very apposite words of Lewis Carroll-"Perhaps, looking-glass milk isn’t good to drink?"
mixtures
on
an
1. Ariens JE, Wuis EW, Veringa EJ. Stereoselectivity of bioactive xenobiotics. Biochem Pharmacol 1988; 37: 9-18. 2. Mason S. The origin of chirality in nature. Trends Pharmacol Sci 1986; 7: 20-23. 3. Laird T. Development and scale-up of process for the manufacture of new pharmaceuticals. In: Hansch C, Sammes PG, Taylor JB, eds. Comprehensive medicinal chemistry, volume 1. Oxford: Pergamon, 1990: 321-60. 4. Blaschke G, Kraft HP, Fickentscher K, Kohler F. Chromatographische Racemattrennung von Thalidomid und teratogene Wirkung der Enantiomere. Arzneim Forsch 1979; 29: 1640-42. 5. Fabro S, Smith RL, Williams RT. Toxicity and teratogenicity of optical isomers of thalidomide. Nature 1967; 215: 296. 6. Lee EJD, Williams KM. Chirality: clinical pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet 1990; 18: 339-45. 7. Lee EJD, Williams KM, Graham GG, Day RO, Champion GD. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 1985; 19: 669-74. 8. Ariens EJ. Implications of the neglect of stereochemistry in pharmacokinetics and clinical pharmacology. Drug Intell Clin Pharmacol 1987; 21: 827-29. 9. Weissinger J. Considerations in the development of stereoisomeric drugs: FDA viewpoint. Drug Inf J 1989; 23: 663-67. 10. Emsley J. Chemists tame the wild side of drugs. New Scientist 1990; 127: 32. 11. Tucker GT, Lennard MS. Enantiomer specific pharmacokinetics. Pharmacol Ther 1990; 45: 309-29.
BRIDGING THE GAP
Large defects in the skeleton arise for various reasonsbecause of injury, either early from traumatic bone loss, or later following debridement of bone for extensive sepsis or atrophic non-union; from wide excision of benign and malignant musculoskeletal tumours; or as a result of failed joint replacement. Patients often undergo several operations in the course of their treatment followed by lengthy immobilisation that leads to muscle wasting, joint stiffness, and considerable disability. Limb-sparing surgery is increasingly practised in preference to amputation, especially in patients with high-grade osteosarcomas, for whom adjuvant chemotherapy has improved the survival rate dramatically. Adequate wide local excision with removal of the tumour and a surrounding layer of normal
1102
tissue leaves a large defect in the bone, and usually also in the adjacent joint, because osteosarcoma has a predilection for the metaphyses. The resulting defects are mainly diaphyseal osteoarticular. Diaphyseal defects can be subdivided into those longer or shorter than 6 cm. Short defects respond well to massive cancellous autografting,l whereas those between 6 and 12 cm do best with avascular autogenous fibular grafting.2 A single fibular graft is sufficient in the upper limb,3but two are desirable in the lower limb because of the greater transmitted loads.4When the gap is longer than 12 cm, one of the grafts should be vascularised to prevent stress fractures along its length.2 If the recipient bed is scarred because of previous infection, surgery, or irradiation, but is less than 12 cm long, a vascularised fibular graft may be indicated.5 Both vascularised and avascular autografts are replaced in the same way, by creeping substitution, but the process occurs more quickly when the graft is vascularised and the resultant strength and stiffness across the graft is improved.6 The patient is therefore immobilised for a shorter time. Osteoarticular defects can be treated similarly, but at the expense of movement at the excised joint. Although this approach is sometimes appropriate, opinion is divided between the merits of massive endoprostheses and cadaveric allografts. There have been no direct comparisons of the two methods, although both are used for the same group of patients. Part of the reason is geographical: European groups have tended to use prostheses whereas US surgeons have tended towards allografts. In less affluent societies, where tumours and extensive bone infections occur no less frequently, financial constraints and limited technological support favour the use of the simpler methods of reconstruction with autogenous fibular grafts.4 The fibular graft, especially when avascular, is easy to harvest, with very little donor site morbidity7 and no opportunity for disease transmission. It is incorporated well and is better suited for skeletal reconstruction than is a rib or iliac crest graft by virtue of its shape, size, and mechanical properties, although it is prone to non-union if inadequately fixed, and to stress fractures if more than 12 cm long.2 However, fibular grafts cannot provide an adequate articulating joint surface, except perhaps in the distal radius,8,9 and should be reserved for the treatment of diaphyseal defects. Vascularised grafts are incorporated more quickly than avascular grafts, thereby reducing the need for lengthy external splintage. The risk of stress fracture and non-union is lower than with avascular grafts and they may be used in less favourable sites; the techniques of harvesting and vascular anastomosis are inevitably more or
complex. Massive endoprostheses may be custom-made 10-14 or modular.15 Custom-made prostheses fit the patient better 16 and are less liable to mechanical failure, but are not available "off the shelf’, and there may be delays in manufacture and delivery. Once implanted, both systems are prone to the complications which can bedevil any prosthesis, especially infection, loosening, and dislocation. They are never truly incorporated into the skeleton and do not increase the bone stock in the limb. They have the great advantage of not requiring long-term immobilisation in patients with short life expectancy, and are not affected by irradiation or chemotherapy, which makes them particularly valuable for limb-sparing procedures in patients with high-grade malignant bone tumours. Doubts have been expressed
about their long-term survival in young patients." Massive cadaveric allografts, by contrast, add bone to the skeleton. The donor bone is matched by size and shape to that of the recipient, and has similar mechanical properties if frozen rather than freeze-dried. 18 Tendons can be reattached to the graft, giving a better functional outcome than can be achieved with a prosthesis. The allograft becomes incorporated into the skeleton but is never fully replaced by host bone. 19 Harvesting and storage of allografts is a complex, labour-intensive, time-consuming process and is consequently expensive.2O Once implanted, these implants excite an immune reaction in the host which results in slower revascularisation and incorporation than would occur with a comparable autograft. 17 Infection develops in 12%21 and fracture in 16%. 22 Transmission of both viral and bacterial infections has occurred ;21 if use of the technique is to continue, it will be essential to eliminate any possibility of human immunodeficiency virus transmission. Each patient who presents with a massive bone defect and in whom limb salvage is being considered must be assessed by a surgical team experienced in all types of reconstructive procedures. The choice of the most appropriate procedure depends not only on the nature of the defect to be bridged but also on the resources and experience available to deal with it. 1. Lortat-Jacob A, Lelong B, Benoit J, Ramadier JO. Les gestes complémentaires de l’opération de Papineau. Rev Chir Orthop 1981; 67: 115-20. 2.
Enneking WF, Eady JL, Burchardt H. Autogenous cortical bone grafts in the reconstruction of segmental skeletal defects. J Bone Joint Surg 1980;
62A: 1039-58. 3. Wood MB. Upper
extremity reconstruction by vascularized bone transfers: results and complications. J Hand Surg (Am) 1987; 12: 422-27. 4. Yadav SS. Dual-fibular grafting for massive bone gaps in the lower extremity. J Bone Joint Surg 1990; 72A: 486-94. 5. Weiland AJ, Moore JR, Daniel RK. Vascularised bone autografts: experience with 41 cases. Clin Orthop 1983; 174: 87-95. 6. Shaffer JW, Field JA, Goldberg VM, Davy DT. Fate of vascularized and non-vascularized autografts. Clin Orthop 1985; 197: 32-43. 7. Lee EH, Goh JCH, Helm R, Pho RWH. Donor site morbidity following resection of the fibula. J Bone Joint Surg 1990; 72B: 129-131. 8. Pho RWH. Free vascularised fibular transplant for replacement of the lower radius. J Bone Joint Surg 1979; 61B: 362-65. 9. Salenius P, Santavirta S, Kiviluoto O, Koskinen EVS. Application offree autogenous fibular graft in the treatment of aggressive bone tumours of the distal end of the radius. Arch Orthop Trauma Surg 1981; 98: 285-87. 10. Dobbs HS, Scales JT, Wilson JN, Kemp HBS, Jackson Burrows H, Sneath RS. Endoprosthetic replacement of the proximal end of the femur and acetabulum. J Bone Joint Surg 1981; 63B: 219-24. 11. Scales JT. Bone and joint replacement for the preservation of limbs. Br J Hosp Med 1983; 30: 220-32. 12. Bradish CF, Kemp HBS, Scales JT, Wilson JN. Distal femoral replacement by custom-made prostheses: clinical follow-up and survivorship analysis. J Bone Joint Surg 1987; 67B: 276-84. 13. Ross AC, Sneath RS, Scales JT. Endoprosthetic replacement of the humerus and elbow joint. J Bone Joint Surg 1987; 69B: 652-55. 14. Ross AC, Wilson JN, Scales JT. Endoprosthetic replacement of the proximal humerus. J Bone Joint Surg 1987; 69B: 656-61. 15. Kotz R, Ritschl P, Trachtenbrodt J. A modular femur-tibia reconstruction system. Orthopedics 1986; 9: 1639-52. 16. Wright K. Bioengineering aspects of prosthetic design. In: Coombs RH, Friedlaender GE, eds. Bone tumour management. London: Butterworths, 1987: 134-44. 17. Mankin HJ, Gebhardt MC, Tomford WW. The use of frozen cadaveric allografts in the management of patients with bone tumors of the extremities. Orthop Clin North Am 1987; 18: 275-89. 18. Pelker RR, Friedlaender GE, Markham TC. Biomechanical properties of bone allografts. Clin Orthop 1983; 174: 54-57. 19. Burchardt H. Biology of bone transplantation. Orthop Clin North Am 1987; 18: 187-96. 20. Tomford WW, Doppelt SH, Mankin HJ, Friedlaender GE. Bone bank procedures. Clin Orthop 1983; 174: 15-21.
1103
21. Lord CF, Gebhardt MC, Tomford WW, Mankin HJ. Infection in bone allografts: incidence, nature and treatment. J Bone Joint Surg 1988; 70A: 369-76. 22. Berrey BH, Lord CF, Gebhardt MC, Mankin HJ. Fractures of allografts: frequency, treatment and end-results. J Bone Joint Surg 1990; 72A: 825-33.
OCCUPATIONAL INFECTION AMONG ANAESTHETISTS Anaesthetists are regularly exposed to blood and body fluids that may carry infectious organisms, of which hepatitis B virus (HBV) and human immunodeficiency virus (HIV) HBV is
highly infectious; minute of blood entering through cuts, mucous membranes, or accidental inoculation are sufficient for disease transmission. The overall risk of contracting hepatitis B from a single needlestick injury contaminated with blood from an infected patient has been estimated to be 5%.’ The fact that anaesthetists have more HBV markers than the general population suggests that occupational infection does occur.2 Immunisation against hepatitis B gives a high level of protection, although the existence of a vaccine-induced escape mutant of the virus has been reported.3 Hepatitis B immune globulin given to nonimmunised subjects after needlestick injury is only partly effective in preventing infection 4 The frequency of HIV infection in the population is not uniform, and people in high-risk groups may have higher than normal hospital attendance rates.5 Although there have been no fully documented cases of accidental HIV infection
cause most concern.
amounts
anaesthetists, such incidents have been reported in other health care workers.5 Infection appears to require the transfer of larger volumes of blood than is the case with HBV,6so one might expect hollow instruments such as the needles used mainly by anaesthetists to be more dangerous than surgical scalpel blades or sewing needles. Most documented occupational HIV transmissions result from needlestick injuries involving blood, but transmission via other body fluids and routes has been reported.5 There is little information about the frequency of seroconversion after occupational exposure to HIV; a figure of 0-4% is widely cited.’ Although the risk of contracting HIV as a result of occupational exposure may be low compared with HBV, the consequences of infection are far more serious: whereas only 2% of people infected with HBV die of the infection6 50% of those infected with HIV will have AIDS within six years.8 There is no protective vaccine against HIV and prompt treatment with zidovudine after needlestick injury has proved ineffective in two cases.9 In the UK, 0-1-0-5% of the population are said to be carriers of HBV, although many more have serological evidence of past infection." For HIV, in 1988 it was reported that 0.1-0-3% of the population were infected;"aa later study12 suggested that the lower figure may be more accurate. Because polymerase chain reaction techniques may pick up those without antibodies, these figures may slightly underestimate the true level of HIV infection.13 Up-to-date information on the extent of exposure of anaesthetists to blood and body fluids is available from independent surveys conducted in two hospitals. The first showed that during the course of 270 anaesthetics, blood from 14% of patients caused skin contamination of 65 people during 46 incidents.14 8% of staff had skin cuts at the time of the events and one needlestick injury occurred among
the survey. In the second survey of 7000 anaesthetics15 the frequency of needlestick injury was 013%, of which two-thirds were with contaminated needles. 20% of the anaesthetists received a needlestick injury during the three-month study. The Association of Anaesthetists10 and the Expert Advisory Group on AIDS’ both advise anaesthetists to wear gloves as a minimum protective measure when there is likely to be contact with blood. The first survey14 showed that glove-wearing varied with procedure from 8% for peripheral venous cannulation to 90% for central venous cannulation. Failure to wear gloves led to many avoidable contamination incidents. Although gloves did not prevent needlestick injury in these surveys, double-gloving has been shown to reduce the frequency of skin contamination from needle punctures.16
during
Only 71 %14 and 74%ls of anaesthetists in these were immunised against HBV, despite the
surveys proven
effectiveness of the vaccine. If these levels of immunisation apply throughout the UK, about 1500 anaesthetists are putting themselves at unnecessary risk of infection. These surveys suggest that many UK anaesthetists are not adopting simple measures to reduce the risk of occupationally acquired infections. Perhaps they are complacent because the risk of a single incident leading to infection is very small. However, the average anaesthetist will treat many thousands of patients during his or her working life, so the cumulative risk of occupationally acquired HIV infection may be as high as 1 in 25. 1. Guidance for Clinical Health Care Workers: protection against infection with HIV and hepatitis viruses. Recommendations of the Expert Advisory Group on AIDS. London: HM Stationery Office, 1990. 2. Berry AJ, Isaacson IJ, Kane MA, et al. A multicentre study of the prevalence of hepatitis B viral serologic markers in anesthesia personnel. Anesth Analg 1984; 63: 738-42. 3. Carman WF, Zanetti AR, Karayiannis P, et al. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990; 336: 325-29. 4. Seeff LB, Wright EC, Zimmerman HJ, et al. Type B hepatitis after needle-stick exposure: prevention with hepatitis B immune globulin. Ann Intern Med 1978; 88: 285-87. 5. Kelen GD. Human immunodeficiency virus and the emergency department: risks and risk protection for health care providers. Ann Emerg Med 1990; 19: 242-48. 6. Morgan DR. HIV and needlestick injuries. Lancet 1990; 335: 1280. 7. Ruthane M, and the CDC Cooperative Needlestick Surveillance Group. Surveillance of health care workers exposed to blood from patients infected with the human immunodeficiency virus. N Engl J Med 1988; 319: 1118-23. 8. Moss AR, Bacchetti P, Osmond D, et al. Seropositivity for HIV and the development of AIDS or AIDS related condition: three year follow up of the San Francisco General Hospital cohort. Br Med J 1988; 296: 745-50. 9. Anon. Zidovudine and needlestick exposure. Lancet 1990; 335: 1271. 10. AIDS and Hepatitis B Guidelines for Anaesthetists. London: Association of Anaesthetists, April, 1989. 11. Wilkie AD. Forecasting AIDS using an actuarial model. In: Cox D. Short-term prediction of HIV infection and AIDS in England and Wales. Report of the working group. London: HM Stationery Office, 1988. 12. Acquired Immune Deficiency Syndrome in England and Wales to end 1993: projections using data to end September 1989. Report of a working group convened by the Director of the Public Health Laboratory Service. London: Public Health Laboratory Service, 1990. 13. Soriano V, Hewlett I, Tor J, Clotet B, Epstein J, Foz M. Silent HIV infection in heterosexual partners of seropositive drug abusers in Spain. Lancet 1990; 335: 860. 14. Harrison CA, Rogers DW, Rosen M. Blood contamination of anaesthetic and related staff. Anaesthesia 1990; 45: 831-33. 15. Maz S, Lyons G. Needlestick injuries in anaesthetists. Anaesthesia 1990; 45: 677-78. 16. Matta H, Thompson AM, Rainey JB. Does wearing two pairs of gloves protect operating theatre staff from skin contamination? Br Med J 1988; 297: 597-98. 17. Jones ME. A thing about AIDS. Anaesth Intens Care 1989; 17: 253-63.
the human body itself or are produced by techniques of molecular biology will be single isomers. However, about 90% of
that are derived from plants
or
synthetic chiral compounds, including many common drugs such as labetalol, propranolol, mexiletine, terbutaline, and warfarin, are supplied only as racemic mixtures. Consequently, half the drug given to the patient will not produce the effect that had been observed in animal pharmacology tests, for which pure stereoisomers are used. Pharmaceutical companies have long been aware of these difficulties, but the second stereoisomer has been regarded as inactive harmless ballast. Because of the high purification costs, it has seldom been judged worthwhile to produce large quantities of single stereoisomers.33 However, evidence has been accumulating slowly, especially over the past decade, that these "inactive" stereoisomers, in addition to exerting different effects, may also produce unwanted side-effects. For example, propoxyphene is a chiral compound whose two stereoisomers have very different properties--dextropropoxyphene is an established analgesic, whereas levopropoxyphene is an antitussive. (The chirality of the two products is even reflected in their trade names, ’Darvon’ and
’Novrad’.) Thalidomide provides a dramatic illustration of the side-effects of stereoisomers. German researchers showed that, in mice, although the two stereoisomers were sedative only one was responsible for the teratogenicity.4 Although this example has been used to support the case for the supply of single pure isomers as drug substances, further work showed that both isomers were teratogenic in rabbits,and we shall probably never determine what happened in pregnant women.
Advances in analytical chemistry have simplified the separation of stereoisomers, and we now know that they have different pharmacokinetic properties, particularly with respect to distribution and elimination.6 Some non-steroidal anti-inflammatory agents have been shown to convert from one stereoisomer to the other in the body.7 Such differences are especially important for drugs with a low therapeutic index. This knowledge is of little help to prescribing doctors, who are entirely dependent on what the companies choose to supply. Pharmaceutical companies have been severely criticised for not being quicker to act and also for not making clear in much of their promotional material that their chiral products are supplied only as racemic mixtures.8 However, things are changing—eg, the racemic product, fenfluramine, has already been relicensed by one company as the active stereoisomer, dexfenfluramine. Some companies who have taken racemic mixtures off the market because of sideeffects may even decide to re-examine the single isomers. Regulatory authorities are now starting to ask for more detailed information about the relative
pharmacokinetics of stereoisomers.9 Since January, 1989, the US Food and Drug Administration Center for Drug Evaluation and Research has had a stereoisomer committee, and from 1992 the FDA will insist that US companies show that the active stereoisomer of their chiral drugs is safe and effective and that the other isomer is harmless. Those companies who are already producing single stereoisomers may well start to emphasise this fact
when
promoting their products. Nevertheless, separation of individual stereoisomers from racemic industrial scale is not easy and stereospecific synthesis still has a long way to go, although progress is being made. 10 Single stereoisomers will be more expensive to produce than racemic mixtures. A wider issue that concerns us all and that probably poses a greater threat is the fact that several pesticides and fungicides are chiral. These agents are used in large quantities and it is unsettling to think that only half of what is used is doing what it is intended to do. A review1 lately used the very apposite words of Lewis Carroll-"Perhaps, looking-glass milk isn’t good to drink?"
mixtures
on
an
1. Ariens JE, Wuis EW, Veringa EJ. Stereoselectivity of bioactive xenobiotics. Biochem Pharmacol 1988; 37: 9-18. 2. Mason S. The origin of chirality in nature. Trends Pharmacol Sci 1986; 7: 20-23. 3. Laird T. Development and scale-up of process for the manufacture of new pharmaceuticals. In: Hansch C, Sammes PG, Taylor JB, eds. Comprehensive medicinal chemistry, volume 1. Oxford: Pergamon, 1990: 321-60. 4. Blaschke G, Kraft HP, Fickentscher K, Kohler F. Chromatographische Racemattrennung von Thalidomid und teratogene Wirkung der Enantiomere. Arzneim Forsch 1979; 29: 1640-42. 5. Fabro S, Smith RL, Williams RT. Toxicity and teratogenicity of optical isomers of thalidomide. Nature 1967; 215: 296. 6. Lee EJD, Williams KM. Chirality: clinical pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet 1990; 18: 339-45. 7. Lee EJD, Williams KM, Graham GG, Day RO, Champion GD. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 1985; 19: 669-74. 8. Ariens EJ. Implications of the neglect of stereochemistry in pharmacokinetics and clinical pharmacology. Drug Intell Clin Pharmacol 1987; 21: 827-29. 9. Weissinger J. Considerations in the development of stereoisomeric drugs: FDA viewpoint. Drug Inf J 1989; 23: 663-67. 10. Emsley J. Chemists tame the wild side of drugs. New Scientist 1990; 127: 32. 11. Tucker GT, Lennard MS. Enantiomer specific pharmacokinetics. Pharmacol Ther 1990; 45: 309-29.
BRIDGING THE GAP
Large defects in the skeleton arise for various reasonsbecause of injury, either early from traumatic bone loss, or later following debridement of bone for extensive sepsis or atrophic non-union; from wide excision of benign and malignant musculoskeletal tumours; or as a result of failed joint replacement. Patients often undergo several operations in the course of their treatment followed by lengthy immobilisation that leads to muscle wasting, joint stiffness, and considerable disability. Limb-sparing surgery is increasingly practised in preference to amputation, especially in patients with high-grade osteosarcomas, for whom adjuvant chemotherapy has improved the survival rate dramatically. Adequate wide local excision with removal of the tumour and a surrounding layer of normal
1102
tissue leaves a large defect in the bone, and usually also in the adjacent joint, because osteosarcoma has a predilection for the metaphyses. The resulting defects are mainly diaphyseal osteoarticular. Diaphyseal defects can be subdivided into those longer or shorter than 6 cm. Short defects respond well to massive cancellous autografting,l whereas those between 6 and 12 cm do best with avascular autogenous fibular grafting.2 A single fibular graft is sufficient in the upper limb,3but two are desirable in the lower limb because of the greater transmitted loads.4When the gap is longer than 12 cm, one of the grafts should be vascularised to prevent stress fractures along its length.2 If the recipient bed is scarred because of previous infection, surgery, or irradiation, but is less than 12 cm long, a vascularised fibular graft may be indicated.5 Both vascularised and avascular autografts are replaced in the same way, by creeping substitution, but the process occurs more quickly when the graft is vascularised and the resultant strength and stiffness across the graft is improved.6 The patient is therefore immobilised for a shorter time. Osteoarticular defects can be treated similarly, but at the expense of movement at the excised joint. Although this approach is sometimes appropriate, opinion is divided between the merits of massive endoprostheses and cadaveric allografts. There have been no direct comparisons of the two methods, although both are used for the same group of patients. Part of the reason is geographical: European groups have tended to use prostheses whereas US surgeons have tended towards allografts. In less affluent societies, where tumours and extensive bone infections occur no less frequently, financial constraints and limited technological support favour the use of the simpler methods of reconstruction with autogenous fibular grafts.4 The fibular graft, especially when avascular, is easy to harvest, with very little donor site morbidity7 and no opportunity for disease transmission. It is incorporated well and is better suited for skeletal reconstruction than is a rib or iliac crest graft by virtue of its shape, size, and mechanical properties, although it is prone to non-union if inadequately fixed, and to stress fractures if more than 12 cm long.2 However, fibular grafts cannot provide an adequate articulating joint surface, except perhaps in the distal radius,8,9 and should be reserved for the treatment of diaphyseal defects. Vascularised grafts are incorporated more quickly than avascular grafts, thereby reducing the need for lengthy external splintage. The risk of stress fracture and non-union is lower than with avascular grafts and they may be used in less favourable sites; the techniques of harvesting and vascular anastomosis are inevitably more or
complex. Massive endoprostheses may be custom-made 10-14 or modular.15 Custom-made prostheses fit the patient better 16 and are less liable to mechanical failure, but are not available "off the shelf’, and there may be delays in manufacture and delivery. Once implanted, both systems are prone to the complications which can bedevil any prosthesis, especially infection, loosening, and dislocation. They are never truly incorporated into the skeleton and do not increase the bone stock in the limb. They have the great advantage of not requiring long-term immobilisation in patients with short life expectancy, and are not affected by irradiation or chemotherapy, which makes them particularly valuable for limb-sparing procedures in patients with high-grade malignant bone tumours. Doubts have been expressed
about their long-term survival in young patients." Massive cadaveric allografts, by contrast, add bone to the skeleton. The donor bone is matched by size and shape to that of the recipient, and has similar mechanical properties if frozen rather than freeze-dried. 18 Tendons can be reattached to the graft, giving a better functional outcome than can be achieved with a prosthesis. The allograft becomes incorporated into the skeleton but is never fully replaced by host bone. 19 Harvesting and storage of allografts is a complex, labour-intensive, time-consuming process and is consequently expensive.2O Once implanted, these implants excite an immune reaction in the host which results in slower revascularisation and incorporation than would occur with a comparable autograft. 17 Infection develops in 12%21 and fracture in 16%. 22 Transmission of both viral and bacterial infections has occurred ;21 if use of the technique is to continue, it will be essential to eliminate any possibility of human immunodeficiency virus transmission. Each patient who presents with a massive bone defect and in whom limb salvage is being considered must be assessed by a surgical team experienced in all types of reconstructive procedures. The choice of the most appropriate procedure depends not only on the nature of the defect to be bridged but also on the resources and experience available to deal with it. 1. Lortat-Jacob A, Lelong B, Benoit J, Ramadier JO. Les gestes complémentaires de l’opération de Papineau. Rev Chir Orthop 1981; 67: 115-20. 2.
Enneking WF, Eady JL, Burchardt H. Autogenous cortical bone grafts in the reconstruction of segmental skeletal defects. J Bone Joint Surg 1980;
62A: 1039-58. 3. Wood MB. Upper
extremity reconstruction by vascularized bone transfers: results and complications. J Hand Surg (Am) 1987; 12: 422-27. 4. Yadav SS. Dual-fibular grafting for massive bone gaps in the lower extremity. J Bone Joint Surg 1990; 72A: 486-94. 5. Weiland AJ, Moore JR, Daniel RK. Vascularised bone autografts: experience with 41 cases. Clin Orthop 1983; 174: 87-95. 6. Shaffer JW, Field JA, Goldberg VM, Davy DT. Fate of vascularized and non-vascularized autografts. Clin Orthop 1985; 197: 32-43. 7. Lee EH, Goh JCH, Helm R, Pho RWH. Donor site morbidity following resection of the fibula. J Bone Joint Surg 1990; 72B: 129-131. 8. Pho RWH. Free vascularised fibular transplant for replacement of the lower radius. J Bone Joint Surg 1979; 61B: 362-65. 9. Salenius P, Santavirta S, Kiviluoto O, Koskinen EVS. Application offree autogenous fibular graft in the treatment of aggressive bone tumours of the distal end of the radius. Arch Orthop Trauma Surg 1981; 98: 285-87. 10. Dobbs HS, Scales JT, Wilson JN, Kemp HBS, Jackson Burrows H, Sneath RS. Endoprosthetic replacement of the proximal end of the femur and acetabulum. J Bone Joint Surg 1981; 63B: 219-24. 11. Scales JT. Bone and joint replacement for the preservation of limbs. Br J Hosp Med 1983; 30: 220-32. 12. Bradish CF, Kemp HBS, Scales JT, Wilson JN. Distal femoral replacement by custom-made prostheses: clinical follow-up and survivorship analysis. J Bone Joint Surg 1987; 67B: 276-84. 13. Ross AC, Sneath RS, Scales JT. Endoprosthetic replacement of the humerus and elbow joint. J Bone Joint Surg 1987; 69B: 652-55. 14. Ross AC, Wilson JN, Scales JT. Endoprosthetic replacement of the proximal humerus. J Bone Joint Surg 1987; 69B: 656-61. 15. Kotz R, Ritschl P, Trachtenbrodt J. A modular femur-tibia reconstruction system. Orthopedics 1986; 9: 1639-52. 16. Wright K. Bioengineering aspects of prosthetic design. In: Coombs RH, Friedlaender GE, eds. Bone tumour management. London: Butterworths, 1987: 134-44. 17. Mankin HJ, Gebhardt MC, Tomford WW. The use of frozen cadaveric allografts in the management of patients with bone tumors of the extremities. Orthop Clin North Am 1987; 18: 275-89. 18. Pelker RR, Friedlaender GE, Markham TC. Biomechanical properties of bone allografts. Clin Orthop 1983; 174: 54-57. 19. Burchardt H. Biology of bone transplantation. Orthop Clin North Am 1987; 18: 187-96. 20. Tomford WW, Doppelt SH, Mankin HJ, Friedlaender GE. Bone bank procedures. Clin Orthop 1983; 174: 15-21.
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21. Lord CF, Gebhardt MC, Tomford WW, Mankin HJ. Infection in bone allografts: incidence, nature and treatment. J Bone Joint Surg 1988; 70A: 369-76. 22. Berrey BH, Lord CF, Gebhardt MC, Mankin HJ. Fractures of allografts: frequency, treatment and end-results. J Bone Joint Surg 1990; 72A: 825-33.
OCCUPATIONAL INFECTION AMONG ANAESTHETISTS Anaesthetists are regularly exposed to blood and body fluids that may carry infectious organisms, of which hepatitis B virus (HBV) and human immunodeficiency virus (HIV) HBV is
highly infectious; minute of blood entering through cuts, mucous membranes, or accidental inoculation are sufficient for disease transmission. The overall risk of contracting hepatitis B from a single needlestick injury contaminated with blood from an infected patient has been estimated to be 5%.’ The fact that anaesthetists have more HBV markers than the general population suggests that occupational infection does occur.2 Immunisation against hepatitis B gives a high level of protection, although the existence of a vaccine-induced escape mutant of the virus has been reported.3 Hepatitis B immune globulin given to nonimmunised subjects after needlestick injury is only partly effective in preventing infection 4 The frequency of HIV infection in the population is not uniform, and people in high-risk groups may have higher than normal hospital attendance rates.5 Although there have been no fully documented cases of accidental HIV infection
cause most concern.
amounts
anaesthetists, such incidents have been reported in other health care workers.5 Infection appears to require the transfer of larger volumes of blood than is the case with HBV,6so one might expect hollow instruments such as the needles used mainly by anaesthetists to be more dangerous than surgical scalpel blades or sewing needles. Most documented occupational HIV transmissions result from needlestick injuries involving blood, but transmission via other body fluids and routes has been reported.5 There is little information about the frequency of seroconversion after occupational exposure to HIV; a figure of 0-4% is widely cited.’ Although the risk of contracting HIV as a result of occupational exposure may be low compared with HBV, the consequences of infection are far more serious: whereas only 2% of people infected with HBV die of the infection6 50% of those infected with HIV will have AIDS within six years.8 There is no protective vaccine against HIV and prompt treatment with zidovudine after needlestick injury has proved ineffective in two cases.9 In the UK, 0-1-0-5% of the population are said to be carriers of HBV, although many more have serological evidence of past infection." For HIV, in 1988 it was reported that 0.1-0-3% of the population were infected;"aa later study12 suggested that the lower figure may be more accurate. Because polymerase chain reaction techniques may pick up those without antibodies, these figures may slightly underestimate the true level of HIV infection.13 Up-to-date information on the extent of exposure of anaesthetists to blood and body fluids is available from independent surveys conducted in two hospitals. The first showed that during the course of 270 anaesthetics, blood from 14% of patients caused skin contamination of 65 people during 46 incidents.14 8% of staff had skin cuts at the time of the events and one needlestick injury occurred among
the survey. In the second survey of 7000 anaesthetics15 the frequency of needlestick injury was 013%, of which two-thirds were with contaminated needles. 20% of the anaesthetists received a needlestick injury during the three-month study. The Association of Anaesthetists10 and the Expert Advisory Group on AIDS’ both advise anaesthetists to wear gloves as a minimum protective measure when there is likely to be contact with blood. The first survey14 showed that glove-wearing varied with procedure from 8% for peripheral venous cannulation to 90% for central venous cannulation. Failure to wear gloves led to many avoidable contamination incidents. Although gloves did not prevent needlestick injury in these surveys, double-gloving has been shown to reduce the frequency of skin contamination from needle punctures.16
during
Only 71 %14 and 74%ls of anaesthetists in these were immunised against HBV, despite the
surveys proven
effectiveness of the vaccine. If these levels of immunisation apply throughout the UK, about 1500 anaesthetists are putting themselves at unnecessary risk of infection. These surveys suggest that many UK anaesthetists are not adopting simple measures to reduce the risk of occupationally acquired infections. Perhaps they are complacent because the risk of a single incident leading to infection is very small. However, the average anaesthetist will treat many thousands of patients during his or her working life, so the cumulative risk of occupationally acquired HIV infection may be as high as 1 in 25. 1. Guidance for Clinical Health Care Workers: protection against infection with HIV and hepatitis viruses. Recommendations of the Expert Advisory Group on AIDS. London: HM Stationery Office, 1990. 2. Berry AJ, Isaacson IJ, Kane MA, et al. A multicentre study of the prevalence of hepatitis B viral serologic markers in anesthesia personnel. Anesth Analg 1984; 63: 738-42. 3. Carman WF, Zanetti AR, Karayiannis P, et al. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990; 336: 325-29. 4. Seeff LB, Wright EC, Zimmerman HJ, et al. Type B hepatitis after needle-stick exposure: prevention with hepatitis B immune globulin. Ann Intern Med 1978; 88: 285-87. 5. Kelen GD. Human immunodeficiency virus and the emergency department: risks and risk protection for health care providers. Ann Emerg Med 1990; 19: 242-48. 6. Morgan DR. HIV and needlestick injuries. Lancet 1990; 335: 1280. 7. Ruthane M, and the CDC Cooperative Needlestick Surveillance Group. Surveillance of health care workers exposed to blood from patients infected with the human immunodeficiency virus. N Engl J Med 1988; 319: 1118-23. 8. Moss AR, Bacchetti P, Osmond D, et al. Seropositivity for HIV and the development of AIDS or AIDS related condition: three year follow up of the San Francisco General Hospital cohort. Br Med J 1988; 296: 745-50. 9. Anon. Zidovudine and needlestick exposure. Lancet 1990; 335: 1271. 10. AIDS and Hepatitis B Guidelines for Anaesthetists. London: Association of Anaesthetists, April, 1989. 11. Wilkie AD. Forecasting AIDS using an actuarial model. In: Cox D. Short-term prediction of HIV infection and AIDS in England and Wales. Report of the working group. London: HM Stationery Office, 1988. 12. Acquired Immune Deficiency Syndrome in England and Wales to end 1993: projections using data to end September 1989. Report of a working group convened by the Director of the Public Health Laboratory Service. London: Public Health Laboratory Service, 1990. 13. Soriano V, Hewlett I, Tor J, Clotet B, Epstein J, Foz M. Silent HIV infection in heterosexual partners of seropositive drug abusers in Spain. Lancet 1990; 335: 860. 14. Harrison CA, Rogers DW, Rosen M. Blood contamination of anaesthetic and related staff. Anaesthesia 1990; 45: 831-33. 15. Maz S, Lyons G. Needlestick injuries in anaesthetists. Anaesthesia 1990; 45: 677-78. 16. Matta H, Thompson AM, Rainey JB. Does wearing two pairs of gloves protect operating theatre staff from skin contamination? Br Med J 1988; 297: 597-98. 17. Jones ME. A thing about AIDS. Anaesth Intens Care 1989; 17: 253-63.