final height (and that includes in my view patients with Turner's syncdrome) chld .c .ren in t.hzese categories should be treated only within the confines of a clinical trial.'4 From recent experience it seems that giving growthz hormone to normal children may result in an increase in final stature of about 4 cm after 10 years of treatment at a cost of £80 000 and the trauma of daily injections.' This hardly seems warranted. A possible way forward in several groups of short children,
1 Hindmarsh PC, Smith PJ, Brook CGD, Matthews DR. The relationship between height velocity and growth hormone secretion in short prepubertal children. Clin Endocnrnol 1987;27:581-91. Darendeliler F, Hindmarsh PC, Brook CGD. Dose response curves for treatment with biosynthetic
2
humangrowthhormone.JEndocrnol1990;125:311-6.
3 Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone
deficiency. N EnglJ MedHagraj 1989;321:1797-803. HS, Gergans GA, Lalitha PY, Goldberg RA, et al. Effects of
4 Rudman DR, Feller AG,
human growth hormone in men over 60 years old. N EnglJ Med 1990;323:1-6.
DW.MCatabolic
recovery.BNEnglJMed991;325:695-702. BMJ1991;303: 1147-8.
illness strategies forenhancing 6 osRJM, Miell JP, Buchanan CR. Avoiding autocannibalism.
5 Wilmore
and girls with Turner's
7 Rosen T, Bengtsson B-A. Premature mortality due to cardiovascular disease in hypopituitarism. 8 Darendeliler F, Hindmarsh PC, Preece MA, Cox L, Brook CGD. Growth hormone increases rate of
syndrome, may be to induce a short term increase in growth
9 Stanhope R, Preece MA, Hamill G. Does growth hormone treatment improve final height
particularly short normal
ones
rate in childhood to alleviate the handicap that short stature in
pubertal maturation. Acta Endocrinol 1990;120:414-6.
attainment of children with intrauterine growth retardation? Arch Dis
Child 1991;66:1180-3.
childhood undoubtedly constitutes. The effect of a short (one 10 Waford E Responzbility for prescribing between hospitals and GPs. London: NHS Management 11 Brook CGD, Hindmarsh PC, Healy MJR. A better way to detect growth failure. BM3r year) course of growth hormone for candidate groups of short 121986;293: chlrnis children CGD,1186. is probably the next clinical question to answer. Hindmarsh PC. Tests for growth hormone secretion. Arch Dis Child 1991;66:85-7. answer.122Brook 13 Shah A, Stanhope R, Matthew D. Hazards of pharmacological tests of growth hormone secretion in
C G D BROOK
Professor of Paediatric Endocrinology, Middlesex Hospital,
London WIN 8AA
childhood. BMJ 1992;304:173-4. 14 Hindmarsh PC, Bridges NA, Brook CGD. Wider indications for treatment with biosynthetic human growth hormone in children. Clin Endocrinol 1991;34:417-27.
15 Albertsson-Wikland K, Karlberg J. Effect of GH treatment in short children on the timing of
puberty and final height. Horm Res 1991;35(suppl 2):32.
Monoclonal antibodies in sepsis and septic shock Recent progress, vast potential Attempts to combat the high mortality from sepsis initially concentrated on patients who were shocked and led to an appreciation that prompt cardiorespiratory resuscitation, including mechanical ventilation, could substantially improve outcome.' Efforts to reduce mortality further by inhibiting inflammatory mediators have so far proved disappointing, but hope now exists that monoclonal antibodies, which can be precisely targeted against individual mediators or their receptors, may allow more effective manipulation of the systemic response to infection. Monoclonal antibodies have been raised against tumour necrosis factor, a cytokine central to the initiation of the inflammatory response, and against tumour necrosis factor receptors.2 Administering antibodies to tumour necrosis factor has produced encouraging results in animal models of septic shock,34 and its safety has been shown in a small phase 1 clinical study.5 Cytokines, however, play an important part in host resistance, and inhibition could impair patients' ability to eradicate infection and increase their susceptibility to secondary sepsis. Conversely, inhibiting only one of the many cytokines involved in the response to infection may not be sufficient. Targeting the toxic products of the infecting organism rather than the endogenous mediators of the inflammatory process might overcome these problems. Directing treatment specifically against circulating endotoxin (the lipopolysaccharide component ofthe bacterial cell wall that is responsible for many of the systemnic responses to Gram negative infection) is now possible by raising antibodies to the structurally conserved core glycolipid of endotoxin, or against lipid A itself, rather than the very immunogenic but variable oligosacchar'ide side chains. Compared wvith treatments directed against inflammatory mediators this approach is obviously limited to cases of Gram negative bacteraemia or endotoxaemia. Encouraging results have been obtained with human polyclonal antiserum directed against endotoxin core determinants,6~8 and the importance of the IgM class of immunoglobulins in providing this protection is now appreciated.9tl0 132
The practical difficulties associated with using polyclonal antiserum have recently been circumvented with monoclonal antibodies such as HA-lA, a human monoclonal IgM antibody that binds specifically to many endotoxins as well as to a broad range of clinical isolates of Gram negative bacteria. After studies showing its efficacy in animal models" 12 and initial evaluations in humans1314 a rigorous multicentre, prospective, randomised controlled trial of HA-lA has recently been completed.15 Five hundred and forty three patients suspected of having Gram negative infection and fulfilling predefined criteria for sepsis were enrolled; in the 200 who were subsequently proved to have had Gram negative bacteraemia HA-IA significantly reduced 28 day mortality by an impressive 39% in the 105 patients receiving the drug and significantly increased the number of patients who were discharged from hospital. These days, however, even the most impeccably designed study inevitably arouses criticism and comment. Concern has been expressed that the mortality of all 543 patients enrolled in the study was not significantly different between the two groups (HA-lA 39%; placebo 43%) and that in those without Gram negative bacteraemia mortality was higher in those given HA-lA (45%) than in the controls (40%) (although this difference was not significant). Others have been concerned by uncertainties about the mechanism of protection by both polyclonal antiserum'6 17 and monoclonal antiendotoxin antibodies,'819 and the specificity of HA-lA for lipid A has been questioned.'9 The lack of efficacy of HA-lA in the 201 patients with Gram negative infection but without bacteraemia is difficult to explain as endotoxaemia often occurs without bacteraemia'2 This also contrasts with the observation that ES, a murine IgM antiendotoxin monoclonal antibody, improved outcome in non-bacteraemic as well as bacteraemic patients with Gram negative infection.2' It is also disconcerting that, in contrast to HA-lA, which was effective irrespective of whether ornot thepatient was shocked,2' ES was ineffective in those with "refractory" shock. These discrepancies may, of course, be due to differences between human and murine BMJ VOLUME 304
18 JANUARY 1992
antibodies as well as differences in the design of the studies, the patient population, and the definition of shock. The importance of resolving these uncertainties is highlighted by the financial implications of the universal introduction of monoclonal antibodies against endotoxin for treating suspected Gram negative sepsis and septic shock. Not only is HA-lA expensive but vast numbers of patients would fulfil even the strictest criteria for its administration: in the United Kingdom there are perhaps 25 000 cases of Gram negative septicaemia each year. 22 Here expenditure on HA-lA could exceed £1 00m a year22; in the United States the annual cost approach$1 16b.23 These figures have caused considerconsidercould approach could These $1-6b.2 figures have caused able alarm, although they are likely to be overestimates and A HA- will analysing the cost effectiveness of treatment wifti
contribution to improving the outcome of life threatening infections. CJ HINDS Director of Intensive Care, St Bartholomew's Hospital, London ECIA 7BE I
biological effects ofmonoclonal antibodies against a human tumor necrosis factor receptor. JExp 3 Hinshaw LB, Tekamp-Olson P, Chang ACK, Lee PA, Taylor FBtoJr,tumor Murray CK, et al. Survival of primates in LD,, shock with necrosis factor 4
save
between 5000 and 10 000 lives a year at a cost of about $5000 per
with other widely accepted medical interventions.
maximise the likeihood of treated patients having Gram
negative bacteraemia or endotoxaemia endtoxaemia and avoid treating negative bacteraemia treating
patients whose prognosis is hopeless.
Categories of patients in whom the efficacy of treatment with antiendotoxins has not been shown (for example those
with neutropenia) should not receive it.24 The criteria used in Ziegler et al's study
seem to
identify patients with
a
30-40%
(TNFo).
Anti-cachectin/TNF
7 Baumgartner J-D, Glauser MP, McCutchan JA, Zeigler EJ, van Melle G, Klauber MR, et al. Prevention of Gram-negative shock and death in surgical patients by antibody to endotoxin core glycolipid. Lancet 1985;ii:59-63. 8 Schedel I, Dreikhausen U, Nentwig B, Hockenschnieder M, Rauthmann D, Balikcioglu S, et al.
life year saved, an amount that compares very favourably
Some will consider that, particularly in view of the financial implications, introducing treatment with monoclonal antibodies directed against endotoxins should be delayed until confirmatory studies have been performed and some of the uncertainties resolved . Certainly those who wish to introduce HA-lA into their clinical practice on the basis of current evidence must ensure that it is not used indiscriminately.24 The decision to give HA-lA should be taken by experienced intensive care clinicians guided by strict protocols designed to
septic following therapy antibody Circ Shock 1990;30:279-92. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, et al.
monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987;330:662-4. 5 Exley AR, Cohen J, Buurman W, Owen R, Hanson G, Lumley J, et al. Monoclonal antibody to TNF in severe septic shock. Lancet 1990;33S: 1275-6. 6 Ziegler EJ, McCutchan JA, Fierer J, Glauser MP, SadoffJC, Douglas H, et al. Treatment of Gramnegative bacteremia and shock with human antiserum to a mutant Escherichia coli. N EnglJ Med
be imiiportant before concluding that these high costscannot
be justified. In the United Kingdom HA- 1 A might
Ledingham lMcA, McArdle CS. Prospective study of the treatment of septic shock. Lancet
2 Espevik T, Brockhaus M, Loetscher H, Nonstad U, Shalaby R. Characterization of binding and
Treatment of Gram-negative septic shock with an immunoglobulin randomized clinical trial. Crit Care Med 1991 19:1104-13.
preparation: a prospective
9 Calandra T, Glauser MP, Schellekens J, Verhoef J. Treatment of Gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, double-blind, randomized trial. 10
11
McCabe WR, De Maria A Jr, Berberich H, Johns MA. Immunization with rough mutants of salmonella minnesota: prospective activity of IgM and IgG antibody to the R595 (Re Chemotype) mutant. J Infect Dis 1988;158:291-300.
Teng NNH, Kaplan HS, Herbert JM, Moore C, Douglas H, Wunderlich A, et al. Protection against Gram-negative bacteremia and endotoxemia with human monoclonal IgM antibodies.
Proc NatlAcadSci USA 1985;82:1790-4.
12 Ziegler EJ, Teng NNH, Douglas H, Wunderlich A, Berger JH, Bolmer SD. Treatment of pseudomonas bacteria in neutropenic rabbits with human monoclonal IgM antibody against E
coli lipid A. Clin Res 1987;35:619A.
13 Khazaeali MB, Wheeler R, Rogers K, Ziegler E, Haynes A, et al. Initial evvaluation of a human immunoglobuln M monoclonal antibody (HA-lA) in humans. J Biol Response Mod 1990;9:178-84. 14 Fishe CjZmera J, Yhazaeli MB, Albertson TE, Dellinger RP, Panacek EA, et al. Initial evaluation of human monoclonal anti-lipid A antibody (HA-lA) in pautents with sepsis 15
syndrome. CritCareMed 1990;18:1311-5.
Ziegler EJ, Fisher CJ, Sprung CL, Straube RC, Sadoff JC, Foulke GE, et al. Treatment of Gram-
negative bacteremia and septic shock with HA-lA human monoclonal antibody against
endotoxin. NEnglJMed 1991;324:429-36.
16 Baumgartner JD, Heumann D, Calandra T, Glauser MP. Antibodies to lipopolysaccharides after immunisation of humans with the rough mutant Escherichia coli J5. J Infect Dis
probability of having Gram negative bacteraemia,ts but
1
careful clinical assessment increasing this proportion by more r- a- * s ss *s s s s s s s
charide determinants: absence of cross reactivity with heterologous lipopolysaccharides. J Infect 1991-163:762-8. ~~~~~~~~~~~~~Dis 18 Baumgartner JD. Heumann D, Gerain J, Weinbreck P, Grau GE, Glauser MP. Association
of individual cases may be possible. Clearly, the development
of new techniques for reliably and rapidly diagnosing endotoxaemia and Gram negative bacteraemia would resolve many of the difficulties. In the future it should be possible to produce monoclonal antibodies againstoother ther toxic products antibodies against products of of infecting infecting organorgan-
isms,
as
well
as
other
components
of the inflammatory
cascade. Treatment with a combination of monoclonal anti-
bodies will then be feasible. Although still in its infancy, the use of monoclonal antibodies is likely to make animportant
17
1991;163:769-72.
Heumann D,
Baumgartner JD, Jacto-Guillarmod H, Glauser MP. Antibodies to core lipopolysac-
between protective efficacy of anti-lipopolysaccharide (LPS) antibodies and suppression of LPS-
induced tumor necrosis factor a and interleukin 6. Comparison of 0 side chain-specific
antibodies and core LPS antibodies. J Exp Med 1990;171:889-96.
HA-1A
19 Baumgartner JD, Heumann D, Glauser MP. The monoclonal antibody for Gram-negative sepsis (letter). N Engl!JMed 1991;325:281-2. 20 Danner RL, Elin RJ, Hosseini JM, Wesley RA, Reilly JM, Parillo JE. Endotoxin in human septic shock. Chtest 1991;99:169-75. 21 Greenman RL, Schein RMH, Martin MA, Wenzel RP, Maclntyre NR, Emmanuel G, et al. A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of Gram-negative sepsis. JAMA 1991;266:1097-102. 22 Taylor D. Centoxin-birth of a budgetbuster. BMJ 1991;302:1229.
23 Schmidt GA. The HA-lA monoclonal antibody for Gram-negative sepsis (letter). N EnglJ Med 1991;325:280-1. 24 Bone RC. Monoclonalantibodiestoendotoxin. New allies against sepsis?JAMA 1991;266:1125-6.
FHSA medical advisers: friends or foes? A role with a lot ofpromise The medical advisers to family health services authorities were originally intended to help implement the indicative prescribing scheme and to provide advice on prescribing to both general practitioners and the family health services authority.t In fact, in many authorities the medical adviser has a much wider remit. General practitioners were originally suspicious of the part medical advisers were to play in prescribing, but in the long term they may come to welcome their role in developing general practice. Funding for "a prescribing medical. adviser" in each family BMJ
VOLUME
304
18 JANUARY 1992
health services authority was provided by the Department of Health as part of the "improving prescribing" initiative,2 but managers had some discretion on how to use the funding, so that only 47 of the 124 advisers are full time and advice has also been purchased from directors of public health, academic departments ofgeneralpractice, and other specialists, such as community paediatricians. The late appointment of many advisers and the early deadlines for setting indicative prescribing amounts meant t-hat the discussion between advisers and general practitioners were less than desired by either side. 133
1 Hindmarsh PC, Smith PJ, Brook CGD, Matthews DR. The relationship between height velocity and growth hormone secretion in short prepubertal children. Clin Endocnrnol 1987;27:581-91. Darendeliler F, Hindmarsh PC, Brook CGD. Dose response curves for treatment with biosynthetic
2
humangrowthhormone.JEndocrnol1990;125:311-6.
3 Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone
deficiency. N EnglJ MedHagraj 1989;321:1797-803. HS, Gergans GA, Lalitha PY, Goldberg RA, et al. Effects of
4 Rudman DR, Feller AG,
human growth hormone in men over 60 years old. N EnglJ Med 1990;323:1-6.
DW.MCatabolic
recovery.BNEnglJMed991;325:695-702. BMJ1991;303: 1147-8.
illness strategies forenhancing 6 osRJM, Miell JP, Buchanan CR. Avoiding autocannibalism.
5 Wilmore
and girls with Turner's
7 Rosen T, Bengtsson B-A. Premature mortality due to cardiovascular disease in hypopituitarism. 8 Darendeliler F, Hindmarsh PC, Preece MA, Cox L, Brook CGD. Growth hormone increases rate of
syndrome, may be to induce a short term increase in growth
9 Stanhope R, Preece MA, Hamill G. Does growth hormone treatment improve final height
particularly short normal
ones
rate in childhood to alleviate the handicap that short stature in
pubertal maturation. Acta Endocrinol 1990;120:414-6.
attainment of children with intrauterine growth retardation? Arch Dis
Child 1991;66:1180-3.
childhood undoubtedly constitutes. The effect of a short (one 10 Waford E Responzbility for prescribing between hospitals and GPs. London: NHS Management 11 Brook CGD, Hindmarsh PC, Healy MJR. A better way to detect growth failure. BM3r year) course of growth hormone for candidate groups of short 121986;293: chlrnis children CGD,1186. is probably the next clinical question to answer. Hindmarsh PC. Tests for growth hormone secretion. Arch Dis Child 1991;66:85-7. answer.122Brook 13 Shah A, Stanhope R, Matthew D. Hazards of pharmacological tests of growth hormone secretion in
C G D BROOK
Professor of Paediatric Endocrinology, Middlesex Hospital,
London WIN 8AA
childhood. BMJ 1992;304:173-4. 14 Hindmarsh PC, Bridges NA, Brook CGD. Wider indications for treatment with biosynthetic human growth hormone in children. Clin Endocrinol 1991;34:417-27.
15 Albertsson-Wikland K, Karlberg J. Effect of GH treatment in short children on the timing of
puberty and final height. Horm Res 1991;35(suppl 2):32.
Monoclonal antibodies in sepsis and septic shock Recent progress, vast potential Attempts to combat the high mortality from sepsis initially concentrated on patients who were shocked and led to an appreciation that prompt cardiorespiratory resuscitation, including mechanical ventilation, could substantially improve outcome.' Efforts to reduce mortality further by inhibiting inflammatory mediators have so far proved disappointing, but hope now exists that monoclonal antibodies, which can be precisely targeted against individual mediators or their receptors, may allow more effective manipulation of the systemic response to infection. Monoclonal antibodies have been raised against tumour necrosis factor, a cytokine central to the initiation of the inflammatory response, and against tumour necrosis factor receptors.2 Administering antibodies to tumour necrosis factor has produced encouraging results in animal models of septic shock,34 and its safety has been shown in a small phase 1 clinical study.5 Cytokines, however, play an important part in host resistance, and inhibition could impair patients' ability to eradicate infection and increase their susceptibility to secondary sepsis. Conversely, inhibiting only one of the many cytokines involved in the response to infection may not be sufficient. Targeting the toxic products of the infecting organism rather than the endogenous mediators of the inflammatory process might overcome these problems. Directing treatment specifically against circulating endotoxin (the lipopolysaccharide component ofthe bacterial cell wall that is responsible for many of the systemnic responses to Gram negative infection) is now possible by raising antibodies to the structurally conserved core glycolipid of endotoxin, or against lipid A itself, rather than the very immunogenic but variable oligosacchar'ide side chains. Compared wvith treatments directed against inflammatory mediators this approach is obviously limited to cases of Gram negative bacteraemia or endotoxaemia. Encouraging results have been obtained with human polyclonal antiserum directed against endotoxin core determinants,6~8 and the importance of the IgM class of immunoglobulins in providing this protection is now appreciated.9tl0 132
The practical difficulties associated with using polyclonal antiserum have recently been circumvented with monoclonal antibodies such as HA-lA, a human monoclonal IgM antibody that binds specifically to many endotoxins as well as to a broad range of clinical isolates of Gram negative bacteria. After studies showing its efficacy in animal models" 12 and initial evaluations in humans1314 a rigorous multicentre, prospective, randomised controlled trial of HA-lA has recently been completed.15 Five hundred and forty three patients suspected of having Gram negative infection and fulfilling predefined criteria for sepsis were enrolled; in the 200 who were subsequently proved to have had Gram negative bacteraemia HA-IA significantly reduced 28 day mortality by an impressive 39% in the 105 patients receiving the drug and significantly increased the number of patients who were discharged from hospital. These days, however, even the most impeccably designed study inevitably arouses criticism and comment. Concern has been expressed that the mortality of all 543 patients enrolled in the study was not significantly different between the two groups (HA-lA 39%; placebo 43%) and that in those without Gram negative bacteraemia mortality was higher in those given HA-lA (45%) than in the controls (40%) (although this difference was not significant). Others have been concerned by uncertainties about the mechanism of protection by both polyclonal antiserum'6 17 and monoclonal antiendotoxin antibodies,'819 and the specificity of HA-lA for lipid A has been questioned.'9 The lack of efficacy of HA-lA in the 201 patients with Gram negative infection but without bacteraemia is difficult to explain as endotoxaemia often occurs without bacteraemia'2 This also contrasts with the observation that ES, a murine IgM antiendotoxin monoclonal antibody, improved outcome in non-bacteraemic as well as bacteraemic patients with Gram negative infection.2' It is also disconcerting that, in contrast to HA-lA, which was effective irrespective of whether ornot thepatient was shocked,2' ES was ineffective in those with "refractory" shock. These discrepancies may, of course, be due to differences between human and murine BMJ VOLUME 304
18 JANUARY 1992
antibodies as well as differences in the design of the studies, the patient population, and the definition of shock. The importance of resolving these uncertainties is highlighted by the financial implications of the universal introduction of monoclonal antibodies against endotoxin for treating suspected Gram negative sepsis and septic shock. Not only is HA-lA expensive but vast numbers of patients would fulfil even the strictest criteria for its administration: in the United Kingdom there are perhaps 25 000 cases of Gram negative septicaemia each year. 22 Here expenditure on HA-lA could exceed £1 00m a year22; in the United States the annual cost approach$1 16b.23 These figures have caused considerconsidercould approach could These $1-6b.2 figures have caused able alarm, although they are likely to be overestimates and A HA- will analysing the cost effectiveness of treatment wifti
contribution to improving the outcome of life threatening infections. CJ HINDS Director of Intensive Care, St Bartholomew's Hospital, London ECIA 7BE I
biological effects ofmonoclonal antibodies against a human tumor necrosis factor receptor. JExp 3 Hinshaw LB, Tekamp-Olson P, Chang ACK, Lee PA, Taylor FBtoJr,tumor Murray CK, et al. Survival of primates in LD,, shock with necrosis factor 4
save
between 5000 and 10 000 lives a year at a cost of about $5000 per
with other widely accepted medical interventions.
maximise the likeihood of treated patients having Gram
negative bacteraemia or endotoxaemia endtoxaemia and avoid treating negative bacteraemia treating
patients whose prognosis is hopeless.
Categories of patients in whom the efficacy of treatment with antiendotoxins has not been shown (for example those
with neutropenia) should not receive it.24 The criteria used in Ziegler et al's study
seem to
identify patients with
a
30-40%
(TNFo).
Anti-cachectin/TNF
7 Baumgartner J-D, Glauser MP, McCutchan JA, Zeigler EJ, van Melle G, Klauber MR, et al. Prevention of Gram-negative shock and death in surgical patients by antibody to endotoxin core glycolipid. Lancet 1985;ii:59-63. 8 Schedel I, Dreikhausen U, Nentwig B, Hockenschnieder M, Rauthmann D, Balikcioglu S, et al.
life year saved, an amount that compares very favourably
Some will consider that, particularly in view of the financial implications, introducing treatment with monoclonal antibodies directed against endotoxins should be delayed until confirmatory studies have been performed and some of the uncertainties resolved . Certainly those who wish to introduce HA-lA into their clinical practice on the basis of current evidence must ensure that it is not used indiscriminately.24 The decision to give HA-lA should be taken by experienced intensive care clinicians guided by strict protocols designed to
septic following therapy antibody Circ Shock 1990;30:279-92. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, et al.
monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987;330:662-4. 5 Exley AR, Cohen J, Buurman W, Owen R, Hanson G, Lumley J, et al. Monoclonal antibody to TNF in severe septic shock. Lancet 1990;33S: 1275-6. 6 Ziegler EJ, McCutchan JA, Fierer J, Glauser MP, SadoffJC, Douglas H, et al. Treatment of Gramnegative bacteremia and shock with human antiserum to a mutant Escherichia coli. N EnglJ Med
be imiiportant before concluding that these high costscannot
be justified. In the United Kingdom HA- 1 A might
Ledingham lMcA, McArdle CS. Prospective study of the treatment of septic shock. Lancet
2 Espevik T, Brockhaus M, Loetscher H, Nonstad U, Shalaby R. Characterization of binding and
Treatment of Gram-negative septic shock with an immunoglobulin randomized clinical trial. Crit Care Med 1991 19:1104-13.
preparation: a prospective
9 Calandra T, Glauser MP, Schellekens J, Verhoef J. Treatment of Gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, double-blind, randomized trial. 10
11
McCabe WR, De Maria A Jr, Berberich H, Johns MA. Immunization with rough mutants of salmonella minnesota: prospective activity of IgM and IgG antibody to the R595 (Re Chemotype) mutant. J Infect Dis 1988;158:291-300.
Teng NNH, Kaplan HS, Herbert JM, Moore C, Douglas H, Wunderlich A, et al. Protection against Gram-negative bacteremia and endotoxemia with human monoclonal IgM antibodies.
Proc NatlAcadSci USA 1985;82:1790-4.
12 Ziegler EJ, Teng NNH, Douglas H, Wunderlich A, Berger JH, Bolmer SD. Treatment of pseudomonas bacteria in neutropenic rabbits with human monoclonal IgM antibody against E
coli lipid A. Clin Res 1987;35:619A.
13 Khazaeali MB, Wheeler R, Rogers K, Ziegler E, Haynes A, et al. Initial evvaluation of a human immunoglobuln M monoclonal antibody (HA-lA) in humans. J Biol Response Mod 1990;9:178-84. 14 Fishe CjZmera J, Yhazaeli MB, Albertson TE, Dellinger RP, Panacek EA, et al. Initial evaluation of human monoclonal anti-lipid A antibody (HA-lA) in pautents with sepsis 15
syndrome. CritCareMed 1990;18:1311-5.
Ziegler EJ, Fisher CJ, Sprung CL, Straube RC, Sadoff JC, Foulke GE, et al. Treatment of Gram-
negative bacteremia and septic shock with HA-lA human monoclonal antibody against
endotoxin. NEnglJMed 1991;324:429-36.
16 Baumgartner JD, Heumann D, Calandra T, Glauser MP. Antibodies to lipopolysaccharides after immunisation of humans with the rough mutant Escherichia coli J5. J Infect Dis
probability of having Gram negative bacteraemia,ts but
1
careful clinical assessment increasing this proportion by more r- a- * s ss *s s s s s s s
charide determinants: absence of cross reactivity with heterologous lipopolysaccharides. J Infect 1991-163:762-8. ~~~~~~~~~~~~~Dis 18 Baumgartner JD. Heumann D, Gerain J, Weinbreck P, Grau GE, Glauser MP. Association
of individual cases may be possible. Clearly, the development
of new techniques for reliably and rapidly diagnosing endotoxaemia and Gram negative bacteraemia would resolve many of the difficulties. In the future it should be possible to produce monoclonal antibodies againstoother ther toxic products antibodies against products of of infecting infecting organorgan-
isms,
as
well
as
other
components
of the inflammatory
cascade. Treatment with a combination of monoclonal anti-
bodies will then be feasible. Although still in its infancy, the use of monoclonal antibodies is likely to make animportant
17
1991;163:769-72.
Heumann D,
Baumgartner JD, Jacto-Guillarmod H, Glauser MP. Antibodies to core lipopolysac-
between protective efficacy of anti-lipopolysaccharide (LPS) antibodies and suppression of LPS-
induced tumor necrosis factor a and interleukin 6. Comparison of 0 side chain-specific
antibodies and core LPS antibodies. J Exp Med 1990;171:889-96.
HA-1A
19 Baumgartner JD, Heumann D, Glauser MP. The monoclonal antibody for Gram-negative sepsis (letter). N Engl!JMed 1991;325:281-2. 20 Danner RL, Elin RJ, Hosseini JM, Wesley RA, Reilly JM, Parillo JE. Endotoxin in human septic shock. Chtest 1991;99:169-75. 21 Greenman RL, Schein RMH, Martin MA, Wenzel RP, Maclntyre NR, Emmanuel G, et al. A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of Gram-negative sepsis. JAMA 1991;266:1097-102. 22 Taylor D. Centoxin-birth of a budgetbuster. BMJ 1991;302:1229.
23 Schmidt GA. The HA-lA monoclonal antibody for Gram-negative sepsis (letter). N EnglJ Med 1991;325:280-1. 24 Bone RC. Monoclonalantibodiestoendotoxin. New allies against sepsis?JAMA 1991;266:1125-6.
FHSA medical advisers: friends or foes? A role with a lot ofpromise The medical advisers to family health services authorities were originally intended to help implement the indicative prescribing scheme and to provide advice on prescribing to both general practitioners and the family health services authority.t In fact, in many authorities the medical adviser has a much wider remit. General practitioners were originally suspicious of the part medical advisers were to play in prescribing, but in the long term they may come to welcome their role in developing general practice. Funding for "a prescribing medical. adviser" in each family BMJ
VOLUME
304
18 JANUARY 1992
health services authority was provided by the Department of Health as part of the "improving prescribing" initiative,2 but managers had some discretion on how to use the funding, so that only 47 of the 124 advisers are full time and advice has also been purchased from directors of public health, academic departments ofgeneralpractice, and other specialists, such as community paediatricians. The late appointment of many advisers and the early deadlines for setting indicative prescribing amounts meant t-hat the discussion between advisers and general practitioners were less than desired by either side. 133
