398
14. Astrup P. Some physiological and pathological effects of moderate carbon monoxide exposure. Br Med J 1972; 4: 447-52. 15. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985; 312: 82-90. 16. Armstrong JRM, Campbell H. Indoor air pollution exposure and lower respiratory infections in young Gambian children. Int J Epidemiol 1991; 20: 424-29. 17. Pandey MR, Neupane RP, Gautam A, Shrestha IB. Domestic smoke pollution and acute respiratory infections in a rural community of the hill region of Nepal. Environ Int 1989; 15: 337-40. 18. Collings DA, Sithole SD, Martin KS. Indoor woodsmoke pollution causing lower respiratory disease in children. Trop Doctor 1990; 20: 151-55. 19. Morris K, Morganlander M, Coulehan JL, Gahagen S, Arena VC. Wood-burning stoves and lower respiratory tract infection in American Indian children. Am J Dis Child 1990; 144: 105-08.
Vesicoureteric reflux and
nephropathy Reflux nephropathy is responsible for renal failure in 25% of children entering the European dialysis and transplantation programme1 and is one of the main causes of hypertension in children and young adults.It is widely believed that this disorder results from vesicoureteric and intrarenal reflux of infected urine; it is also possible that reflux nephropathy is not a homogeneous condition but the final common pathway of many types of renal tract
dysfunction. Anderson and Rickwood3investigated the finding of renal tract dilatation detected by antenatal ultrasonography, and identified a group of infants (90% of whom were boys) with serious renal tract abnormalities. On cystography, usually with 1 month of birth, of 34 infants with primary vesicoureteric reflux (VUR), about 65% had severe reflux (grade IV or V).4 29% had associated genitourinary abnormalities such as complete duplex system, pelviureteric junction obstruction, and solitary kidney. These infants differ from most children with VUR, among whom girls outnumber boys five to one,’’ those affected are older, and the clinical course is more
benign.
Antenatal sonography detects pelviureteric dilatation and so can only identify infants with grade III VUR or worse. Whilst this fact may account for the predominance of cases with severe reflux it does not explain other features such as the male preponderance and the high frequency of associated abnormalities. Likewise, antenatal detection of VUR does not explain why a significant proportion of such infants have renal perfusion defects as detected by 99Tc dimercaptosuccinic acid (DMSA) renography. Thus Anderson and Rickwood found that DMSA scans done at 1-3 months of age were abnormal in more than 75% of boys with antenatally detected reflux, 80% of whom had never experienced a urinary tract infection (with or without clinical features). It is reasonable to conclude that this high frequency of abnormal DMSA scans is an accurate representation of the state of the kidneys at birth and that most of the renal perfusion defects detected in infancy are the
result of dysplasia rather than infection. These findings accord with those of Najmaldin et al,who reported that antenatally detected reflux was associated with a 65% incidence of reduction in renal function despite the absence of urinary tract infection in all but 2 of 14 patients. Another feature in Anderson and Rickwood’s patients was the histological appearance of severe dysplasia and growth arrest rather than the scarring of reflux and infection in the few who underwent nephrectomy. Several research groups have used DMSA imaging to study children with urinary tract infection and have found a low frequency of progressive scarring despite proven repeated infections.7,8 One interpretation is that most renal scarring occurs at the time of initial infection. Perhaps these scars are renal perfusion defects of prenatal origin,9 noted incidentally when children with renal tract abnormalities present with infection. It had been hoped that routine ultrasound scanning might detect dilatation antenatally, 10 but this does not seem to be the case. In a prospective study, Gunn et al11 did routine ultrasound scanning of 3228 fetuses at 16-20 weeks’ gestation and repeated the scans if there were obstetric indications (761 fetuses). No renal tract abnormalities were detected before 28 weeks’ gestation, even in fetuses with urinary tract abnormalities on later scans. Subsequent ultrasound scans of these 761 fetuses revealed dilatation of the renal pelvis in 8%. Postnatally, 10 (16%) of these infants were found to have serious renal tract abnormalities-5 had pelviureteric junction 2 had and 3 died of associated VUR, obstruction, serious congenital abnormalities. To provide a screening service it would therefore be necessary to repeat ultrasound examinations on all fetuses at more than 28 weeks’ gestation. This strategy would identify otherwise unsuspected renal tract abnormalities in 9-2/1000 (7 of 761) infants, or possibly fewer if the whole population was screened and not merely those with adverse obstetric factors. The small group of male infants identified antenatally is important in terms of individual morbidity, but is not representative of the majority of children (usually girls) with reflux. Closer consideration of this larger group shows that they may have evidence of renal tract dysfunction. In a prospective study12 videourodynamic examinations were done in children with reflux and the results were compared before and during anticholinergic therapy (oxybutynin), with controls receiving oxyphenonium bromide or antibiotic prophylaxis alone. Before treatment, bladder instability was present in 40%. Oxybutynin significantly decreased the strength of detrusor contraction during voiding and detrusor pressure at maximum flow rate. These changes were accompanied by a significant decrease in VUR in 8 of 9 kidneys with reflux, which was not seen in controls. The importance of functional obstruction is further emphasised by the finding that nearly two-thirds of
399
children with symptoms of bladder instability and recurrent urinary tract infection can be maintained infection-free by treatment of their unstable contractions alone.13 This improvement in bladder dysfunction is associated with resolution of VUR in 44% of ureters and with improvement to grade I (minor VUR) in a further 16 % .14 Thus paediatricians should take a careful history of bladder function in their clinical assessment of children with urinary tract infection so as not to overlook a potentially treatable cause. Use of less invasive methods of investigation such as colour doppler ultrasound15 should be
encouraged. 1. Hodson CJ. Reflux nephropathy: scoring the damage. In: Hodson J, Kincaid-Smith P, eds. Reflux neuropathy. New York: Masson, 1979: 29-47. 2. Savage JM, Dillon MJ, Shah V, Barratt TM, Williams DI. Renin and blood-pressure in children with renal scarring and vesicoureteric reflux. Lancet 1978; ii: 441-44. 3. Anderson PAM, Rickwood AMK. Features of primary vesicoureteric reflux detected by prenatal sonography. Br J Urol 1991; 67: 267-71. 4. International Reflux Study Committee. Medical versus surgical management of primary vesicoureteral reflux: a prospective international study in children. J Urol 1981; 125: 277-83. 5. Kincaid-Smith P, Becker G. Reflux nephropathy and chronic pyelonephritis: a review. J Infect Dis 1978; 138: 774-80. 6. Naljmaldin A, Burge DM, Atwell JD. Reflux nephropathy secondary to intrauterine vesicoureteric reflux. J Pediatr Surg 1990; 25: 387-90. 7. Smellie JM. Urinary tract infection in childhood. Br J Hosp Med 1974; 12: 485-94. 8. Ransley PB. Vesicoureteric reflux: continuing surgical dilemma. Urology
1978; 12: 246-55. 9. Editorial. Vesicoureteric reflux: more puzzles. Lancet 1983; ii: 1467-68. 10. Editorial. Prevention of reflux nephropathy. Lancet 1991; 338: 1050. 11. Gunn TR, Mora JD, Pease P. Outcome after antenatal diagnosis of upper urinary tract dilatation by ultrasonography. Arch Dis Child 1988; 63: 1240-43. 12. Scholtmeizer RJ, Van Mastrigt R. The effect of oxyphenonium bromide
and oxybutinin hydrochloride on detrusor contractility and reflux in children with vesicoureteral reflux and detrusor instability. J Urol 1991; 146: 660-62. 13. Koff SA, Lapides J, Piazza DH. Association of urinary tract infection and reflux with uninhibited bladder contractions and voluntary sphincteric obstruction. J Urol 1979; 122: 373-76. 14. Koff SA, Murtagh DS. The uninhibited bladder in children: effect of treatment on vesicoureteral reflux resolution. J Urol 1983; 130: 1138-41. 15. Marshall JL, Johnson ND, DeCampo MP. Vesicoureteric reflux in children: prediction with colour doppler imaging. Radiology 1990; 175: 355-58.
Ethical
emergencies
issue of Dec 21/28 we published two encouraging reports on the effects of nitric oxide inhibition in septic shock and liver failure.1.2 Petros and colleagues1 used specific inhibitors of nitric oxide synthase to increase vascular resistance and blood pressure. Midgley and co-workers2 described their experience with methylene blue, another antagonist of the actions of nitric oxide, in a hypotensive patient with liver failure. The possible clinical relevance of these observations was discussed in an accompanying editorial.3 These reports deserve attention for an entirely different reason. The issue at stake is the use of "unconventional" treatment in emergencies. Petros et al obtained ethical committee approval whereas Midgley et al, in their last-ditch attempt to help a In
our
dying patient, obtained consent from the patient’s wife but did not contact their ethics committee. A not dissimilar case, where the adult patient’s father gave consent, appears on p 435. Methylene blue is an established agent in the treatment of methaemoglobinaemia. Although it has been reported to cause adverse cardiovascular and haemolytic reactions,4the risks associated with its use for accepted indications are probably low. When a patient is in extremis, it could be argued that there is little opportunity for worsening the outcome and so the balance of the risk-benefit equation, even for a novel use of the agent, is tipped in favour of action. Can one justify this view? In similar emergencies, should doctors do more than seek permission from the patient’s closest relatives? The guidelines of the Royal College of Physicians of London state that research in severely ill or unconscious patients requires ethical committee permission to proceed in the absence of the patient’s consent.Unfortunately, there is ambiguity in the term "research". "Innovative therapy", where a clinician departs substantially from accepted practice for the benefit of a particular patient, need not, we are told, be classified as "research", which also implies the quest for generalisable knowledge. An attempt to distinguish between innovative therapy and research in this way is simplistic. Generalisable knowledge is acquired on the basis of individual cases. Innovative therapy is undertaken for the benefit of individual patients, but also to test its efficacy for use in others. The Helsinki Declaration takes a less judgmental line: "In the treatment of the sick person, the doctor must be free to use a new diagnostic and therapeutic measure if in his or her judgment it offers hope of saving life, re-establishing health or alleviating
suffering". There will always be qualms about testing innovative therapy in terminally ill patients; qualms which consent from despairing relatives cannot wholly stifle. Yet there is usually no obvious mechanism for "sounding out" an ethics committee with a vague proposal "just in case". Few would criticise clinicians on ethical grounds for an imaginative attempt to help someone who was critically ill. For the advance of knowledge and patient care, it is no substitute, however, for a planned study meeting previously defined criteria. Ethics committees, when evaluating formal protocols, would do well nonetheless to give some thought to policy on
emergencies. 1. Petros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 1991; 338: 1557-58. 2. Midgley S, Grant IS, Haynes WG, Webb DJ. Nitric oxide in liver failure. Lancet 1991; 338: 1590. 3. Editorial. Nitric oxide in the clinical arena. Lancet 1991; 338: 1560-62. 4. Anon. Methylene blue. In: Dollery C, ed. Therapeutic Drugs. Edinburgh: Churchill Livingstone, 1991: M127-28. 5. Royal College of Physicians Working Party. Guidelines on the practice of ethics committees in medical research involving human subjects. 2nd ed. London: Royal College of Physicians, 1990.
14. Astrup P. Some physiological and pathological effects of moderate carbon monoxide exposure. Br Med J 1972; 4: 447-52. 15. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985; 312: 82-90. 16. Armstrong JRM, Campbell H. Indoor air pollution exposure and lower respiratory infections in young Gambian children. Int J Epidemiol 1991; 20: 424-29. 17. Pandey MR, Neupane RP, Gautam A, Shrestha IB. Domestic smoke pollution and acute respiratory infections in a rural community of the hill region of Nepal. Environ Int 1989; 15: 337-40. 18. Collings DA, Sithole SD, Martin KS. Indoor woodsmoke pollution causing lower respiratory disease in children. Trop Doctor 1990; 20: 151-55. 19. Morris K, Morganlander M, Coulehan JL, Gahagen S, Arena VC. Wood-burning stoves and lower respiratory tract infection in American Indian children. Am J Dis Child 1990; 144: 105-08.
Vesicoureteric reflux and
nephropathy Reflux nephropathy is responsible for renal failure in 25% of children entering the European dialysis and transplantation programme1 and is one of the main causes of hypertension in children and young adults.It is widely believed that this disorder results from vesicoureteric and intrarenal reflux of infected urine; it is also possible that reflux nephropathy is not a homogeneous condition but the final common pathway of many types of renal tract
dysfunction. Anderson and Rickwood3investigated the finding of renal tract dilatation detected by antenatal ultrasonography, and identified a group of infants (90% of whom were boys) with serious renal tract abnormalities. On cystography, usually with 1 month of birth, of 34 infants with primary vesicoureteric reflux (VUR), about 65% had severe reflux (grade IV or V).4 29% had associated genitourinary abnormalities such as complete duplex system, pelviureteric junction obstruction, and solitary kidney. These infants differ from most children with VUR, among whom girls outnumber boys five to one,’’ those affected are older, and the clinical course is more
benign.
Antenatal sonography detects pelviureteric dilatation and so can only identify infants with grade III VUR or worse. Whilst this fact may account for the predominance of cases with severe reflux it does not explain other features such as the male preponderance and the high frequency of associated abnormalities. Likewise, antenatal detection of VUR does not explain why a significant proportion of such infants have renal perfusion defects as detected by 99Tc dimercaptosuccinic acid (DMSA) renography. Thus Anderson and Rickwood found that DMSA scans done at 1-3 months of age were abnormal in more than 75% of boys with antenatally detected reflux, 80% of whom had never experienced a urinary tract infection (with or without clinical features). It is reasonable to conclude that this high frequency of abnormal DMSA scans is an accurate representation of the state of the kidneys at birth and that most of the renal perfusion defects detected in infancy are the
result of dysplasia rather than infection. These findings accord with those of Najmaldin et al,who reported that antenatally detected reflux was associated with a 65% incidence of reduction in renal function despite the absence of urinary tract infection in all but 2 of 14 patients. Another feature in Anderson and Rickwood’s patients was the histological appearance of severe dysplasia and growth arrest rather than the scarring of reflux and infection in the few who underwent nephrectomy. Several research groups have used DMSA imaging to study children with urinary tract infection and have found a low frequency of progressive scarring despite proven repeated infections.7,8 One interpretation is that most renal scarring occurs at the time of initial infection. Perhaps these scars are renal perfusion defects of prenatal origin,9 noted incidentally when children with renal tract abnormalities present with infection. It had been hoped that routine ultrasound scanning might detect dilatation antenatally, 10 but this does not seem to be the case. In a prospective study, Gunn et al11 did routine ultrasound scanning of 3228 fetuses at 16-20 weeks’ gestation and repeated the scans if there were obstetric indications (761 fetuses). No renal tract abnormalities were detected before 28 weeks’ gestation, even in fetuses with urinary tract abnormalities on later scans. Subsequent ultrasound scans of these 761 fetuses revealed dilatation of the renal pelvis in 8%. Postnatally, 10 (16%) of these infants were found to have serious renal tract abnormalities-5 had pelviureteric junction 2 had and 3 died of associated VUR, obstruction, serious congenital abnormalities. To provide a screening service it would therefore be necessary to repeat ultrasound examinations on all fetuses at more than 28 weeks’ gestation. This strategy would identify otherwise unsuspected renal tract abnormalities in 9-2/1000 (7 of 761) infants, or possibly fewer if the whole population was screened and not merely those with adverse obstetric factors. The small group of male infants identified antenatally is important in terms of individual morbidity, but is not representative of the majority of children (usually girls) with reflux. Closer consideration of this larger group shows that they may have evidence of renal tract dysfunction. In a prospective study12 videourodynamic examinations were done in children with reflux and the results were compared before and during anticholinergic therapy (oxybutynin), with controls receiving oxyphenonium bromide or antibiotic prophylaxis alone. Before treatment, bladder instability was present in 40%. Oxybutynin significantly decreased the strength of detrusor contraction during voiding and detrusor pressure at maximum flow rate. These changes were accompanied by a significant decrease in VUR in 8 of 9 kidneys with reflux, which was not seen in controls. The importance of functional obstruction is further emphasised by the finding that nearly two-thirds of
399
children with symptoms of bladder instability and recurrent urinary tract infection can be maintained infection-free by treatment of their unstable contractions alone.13 This improvement in bladder dysfunction is associated with resolution of VUR in 44% of ureters and with improvement to grade I (minor VUR) in a further 16 % .14 Thus paediatricians should take a careful history of bladder function in their clinical assessment of children with urinary tract infection so as not to overlook a potentially treatable cause. Use of less invasive methods of investigation such as colour doppler ultrasound15 should be
encouraged. 1. Hodson CJ. Reflux nephropathy: scoring the damage. In: Hodson J, Kincaid-Smith P, eds. Reflux neuropathy. New York: Masson, 1979: 29-47. 2. Savage JM, Dillon MJ, Shah V, Barratt TM, Williams DI. Renin and blood-pressure in children with renal scarring and vesicoureteric reflux. Lancet 1978; ii: 441-44. 3. Anderson PAM, Rickwood AMK. Features of primary vesicoureteric reflux detected by prenatal sonography. Br J Urol 1991; 67: 267-71. 4. International Reflux Study Committee. Medical versus surgical management of primary vesicoureteral reflux: a prospective international study in children. J Urol 1981; 125: 277-83. 5. Kincaid-Smith P, Becker G. Reflux nephropathy and chronic pyelonephritis: a review. J Infect Dis 1978; 138: 774-80. 6. Naljmaldin A, Burge DM, Atwell JD. Reflux nephropathy secondary to intrauterine vesicoureteric reflux. J Pediatr Surg 1990; 25: 387-90. 7. Smellie JM. Urinary tract infection in childhood. Br J Hosp Med 1974; 12: 485-94. 8. Ransley PB. Vesicoureteric reflux: continuing surgical dilemma. Urology
1978; 12: 246-55. 9. Editorial. Vesicoureteric reflux: more puzzles. Lancet 1983; ii: 1467-68. 10. Editorial. Prevention of reflux nephropathy. Lancet 1991; 338: 1050. 11. Gunn TR, Mora JD, Pease P. Outcome after antenatal diagnosis of upper urinary tract dilatation by ultrasonography. Arch Dis Child 1988; 63: 1240-43. 12. Scholtmeizer RJ, Van Mastrigt R. The effect of oxyphenonium bromide
and oxybutinin hydrochloride on detrusor contractility and reflux in children with vesicoureteral reflux and detrusor instability. J Urol 1991; 146: 660-62. 13. Koff SA, Lapides J, Piazza DH. Association of urinary tract infection and reflux with uninhibited bladder contractions and voluntary sphincteric obstruction. J Urol 1979; 122: 373-76. 14. Koff SA, Murtagh DS. The uninhibited bladder in children: effect of treatment on vesicoureteral reflux resolution. J Urol 1983; 130: 1138-41. 15. Marshall JL, Johnson ND, DeCampo MP. Vesicoureteric reflux in children: prediction with colour doppler imaging. Radiology 1990; 175: 355-58.
Ethical
emergencies
issue of Dec 21/28 we published two encouraging reports on the effects of nitric oxide inhibition in septic shock and liver failure.1.2 Petros and colleagues1 used specific inhibitors of nitric oxide synthase to increase vascular resistance and blood pressure. Midgley and co-workers2 described their experience with methylene blue, another antagonist of the actions of nitric oxide, in a hypotensive patient with liver failure. The possible clinical relevance of these observations was discussed in an accompanying editorial.3 These reports deserve attention for an entirely different reason. The issue at stake is the use of "unconventional" treatment in emergencies. Petros et al obtained ethical committee approval whereas Midgley et al, in their last-ditch attempt to help a In
our
dying patient, obtained consent from the patient’s wife but did not contact their ethics committee. A not dissimilar case, where the adult patient’s father gave consent, appears on p 435. Methylene blue is an established agent in the treatment of methaemoglobinaemia. Although it has been reported to cause adverse cardiovascular and haemolytic reactions,4the risks associated with its use for accepted indications are probably low. When a patient is in extremis, it could be argued that there is little opportunity for worsening the outcome and so the balance of the risk-benefit equation, even for a novel use of the agent, is tipped in favour of action. Can one justify this view? In similar emergencies, should doctors do more than seek permission from the patient’s closest relatives? The guidelines of the Royal College of Physicians of London state that research in severely ill or unconscious patients requires ethical committee permission to proceed in the absence of the patient’s consent.Unfortunately, there is ambiguity in the term "research". "Innovative therapy", where a clinician departs substantially from accepted practice for the benefit of a particular patient, need not, we are told, be classified as "research", which also implies the quest for generalisable knowledge. An attempt to distinguish between innovative therapy and research in this way is simplistic. Generalisable knowledge is acquired on the basis of individual cases. Innovative therapy is undertaken for the benefit of individual patients, but also to test its efficacy for use in others. The Helsinki Declaration takes a less judgmental line: "In the treatment of the sick person, the doctor must be free to use a new diagnostic and therapeutic measure if in his or her judgment it offers hope of saving life, re-establishing health or alleviating
suffering". There will always be qualms about testing innovative therapy in terminally ill patients; qualms which consent from despairing relatives cannot wholly stifle. Yet there is usually no obvious mechanism for "sounding out" an ethics committee with a vague proposal "just in case". Few would criticise clinicians on ethical grounds for an imaginative attempt to help someone who was critically ill. For the advance of knowledge and patient care, it is no substitute, however, for a planned study meeting previously defined criteria. Ethics committees, when evaluating formal protocols, would do well nonetheless to give some thought to policy on
emergencies. 1. Petros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 1991; 338: 1557-58. 2. Midgley S, Grant IS, Haynes WG, Webb DJ. Nitric oxide in liver failure. Lancet 1991; 338: 1590. 3. Editorial. Nitric oxide in the clinical arena. Lancet 1991; 338: 1560-62. 4. Anon. Methylene blue. In: Dollery C, ed. Therapeutic Drugs. Edinburgh: Churchill Livingstone, 1991: M127-28. 5. Royal College of Physicians Working Party. Guidelines on the practice of ethics committees in medical research involving human subjects. 2nd ed. London: Royal College of Physicians, 1990.
