Guidelines and statements

Position Statement Use, misuse and abuse of androgens The Endocrine Society of Australia consensus guidelines for androgen prescribing Ann J Conway, David J Handelsman, Douglas W Lording, Bronwyn Stuckey, Jeffrey D Zajac on behalf of the Endocrine Society of Australia MJA 2000; 172: 220-224 Abstract - Use of androgens - Misuse of androgens - Abuse of androgens - Key references - Authors' details - - More articles on Endocrinology Abstract Androgen replacement therapy (ART) is usually life-long, and should only be started after androgen deficiency has been proven by hormone assays. The therapeutic goal is to maintain physiological testosterone levels. Testosterone rather than synthetic androgens should be used. Oral 17α-alkylated androgens are hepatotoxic and should not be used for ART. There is no indication for androgen therapy in male infertility. Although androgen deficiency is an uncommon cause of erectile dysfunction, all men presenting with erectile dysfunction should be evaluated for androgen deficiency. If androgen deficiency is confirmed, investigation for the underlying pathological cause is required. Contraindications to androgen therapy are prostate and breast cancer. Precautions include using lower starting doses for older men and induction of puberty. Intramuscular injections should be avoided in men with bleeding disorders. Androgen-sensitive epilepsy, migraine, sleep apnoea, polycythaemia or fluid overload need to be considered. Competitive athletes should be warned about the risks of disqualification. ART should be initiated with intramuscular injections of testosterone esters, 250 mg every two weeks. Maintenance requires tailoring treatment modality to the patient's convenience. Modalities currently available include testosterone injections, implants, or capsules. Choice depends on convenience, cost, availability and familiarity. There is no convincing evidence that, in the absence of proven androgen deficiency, androgen therapy is effective and safe for older men per se, in men with chronic non-gonadal disease, or for treatment of non-specific symptoms. Until further evidence is available, such treatment cannot be recommended. Androgens are hormones that are based on the structure of testosterone, the major male sex hormone, and are capable of developing and maintaining masculine sexual characteristics (including the genital tract, secondary sexual characteristics, and fertility) and the anabolic status of somatic tissues. All androgens have similar biological effects because they all act through the single androgen receptor. Their effects in different tissues are diversified by metabolism of testosterone to its active metabolites by the enzymes 5α reductase (which converts testosterone to 5α-dihydrotestosterone, an androgen with enhanced potency acting on the androgen receptor) and aromatase (which converts testosterone to oestradiol, which acts on the oestrogen receptor). Use of androgens The main medical use of androgens (Box 1) is as androgen replacement therapy (ART) for established androgen deficiency.1-3 Classical androgen deficiency occurs in about 1 in 200 men, due to testicular disorders that directly reduce testosterone output, or hypothalamic-pituitary disorders that reduce pituitary luteinising hormone (LH) secretion, which is the main drive to testosterone production by the interstitial (Leydig) cells of the testes. Although classical androgen deficiency is relatively easy to recognise, diagnosis of less severe androgen deficiency can be more difficult. Owing to its subtle and variable clinical features, the diagnosis may easily be missed, denying patients simple and effective medical treatment with often striking subjective benefits. Potential extensions of classical indications to partial androgen deficiency remain to be fully evaluated for clinical safety and efficacy. These indications include age, androgen deficiency secondary to a chronic medical condition or its treatment, hormonal male contraception, and postmenopausal symptoms.4-6 Until more definitive objective evidence is available regarding the safety and efficacy of prescribing androgens for these indications, they remain suitable for carefully monitored, controlled clinical research trials, but not for routine medical treatment. Pharmacological applications of androgens (Box 1) usually represent second-line therapy where more specific treatments are not yet available or have failed. Androgen treatment can evoke a strong placebo response. In men without genuine androgen deficiency, this placebo effect invariably wanes with time, leading to confusion and dissatisfaction with treatment. In addition, once androgen therapy has commenced, the biochemical changes can cloud further interpretation of results for months. Therefore, androgen replacement therapy should be commenced only after androgen deficiency is clearly established.2,3 Diagnosis of androgen deficiency1-3 Diagnosis of androgen deficiency involves the recognition of appropriate clinical features, with confirmation by biochemical testing. Important clinical features required to evaluate testicular function include reproductive history (including pubertal development), fertility status, changes in sexual function and body hair growth, known testicular pathology, drug use, and occupation. Physical examination should record androgenisation (secondary sexual characteristics, especially body hair distribution, musculature and gynaecomastia) and testis volumes (by orchidometry). Serum LH, follicle-stimulating hormone and testosterone levels should be measured, on at least two separate days and preferably in the morning, to minimise the effects of random and laboratory fluctuations and diurnal rhythms. Direct measurements of free testosterone, if available, may help establish the diagnosis of androgen deficiency, but require extensive validation. Indirect measurements of free testosterone, such as the free androgen index (testosterone/sex hormone binding globulin [SHBG] ratio), correspond poorly with direct measurements and lack empirical validation as a diagnostic test. Additional tests that may be required to identify underlying disorders include karyotyping, pituitary radiology and measurement of prolactin levels, serum ferritin levels, iron saturation and, increasingly, genetic diagnosis. Androgen deficiency is unlikely in men with mean testis volume > 20 mL without atrophy, with a plasma testosterone level consistently above 20 nmol/L, or presenting with erectile dysfunction and a plasma testosterone level consistently above 8 nmol/L (Box 2). Where the diagnosis is not clear, referral to a clinical endocrinologist with experience in this area is recommended.1 Androgen replacement therapy1-3 ART is indicated to rectify androgen deficiency of any cause sufficient to cause clinical consequences. After puberty, there is no age limit to ART. Androgen-deficiency effects may manifest as changes in one or more androgen-sensitive functions; for example, psychosexual function, or loss of anabolic effects on bone, muscle, blood-forming marrow and other androgen-responsive tissues. Apart from decreased spermatogenesis, ART can rectify all clinical features of androgen deficiency, which usually respond within 1-2 months of starting therapy, although the full effect may take longer. Dosage: Standard ART is either testosterone enanthate (Primoteston in castor oil; Schering) or mixed testosterone esters (Sustanon in arachis oil; Organon) as 250 mg in 1 mL oil at 14-day intervals. Deep intramuscular injections are usually given into the upper and outer quadrant of the buttock, although some patients prefer the deltoid or lateral thigh muscle sites. Few men can manage self-injection with the viscous oil vehicle. For all ART, testosterone and its esters should be used in preference to synthetic androgens, because of their established safety and efficacy, as well as ease of dose-titration and assay monitoring. Lower starting doses may occasionally be needed, especially in previously untreated elderly men and during first induction of puberty. Less frequent dosing intervals (eg, every three weeks) are occasionally necessary for those unable or unwilling to have standard dosage, but are accompanied by more extreme peaks and troughs in blood testosterone levels, which may exaggerate symptom fluctuations. An inadequate clinical response raises doubt about androgen deficiency as the cause of recalcitrant symptoms. Rarely, an inadequate clinical response may require increased dosage. If suboptimal symptomatic benefit is supported by biochemical evidence of inadequate maintenance of androgen levels (low trough testosterone levels with or without persistently supranormal LH levels in primary hypogonadism), the same dose may be injected at 10-day intervals. Persistently inadequate responses indicate that unresponsive symptoms are not due to androgen deficiency; further escalation in dose or frequency is not warranted. Men with mild or partial androgen resistance due to androgen-receptor mutations may benefit from high-dose androgen therapy. As the underlying disorders are almost always permanent, life-long ART after the age of puberty is usually necessary. Long term therapeutic compliance depends on an acceptable regimen. Crossover studies indicate that patients strongly prefer the stable testosterone levels and smoother clinical effects provided by implants or transdermal formulations, compared with the wide fluctuations in testosterone levels and symptoms during intramuscular testosterone ester injections. Thus, although ART should commence with injections, alternative modalities (Box 3) may improve compliance. Factors to consider include cost, convenience, availability, familiarity with alternatives, and tolerance for frequent injections. Monitoring: Monitoring of ART is mainly to ensure effective androgen replacement by a regimen tailored to the patient's needs, aiming to maintain adequate therapeutic compliance by continuation of treatment. Serial clinical observation of clinical well-being and major symptoms of androgen deficiency, together with limited numbers of hormonal assays, is usually adequate. Restoration of sexual function has a low threshold for androgen action, so adequate libido and potency is a necessary, but not sufficient, indication of clinically adequate androgen replacement. Blood hormone assays have limited utility in optimising an ART regimen at the start of treatment and in evaluating androgen replacement. Trough blood testosterone levels (ie, before the next scheduled dose) within the eugonadal reference range can be a valuable guide to the adequacy of parenteral androgen replacement, but random blood testosterone levels are not useful for monitoring with either oral or injectable testosterone. In men with hypergonadotropic hypogonadism, suppression of blood LH levels into the eugonadal reference range indicates adequate ART, whereas persistent non-suppression of LH after 3-6 months of regular treatment indicates inadequate dosage or compliance. In hypogonadotropic hypogonadism, blood gonadotropin levels are uninterpretable. Serial evaluation of bone density (especially vertebral trabecular bone) by dual-photon absorptiometry at 1-2-year intervals may be useful in evaluating the adequacy of long-term androgen effects on bone. Other biochemical indices of androgen action, such as haemoglobin, SHBG, and high density lipoprotein cholesterol levels, reflect only supraphysiological effects and are too insensitive for routine monitoring of ART. Androgen deficiency is protective against prostate disease, and ART may restore the risks to those equivalent to, but no more than, eugonadal men of similar age. Screening of men receiving ART for cardiovascular and prostate disease need be no more intensive than for men of similar age not on ART. Precautions and side effects14-17 Adverse effects of androgen treatment are uncommon. Virilisation may occur with androgen therapy in women or children; androgen therapy in these settings requires expert management. Truncal acne and hair growth, weight gain, gynaecomastia and male-pattern hair loss may be observed, and should be managed symptomatically. Certain side effects are characteristic of specific therapeutic modalities (eg, discomfort from intramuscular injections, extrusion of subdermal implants, gastrointestinal disturbance from oral testosterone undecanoate). Polycythaemia may occur disproportionately often in older men treated with testosterone ester injections. In addition, certain testosterone formulations have distinctive effects due to their pharmacokinetic features (eg, reduced levels of SHBG, high density lipoprotein cholesterol and other hepatic proteins due to supraphysiological hepatic testosterone exposure). This may be due to injectable testosterone esters (via high peak blood testosterone concentrations) or oral testosterone undecanoate (via high first-pass portal testosterone concentrations), whereas more steady formulations (transdermal, implants) exhibit fewer or no such effects. Oral synthetic androgens that have a 17α-alkyl substituent (oxandrolone, fluoxymesterone, danazol) are inherently hepatotoxic, causing cholestatic hepatitis, peliosis hepatis and hepatic tumours. Other classes of synthetic androgen, such as 19-nortestosterone derivatives (nandrolone, MENT) and the 1-methyl androgens (mesterolone, methenolone), are not hepatotoxic. Absolute contraindications to androgen therapy are prostate or breast cancer in men. Androgen therapy should be started in men over the age of 40 only after exclusion of undiagnosed prostate disease. Precautions are required for: older men starting androgen treatment, where it may precipitate urinary obstruction or unfamiliar increases in libido; pubertal boys, in whom excessive dosage may accelerate epiphyseal closure, leading to shortened final stature; parenteral androgen therapy in men with bleeding disorders; competitive athletes, who may be disqualified; androgen-sensitive epilepsy, migraine, sleep apnoea or polycythaemia; and cardiac or renal failure or severe hypertension susceptible to fluid overload from sodium and fluid retention. Misuse of androgens Medical misuse of androgens involves prescription with no acceptable medical indication. Some common examples of misguided prescribing of androgens in the absence of established androgen deficiency include: Male infertility: There is no indication for androgen therapy in male infertility. The only likely consequence is an adverse effect of suppressing spermatogenesis. Male sexual dysfunction or impotence: Androgen deficiency (with or without hyperprolactinaemia) is an uncommon (< 5%) cause of men presenting with erectile dysfunction. In such men, excluding androgen deficiency as a readily treatable underlying cause is essential. In the unusual event of severe androgen deficiency presenting with erectile dysfunction, the underlying cause needs to be identified, and plans for life-long ART need to be established. "Male menopause" or "andropause": There is still no evidence that the modest decreases in circulating blood testosterone levels which commence during mid-life have any clinical importance. The risks and benefits of androgen supplementation for partially androgen-deficient older men require further evaluation by placebo-controlled studies. Androgen treatment may be inappropriate, wasteful, and involve placebo effects. Terms such as "male menopause" and "andropause" are misleading; they have little place in meaningful medical or scientific discourse. Elderly men (> 65 years):18 There is no basis for androgen therapy based on age per se. Further controlled clinical trials are needed to evaluate the potential role of androgen supplementation in ageing. While some preliminary placebo-controlled studies suggest short-term benefits for muscle, bone and quality of life, findings are not yet consistent and the identification of appropriate treatment objectives and target subgroups, as well as overall analyses of risks, benefits and costs, are lacking. Specifically, it remains to be determined whether androgen supplementation has significant and sustained clinical benefits in older men with low-normal plasma total testosterone and normal LH levels. At present, there is no basis for androgen treatment outside properly designed clinical trials. Treatment of non-specific symptoms: There is no basis for androgen therapy based on symptoms in the absence of established androgen deficiency. In addition to the unproven safety and efficacy, the placebo effect of androgen injections may be confusing to both doctor and patient. When placebo effects wane, further confusion and dissatisfaction with treatment may be expected. Abuse of androgens Illicit use of androgens19-24 ("anabolic steroids") depends largely on obtaining androgens without legal prescription to be used in the absence of any medical indication. Illicit androgen use became epidemic over the past four decades, since androgens were reportedly first used in elite competitive power sports. A recent placebo-controlled study has shown that high-dose androgen administration does improve muscle size and strength in healthy eugonadal men. Whether these changes enhance athletic performance, whether they are sustained, and whether they apply to older men remains to be clarified. Medical prescription appears to support only a small proportion of illicit androgen use, but such activity has been formally ruled as a breach of professional standards by medical boards in most States and by the Royal Australasian College of Physicians. Highly motivated young men can be very sophisticated in manipulating and pressuring general practitioners while attempting to obtain prescriptions for androgens. The doctor is often led to believe that other practitioners are prescribing androgens for young men, and that he or she is being uncaring or negligent by not acceding to the patient's wishes. We recommend that general practitioners resist these pressures. Fortunately, most people appear ultimately to lose interest in this form of drug abuse. Background and evidence basis of recommendations The Endocrine Society of Australia (ESA) Consensus Guidelines for Androgen Prescribing were written on behalf of the Endocrine Society of Australia. The ad hoc Writing Committee commissioned by the ESA's Council was Dr A J Conway, Professor D J Handelsman (Chair), Associate Professor D W Lording, Dr B Stuckey, and Associate Professor J D Zajac. The draft guidelines were extensively circulated for comment to active members of the ESA with clinical expertise or interests in male reproductive endocrinology. Comments were incorporated into the final document, which was ratified by the ESA's Council. Androgen therapy, in regular clinical use for over 60 years, is one of the oldest hormonal regimens in modern therapeutics. As a long established standard and effective form of hormone replacement for many decades, placebo-controlled studies are unavailable and now unacceptable. Consequently, the NHMRC Quality of Evidence Ratings for these recommendations are those appropriate to an expert committee reviewing all available evidence from controlled experimental and observational studies as well as clinical experience. Key references Diagnosis and management of androgen deficiency Behre HM, Yeung CH, Nieschlag E. Diagnosis of male infertility and hypogonadism. In: Nieschlag E, Behre HM (eds): Andrology: Male Reproductive Health and Dysfunction. Berlin:Springer, 1997: 87-111. Plymate SR. Male Hypogonadism. In: Becker KL (ed): Principles and Practice of Endocrinology and Metabolism. 2nd ed. Philadelphia: J B Lippincott Company, 1995: 1056-1082. Nieschlag E, Wang C, Handelsman DJ, et al (eds) (1992). Guidelines for the use of androgens in men. Geneva, Special Programme of Research, Development and Research Training in Human Reproduction of the World Health Organisation. Male contraception Cummings DE, Bremner WJ. Prospects for new hormonal male contraceptives. In: Bremner WJ (ed): Clinical Andrology. Philadelphia: W B Saunders Company, 1994: 893-922. Handelsman DJ. Contraception in the male. In: DeGroot LJ (ed): Endocrinology. 3rd ed. Philadelphia: W B Saunders, 1994: 2449-2458. Androgen therapy in systemic disease Liu PY, Handelsman DJ. Androgen therapy in non-gonadal disease. In: Nieschlag E, Behre HM (eds):Testosterone: Action, Deficiency and Substitution. 2nd ed. E Nieschlag, Behre HM (eds), Berlin, Springer-Verlag, 1998. Comparative pharmacology of androgen formulations Bals-Pratsch M, Langer K, Place VA, Nieschlag E. Substitution therapy of hypogonadal men with transdermal testosterone over one year. Acta Endocrinologica 1988; 118: 7-13. Behre HM, Oberpenning F, Nieschlag E. Comparative pharmacokinetics of androgen preparations: application of computer analysis and simulation. In: Nieschlag E, Behre HM (eds): Testosterone: Action, Deficiency and Substitution. Berlin: Springer-Verlag, 1990: 115-135. Cantrill JA, Dewis P, Large DM et al. Which testosterone replacement therapy? Clin Endocrinol (Oxf) 1984; 24: 97-107. Conway AJ, Boylan LM, Howe C, Ross G, Handelsman DJ. A randomised clinical trial of testosterone replacement therapy in hypogonadal men. Int J Androl 1988; 11: 247-264. Handelsman DJ, Conway AJ, Boylan LM. Pharmacokinetics and pharmacodynamics of testosterone pellets in man. J Clin Endocrinol Metab 1990; 71: 216-222. Meikle AW, Mazer NA, Moellmer JF, et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinol Metab 1992; 74: 623-628. Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab 1980; 51: 1335-1339. Safety of androgens Alexandersen P, Haarbo J, Christiansen C. The relationship of natural androgens to coronary heart disease in males: a review. Atherosclerosis 1996; 125: 1-13. Barrett-Connor E. Testosterone, HDL-cholesterol and cardiovascular disease. In: Bhasin S, Gabelnick HL, Spieler JM et al (eds): Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996: 215-223. Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf) 1994; 40: 341-349. Gooren LJ, Polderman KH. Safety aspects of androgen therapy. In: Nieschlag E, Behre HM (eds): Testosterone: Action, Deficiency and Substitution. Berlin: Springer-Verlag, 1990: 182-203. Androgen and the ageing male Tenover JL. Androgen therapy in aging men. In: Bhasin S, Gabelnick HL, Spieler JM, et al (eds): Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996: 309-318. Androgen abuse Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996; 335: 1-7. Handelsman DJ, Gupta L. Prevalence and risk factors for anabolic-androgenic steroid abuse in Australian secondary school students. Int J Androl 1997; 20: 159-164. Lin GC, Erinoff L (eds). (1990). Anabolic Steroid Abuse. National Institute on Drug Abuse Research Monograph Series. Rockville, US Department of Health and Human Services. Wilson JD. Androgen abuse by athletes. Endocr Rev 1988; 9: 181-199. Yesalis CE, Kennedy NJ, Kopstein AN, Bahrke MS. Anabolic-androgenic steroid use in the United States. JAMA 1993; 270: 1217-1221. Young NR, Baker HWG, Liu G, Seeman E. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol Metab 1993; 77: 1028-1032. Authors' details Endocrine Society of Australia, Sydney, NSW. Ann J Conway, MB BS, FRACP; David J Handelsman, MB BS, PhD, FRACP; Douglas W Lording, MB BS, FRACP; Bronwyn Stuckey, MB BS, FRACP; Jeffrey D Zajac, PhD, FRACP. Reprints will not be available from the authors. Correspondence: Associate Professor J D Zajac, Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050. j.zajacATmedicine.unimelb.edu.au Make a comment 1: Use, misuse and abuse of androgens Use Physiological (androgen deficiency) 1-3 Classical androgen deficiency ("hypogonadism") Age-related partial androgen deficiency Micropenis (neonatal) Delayed puberty Aged men* Androgen deficiency secondary to chronic disease* Induced androgen deficiency Hormonal male contraception* Pharmacological (non-androgen deficiency)4-6 Osteoporosis Anaemia due to marrow or renal failure Advanced breast cancer Excessively tall stature in boys Misuse Inappropriate indications In absence of proven androgen deficiency: Male infertility Sexual dysfunction/impotence "Male menopause", "andropause" Older men (>65 years) Non-specific symptoms Abuse19-24 Absence of medical indication Sporting Competitive power sports (athletics, weightlifting, football, swimming, rowing, boxing) RecreationalBodybuilding Cosmetic"Body beautiful" subculture OccupationalSecurity, police, armed forces, professional sports * These indications remain to be fully evaluated for safety and efficacy in controlled clinical trials. Back to text 2: Biochemical evaluation of the diagnosis of androgen deficiency in men with clinical features consistent with hypogonadism* Testosterone level†Luteinising hormone level†Diagnosis<8 nMHigh‡Androgen deficiency (hypergonadotropic hypogonadism§)<8 nMNot highAndrogen deficiency (hypogonadotropic hypogonadism§)8-15 nMHigh‡Androgen deficiency (Leydig cell failure)8-15 nMNot highAndrogen deficiency not confirmed: unproven therapeutic benefit of androgen replacement therapy>20 nMAnyExcludes androgen deficiency>30 nM**High‡Androgen resistance*There is necessarily an arbitrary component to this type of table. It is based on current experience and should be subject to changes according to further clinical evidence. †Blood sample classification based on at least two separate morning blood samples. ‡"High" luteinising hormone level is defined as > 1.5 times the upper limit of the eugonadal reference range for young men. §Hypergonadotropic and hypogonadotropic hypogonadism are also referred to as primary and secondary hypogonadism, respectively. Compensated Leydig cell failure is a form of partial androgen deficiency in which androgen replacement is often beneficial. **Elevated testosterone is defined as above the upper limit of the eugonadal reference range for young men. Back to text 3: Androgen treatment modalities7-13 Testosterone implants Fused cylindrical pellets of pure crystalline testosterone that form a subdermal depot Provide stable, physiological levels of testosterone for 4-6 months following a single implantation of four 200 mg (800 mg) implants Implantation uses a trochar and cannula technique under office sterile conditions, and requires local anaesthesia Main adverse effect is extrusion of implants via the insertion site 1-2 months after implantation Extrusion rate (about 10%) depends on operator experience and patient's physical activity Minor adverse effects related to the minor office surgery (bleeding, infection) are infrequent (<5%) Should only be used for patients who have demonstrated satisfactory tolerance of androgen effects with shorter-acting preparations Transdermal testosterone Administered daily via androgen-impregnated adhesive skin patches or hydroalcoholic gels (not yet available in Australia) Other depot testosterone formulations Newer injectable esters (testosterone undecanoate, testosterone buciclate) Testosterone-laden biodegradable microspheres Both these formulations deliver stable, physiological testosterone levels for 2-3 months following injection Oral testosterone undecanoate Useful where parenteral testosterone is undesirable (eg, bleeding disorders or anticoagulation) or poorly tolerated Administered as 160-240 mg (four to six 40 mg capsules), divided into 2-4 doses per day Second-line formulation for routine ART, because of frequency of administration, high hepatic load, gastrointestinal intolerance, and higher cost Back to text

Ann J Conway · David J Handelsman · Douglas W Lording · Bronwyn Stuckey · Jeffrey D Zajac

Position Statement New classification and criteria for diagnosis of diabetes mellitus Position Statement from the Australian Diabetes Society,* New Zealand Society for the Study of Diabetes, Royal College of Pathologists of Australasia and Australasian Association of Clinical Biochemists Peter G Colman,* David W Thomas, Paul Z Zimmet,* Timothy A Welborn, * Peter Garcia-Webb and M Peter Moore MJA 1999; 170: 375-378 Introduction - What are the new diagnostic criteria? - What about the oral glucose tolerance test? - Diabetes in pregnancy - How has the classification of diabetes changed? - Impaired glucose tolerance and impaired fasting glycaemia - References - Authors' details - - More articles on Endocrinology Introduction Recently, there has been major growth in knowledge about the aetiology and pathogenesis of different types of diabetes and about the predictive value of different blood glucose levels for development of complications. In response, both the American Diabetes Association (ADA) and the World Health Organization (WHO) have re-examined, redefined and updated the classification of and criteria for diabetes, which have been unchanged since 1985. While the two working parties had cross-representation, they met separately, and differences have emerged between their recommendations. The ADA published its final recommendations in 1997,1 while the WHO group published its provisional conclusions for consultation and comment in June 1998.2 The WHO process called for comments on the proposal by the end of September 1998, with the intention of finalising definitive classification and criteria by the end of December 1998 and of publishing these soon thereafter. However, WHO publications need to go through an internal approval process and it may be up to 12 months before the final WHO document appears. A combined working party of the Australian Diabetes Society, New Zealand Society for the Study of Diabetes, Royal College of Pathologists of Australasia and Australasian Association of Clinical Biochemists was formed to formulate an Australasian position on the two sets of recommendations and, in particular, on the differences between them. This is an interim statement pending the final WHO report, which will include recommendations on diabetes classification as well as criteria for diagnosis. We see it as very important to inform Australasian health professionals treating patients with diabetes about these changes. Position Statement key messages What are the new diagnostic criteria? The new WHO criteria for diagnosis of diabetes mellitus and hyperglycaemia are shown in Box 1. The major change from the previous WHO recommendation3 is the lowering of the diagnostic level of fasting plasma glucose to 7.0 mmol/L, from the former level of 7.8 mmol/L. For whole blood, the proposed new level is 6.1 mmol/L, from the former 6.7 mmol/L. This change is based primarily on cross-sectional studies demonstrating the presence of microvascular4 and macrovascular complications5 at these lower glucose concentrations. In addition, the 1985 WHO diagnostic criterion for diabetes based on fasting plasma glucose level ( 7.8 mmol/L) represents a greater degree of hyperglycaemia than the criterion based on plasma glucose level two hours after a 75 g glucose load ( 11.1 mmol/L).6 A fasting plasma glucose level of 7 mmol/L accords more closely with this 2 h post-glucose level. Recommendation: The ADA and the WHO committee are unanimous in adopting the changed diagnostic level, and the Australasian Working Party on Diagnostic Criteria recommends that healthcare providers in Australia and New Zealand should adopt it immediately. Clinicians should note that the diagnostic criteria differ between clinical and epidemiological settings. In clinical practice, when symptoms are typical of diabetes, a single fasting plasma glucose level of 7.0 mmol/L or 2 h post-glucose or casual postprandial plasma glucose level of 11.1 mmol/L suffices for diagnosis. If there are no symptoms, or symptoms are equivocal, at least one additional glucose measurement (preferably fasting) on a different day with a value in the diabetic range is necessary to confirm the diagnosis. Furthermore, severe hyperglycaemia detected under conditions of acute infective, traumatic, circulatory or other stress may be transitory and should not be regarded as diagnostic of diabetes. The situation should be reviewed when the primary condition has stabilised. In epidemiological settings, for study of high-prevalence populations or selective screening of high-risk individuals, a single measure -- the glucose-level 2 h post-glucose load -- will suffice to describe prevalence of impaired glucose tolerance (IGT). What about the oral glucose tolerance test? Previously, the oral glucose tolerance test (OGTT) was recommended in people with a fasting plasma glucose level of 5.5-7.7 mmol/L or random plasma glucose level of 7.8-11.0 mmol/L. After a 75 g glucose load, those with a 2 h plasma glucose level of < 7.8 mmol/L were classified as normoglycaemic, of 7.8-11.0 mmol/L as having IGT and of 11.1 mmol/L as having diabetes. The new diagnostic criteria proposed by the ADA and WHO differ in their recommendations on use of the OGTT. The ADA makes a strong recommendation that fasting plasma glucose level can be used on its own and that, in general, the OGTT need not be used.1 The WHO group2 argues strongly for the retention of the OGTT and suggests using fasting plasma glucose level alone only when circumstances prevent the performance of the OGTT. There are concerns that many people with a fasting plasma glucose level < 7.0 mmol/L will have manifestly abnormal results on the OGTT and are at risk of microvascular and macrovascular complications. This has major ramifications for the approach to diabetes screening, particularly when the Australian National Diabetes Strategy proposal,7 launched in June 1998 by Dr Michael Wooldridge, Federal Minister for Health and Aged Care, has early detection of type 2 diabetes as a key priority. Recommendation: The Australasian Working Party on Diagnostic Criteria has major concerns about discontinuing use of the OGTT and recommends that a formal recommendation on its use in diabetes screening be withheld until the final WHO recommendation is made. However, in the interim, the OGTT should continue to be used. Diabetes in pregnancy The ADA has retained its old criteria for diagnosis of gestational diabetes.1 These differ from those recommended by both WHO2 and the Australian Working Party on Diabetes in Pregnancy8 and are generally not recognised outside the United States. The new WHO statement retains the 1985 WHO recommendation that both IGT and diabetes should be classified as gestational diabetes. This is consistent with the recommendations of the Australasian Diabetes in Pregnancy Society, which recommended a diagnostic 2 h venous plasma glucose level on the OGTT of 8.0 mmol/L. In New Zealand, a cut-off level of 9.0 mmol/L has been applied.8 How has the classification of diabetes changed? The proposed new classification encompasses both clinical stages and aetiological types of hyperglycaemia and is supported by numerous epidemiological studies. The classification by aetiological type (Box 2) results from new knowledge of the causes of hyperglycaemia, including diabetes. The terms insulin-dependent and non-insulin-dependent diabetes (IDDM and NIDDM) are eliminated and the terms type 1 and type 2 diabetes retained. Other aetiological types, such as diabetes arising from genetic defects of -cell function or insulin action, are grouped as "other specific types", with gestational diabetes as a fourth category. The proposed staging (Box 3) reflects the fact that any aetiological type of diabetes can pass or progress through several clinical phases (both asymptomatic and symptomatic) during its natural history. Moreover, individuals may move in either direction between stages. Impaired glucose tolerance and impaired fasting glycaemia Impaired glucose tolerance (IGT), a discrete class in the previous classification, is now categorised as a stage in the natural history of disordered carbohydrate metabolism. Individuals with IGT are at increased risk of cardiovascular disease, and not all will be identified by fasting glucose level. In reducing the use of the OGTT, the ADA recommended a new category -- impaired fasting glycaemia (IFG) -- when fasting plasma glucose level is lower than that required to diagnose diabetes but higher than the reference range (< 7.0 mmol/L but 6.1 mmol/L). Limited data on this category show that it increases both risk of progressing to diabetes9 and cardiovascular risk.5 However, data are as yet insufficient to determine whether IFG has the same status as IGT as a risk factor for developing diabetes and cardiovascular disease and as strong an association with the metabolic syndrome (insulin resistance syndrome). IFG can be diagnosed by fasting glucose level alone, but if 2 h glucose level is also measured some individuals with IFG will have IGT and some may have diabetes. In addition, the number of people with OGTT results indicating diabetes but fasting plasma glucose level < 7.0 mmol/L is unknown, but early data suggest there may be major variation across different populations.10 A number of studies, including the DECODE initiative of the European Diabetes Epidemiology Group, have reported that individuals classified with IFG are not the same as the IGT group.11-15 The European Group believes that, on available European evidence, the ADA decision to rely solely on fasting glucose level would be unwise. Recommendation: The Australasian Working Party on Diagnostic Criteria recommends immediate adoption of the new classification. However, clinicians should be aware that some cases of diabetes will be missed unless an OGTT is performed. Thus, if there is any suspicion or other risk factor suggesting glucose intolerance, the working party continues to recommend use of an OGTT pending the final WHO recommendation. References Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183-1197. Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional Report of a WHO Consultation. Diabet Med 1998; 15: 539-553. World Health Organization. Diabetes mellitus. Report of a WHO study group. Technical report series 727. Geneva: WHO, 1985. McCance DR, Hanson RL, Charles MA, et al. Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes. BMJ 1994; 308: 1323-1328. Charles MA, Balkau B, Vauzelle-Kervoeden F, et al. Revision of diagnostic criteria for diabetes [letter]. Lancet 1996; 348: 1657-1658. Finch CF, Zimmet PZ, Alberti KGMM. Determining diabetes prevalence: a rational basis for the use of fasting plasma glucose concentrations? Diabet Med 1990; 7: 603-610. Colagiuri S, Colagiuri R, Ward J. National diabetes strategy and implementation plan. Canberra: Diabetes Australia, 1998. Hoffman L, Nolan C, Wilson D, et al. Gestational diabetes mellitus -- management guidelines. The Australasian Diabetes in Pregnancy Society. Med J Aust 1998; 169: 93-97. Charles MA, Fontbonne A, Thibult N, et al. Risk factors for NIDDM in white population. Diabetes 1991; 40: 796-799. Keen H. Impact of new criteria for diabetes on pattern of disease. Lancet 1998; 352: 1000-1001. DECODE Study Group on behalf of the European Diabetes Epidemiology Study Group. Will new diagnostic criteria for diabetes mellitus change phenotype of patients with diabetes? Reanalysis of European epidemiological data. BMJ 1998; 317: 371-375. De Vegt F, Dekker JM, Stehouwer CDA, et al. The 1997 American Diabetes Association criteria versus the 1985 World Health Organization criteria for the diagnosis of abnormal glucose tolerance. Diabetes Care 1998; 21: 1686-1690. Harris MI, Eastman RC, Cowie CC, et al. Comparison of diabetes diagnostic categories in the US population according to 1997 American Diabetes Association and 1980-1985 World Health Organization diagnostic criteria. Diabetes Care 1997; 20: 1859-1862. Unwin N, Alberti KGMM, Bhopal R, et al. Comparison of the current WHO and new ADA criteria for the diagnosis of diabetes mellitus in three ethnic groups in the UK. Diabet Med 1998; 15: 554-557. Chang C-J, Wu J-S, Lu F-H, Lee H-L, et al. Fasting plasma glucose in screening for diabetes in the Taiwanese population. Diabetes Care 1998; 21: 1856-1860. Authors' details Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, VIC. Peter G Colman, FRACP, MD, Director. Chemical Pathology Services, Women's and Children's Hospital, Adelaide, SA. David W Thomas, FRACP, FRCPA, Head. International Diabetes Institute, Melbourne, VIC. Paul Z Zimmet, FRACP, MD, Director. Diabetes Centre, Sir Charles Gairdner Hospital, Perth, WA. Timothy A Welborn, FRACP, PhD, Head. St John of God Pathology, Perth, WA. Peter Garcia-Webb, MD, FRCPA, Chemical Pathologist. Diabetes Centre, Christchurch Hospital, Christchurch, NZ. M Peter Moore, FRACP, Clinical Director. Reprints will not be available from the authors. Correspondence: Dr P G Colman, Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, VIC 3050. Email: peter.colmanATnwhcn.org.au Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> Key messages Diagnosis of diabetes is not in doubt when there are classical symptoms of thirst and polyuria and a random venous plasma glucose level 11.1 mmol/L. The Australasian Working Party on Diagnostic Criteria for Diabetes Mellitus recommends: Immediate adoption of the new criterion for diagnosis of diabetes as proposed by the American Diabetes Association (ADA) and the World Health Organization (WHO) - fasting venous plasma glucose level 7.0 mmol/L; Immediate adoption of the new classification for diabetes mellitus proposed by the ADA and WHO, which comprises four aetiological types - type 1, type 2, other specific types, and gestational diabetes - with impaired glucose tolerance and impaired fasting glycaemia as stages in the natural history of disordered carbohydrate metabolism. Awareness that some cases of diabetes will be missed unless an oral glucose tolerance test (OGTT) is performed. If there is any suspicion or other risk factor suggesting glucose intolerance, the OGTT should continue to be used pending the final WHO recommendation. Back to text 1: Values for diagnosis of diabetes mellitus and other categories of hyperglycaemia2Glucose concentration (mmol/L [mg/dL]) Whole blood Venous Capillary Diabetes mellitusFasting 6.1 ( 110) 6.1 ( 110) or 2 h post-glucose load 10.0 ( 180) 11.1 ( 200) or bothImpaired glucose tolerance (IGT)Fasting (if measured)< 6.1 (< 110) < 6.1 (< 110) and 2 h post-glucose load 6.7 ( 120) 7.8 ( 140) and < 10.0 (< 180) and < 11.1 (< 200) Impaired fasting glycaemia (IFG)Fasting 5.6 ( 100) and 5.6 ( 100) and < 6.1 (< 110) < 6.1 (< 110) 2 h post-glucose load (if measured)< 6.7 (< 120) < 7.8 (< 140) Glucose concentration (mmol/L [mg/dL]) Plasma* Venous Capillary Diabetes mellitusFasting< 7.0 ( 126) 7.0 ( 126) or 2 h post-glucose load 11.1 ( 200) 12.2 ( 220) or bothImpaired glucose tolerance (IGT)Fasting (if measured)<7.0 (<126) < 7.0 (< 126) and 2 h post-glucose load 7.8 ( 140) 8.9 ( 160) and < 11.1 (< 200) and < 12.2 (< 220) Impaired fasting glycaemia (IFG)Fasting 6.1 ( 110) and 6.1 ( 110) and < 7.0 (< 126) < 7.0 (< 126) 2 h post-glucose load (if measured)< 7.8 (< 140) < 8.9 (< 160) For epidemiological or population screening purposes, the fasting or 2 h value after 75 g oral glucose may be used alone. For clinical purposes, the diagnosis of diabetes should always be confirmed by repeating the test on another day, unless there is unequivocal hyperglycaemia with acute metabolic decompensation or obvious symptoms. Glucose concentrations should not be determined on serum unless red cells are immediately removed, otherwise glycolysis will result in an unpredictable underestimation of the true concentrations. It should be stressed that glucose preservatives do not totally prevent glycolysis. If whole blood is used, the sample should be kept at 0-4oC or centrifuged immediately, or assayed immediately. Table reproduced with permission from Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional Report of a WHO Consultation. Diabet Med 1998; 15: 539-553. Copyright John Wiley & Sons Limited. Back to text2: Aetiological classification of disorders of glycaemia* Type 1 (-cell destruction, usually leading to absolute insulin deficiency) Autoimmune Idiopathic Type 2 (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance) Other specific types Genetic defects of -cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug or chemical induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes Gestational diabetes * As additional subtypes are discovered, it is anticipated they will be reclassified within their own specific category. Includes the former categories of gestational impaired glucose tolerance and gestational diabetes. Table reproduced with permission from Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional Report of a WHO Consultation. Diabet Med 1998; 15: 539-553. Copyright John Wiley & Sons Limited. Back to textBack to text

Peter G Colman · David W Thomas · Paul Z Zimmet · Timothy A Welborn · Peter Garcia-Webb

Gestational diabetes mellitus -- management guidelines The Australasian Diabetes in Pregnancy Society Linda Hoffman, Chris Nolan, J Dennis Wilson, Jeremy J N Oats and David Simmons MJA 1998; 169: 93-97 Synopsis - Screening - Diagnosis - Management of GDM - Patient education - Fetal surveillance - Timing of delivery - Delivery - Neonatal management - Maternal follow-up - Directions for future research - Acknowledgements - References - Authors' details - - ©MJA1998 Synopsis GDM is defined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy. Universal screening is recommended. If selective screening is considered more appropriate (because of limited resources or known low GDM incidence), screening may be reserved for those at higher risk. Risk factors include glycosuria, age over 30 years, obesity, family history of diabetes, past history of GDM or glucose intolerance, previous adverse pregnancy outcome and belonging to a high risk ethnic group. The recommended screening test for GDM is performed at 26-28 weeks' gestation and positive results are: 1 hour venous plasma glucose level ≥7.8 mmol/L after a 50 g glucose load (morning, non-fasting); or 1 hour venous plasma glucose level ≥8.0 mmol/L after a 75 g glucose load (morning, non-fasting). Confirmation of diagnosis after a positive screening test: a 75 g oral glucose tolerance test (fasting) with a venous plasma glucose level at 0 hours of ≥5.5 mmol/L and/or at 2 hours of ≥8.0 mmol/L.* Patient education is very important and a team approach, if available, is beneficial. Dietary therapy is the primary therapeutic strategy, with insulin added where required to achieve the minimum goals for glycaemic control: fasting blood glucose <5.5 mmol/L, 1 hour postprandial <8.0 mmol/L or 2 hour postprandial <7.0 mmol/L. Careful antepartum fetal surveillance is essential. Continuation of the pregnancy in uncomplicated GDM to 10 days beyond term is acceptable provided that indications from fetal monitoring are reassuring. Close neonatal monitoring is important, particularly for the detection of hypoglycaemia. Maternal follow-up, with an oral glucose tolerance test, should be performed 6-8 weeks postpartum, then at least every 2 years, because of the increased risk of developing permanent diabetes. Prospective trials are needed to clarify whether universal screening is justified, and to determine the degree of maternal hyperglycaemia that causes an adverse outcome for the offspring. The management strategies in this article have been the subject of widespread discussion with the ADIPS membership between 1991 and 1998 at annual scientific meetings, annual general meetings, and in ADIPS newsletters. They represent the majority opinion. * Cut-off point for Australia; cut-off point in New Zealand ≥9.0 mmol/L. Introduction Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy.1 Women with GDM are a heterogeneous group and may include those with unrecognised pre-existing non-insulin-dependent diabetes (type 2) and also a small number with insulin-dependent diabetes. The presence of GDM has implications for both the baby and the mother. Although there is no evidence that perinatal mortality is increased in pregnancies with treated GDM, some studies have shown perinatal mortality to be increased in untreated GDM.2-4 GDM is associated with increased perinatal morbidity, the characteristics of which are the same as for infants of mothers with overt diabetes (eg, macrosomia, neonatal hypoglycaemia, hyperbilirubinaemia, respiratory distress syndrome).5 In considering longer term outcomes for the baby, evidence is gradually mounting that GDM adds an intrauterine environmental risk factor to an already increased genetic risk for the development of obesity and/or diabetes.6-8 In one follow-up study insulin therapy for GDM was associated with less adiposity in the offspring.9 For the mother, GDM is a very strong risk factor for the development of permanent diabetes later in life (49.9% with up to 28 years' follow-up).10 Screening There has been much debate about whether universal or selective screening of pregnant women for GDM is more appropriate.11-13 Moses and Colagiuri recently estimated that, between 1991 and 1994, 50% of pregnant women in New South Wales were not screened for gestational diabetes.14The Australasian Diabetes in Pregnancy Society (ADIPS) recommends that screening for GDM should be considered in all pregnant women. However, if resources are limited, screening may be reserved for those at highest risk. Risk factors include: Glycosuria; Age over 30 years; Obesity; Family history of diabetes; Past history of GDM or glucose intolerance; Previous adverse pregnancy outcome; and Belonging to an ethnic group with a high risk for GDM. Ethnicity is a particularly important factor determining incidence of GDM (eg, very high risk -- Australian Indigenous, Polynesian and South Asian [Indian] groups; moderate high risk -- Middle Eastern and other Asian groups).15 Most Australian centres report a GDM incidence of 5.5%-8.8%.16-19 When selective screening is deemed more appropriate because of known low GDM incidence, the ADIPS criteria are similar to those recommended by the American "Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus".20 A recent article by Naylor et al21 derived a risk factor scoring system that excluded the need for screening up to a third of pregnant women. However, complex criteria for selective screening may cause difficulties in busy clinical practice. A summary of the screening and diagnostic procedures recommended by ADIPS is given in the Table. Diagnosis The guidelines for diagnosing GDM in Australia are essentially unchanged from those recommended for use in Australasia in 1991.22 Although there are no uniform international criteria for the diagnosis of GDM, commonly used criteria are those of O'Sullivan and Mahan23 and the World Health Organization (WHO).24 One problem with the development of absolute diagnostic criteria is the lack of evidence that perinatal mortality is increased in pregnancies associated with mild degrees of hyperglycaemia. The commonly used diagnostic criteria were not formulated to assess the risk of adverse perinatal outcomes, although this was a factor taken into account in the diagnostic criteria at the Mercy Hospital for Women, Melbourne.4 The existence of different methods of performing glucose tolerance tests has also hindered the development of uniform diagnostic criteria for GDM. After consensus, ADIPS has endorsed the diagnostic criteria developed by the working party chaired by Dr F I R Martin in 1991, which are modified WHO criteria.22 In New Zealand, the 2 hour oral glucose tolerance test (OGTT) cut-off value for a positive diagnosis is a venous plasma glucose level of 9.0 mmol/L. This figure was chosen by a majority decision of specialists at the 1992 meeting of the New Zealand Society for the Study of Diabetes. They chose the higher figure to reduce the worry and inconvenience for women of being given a false positive diagnosis and to reduce the strain on stretched specialist resources in many centres. ADIPS recognises the importance of working towards an Australasian consensus on this issue. If the clinical suspicion of GDM is high, a diagnostic OGTT is indicated, irrespective of the stage of pregnancy. In such circumstances, if an OGTT gives normal results early in pregnancy the test should be repeated between 26 and 30 weeks' gestation. A 75 g OGTT should use 75 g of anhydrous glucose or the equivalent, and preferably should also be performed after a high carbohydrate diet of at least 150 g of carbohydrate for three days. Management of GDM A team approach is ideal for managing women with GDM and, if available, should be used. The team would usually comprise an obstetrician, diabetes physician, a diabetes educator (diabetes midwifery educator), dietitian, midwife and paediatrician. In practice, however, the team approach is not always possible due to limited resources. In such circumstances, management by an obstetrician or obstetric general practitioner knowledgeable in GDM management, often with the assistance of an appropriately skilled dietitian, diabetes educator or midwife, is acceptable. Patient education The importance of educating women with GDM (and their partners) about the condition and its management cannot be overemphasised. Compliance with the treatment plan depends on the patient's understanding of: The implications of GDM for her baby and herself; The dietary and exercise recommendations; and The how and when as well as the goals of self monitoring of blood glucose level. Care should be taken to minimise the anxiety of the women. Glycaemic control Dietary therapy: Dietary therapy is the primary therapeutic strategy for the achievement of acceptable glycaemic control in GDM. All women should receive nutritional advice, preferably from an appropriately skilled dietitian. However, it is important to avoid a severe calorie-restricted diet, as this can predispose to ketonuria, and also to infants that are small for their gestational age, which carries an increased risk of diabetes in later life.25 The diet needs to: Conform with the principles of dietary management of diabetes in general; Meet the nutritional requirements of pregnancy; Be individualised for each patient, depending on maternal weight and body mass index; and Be culturally appropriate. Moderate exercise has recently been recognised as an adjunct therapy, with potential benefits when used together with diet, or diet and insulin therapy, in the management of gestational diabetes in women without a medical or obstetric contraindication.26 Monitoring: Glycaemic control needs to be monitored. Self monitoring of blood glucose level is the optimal method and is well tolerated by most women. On commencement of self monitoring, at least one fasting and one 1 or 2 hour postprandial glucose level should be obtained daily. The frequency may be decreased or increased depending on the results of the blood glucose monitoring and the progress of the pregnancy. If self monitoring is not possible, fasting and 1 or 2 hour postprandial laboratory capillary blood or venous plasma glucose levels should be performed regularly (at 1 to 2 weekly intervals). In pregnancies complicated by GDM, the value of self monitoring of blood glucose and appropriate insulin therapy in the prevention of macrosomia and its associated perinatal complications has previously been demonstrated.27,28 The minimum goals for glycaemic control are: a fasting capillary (venous plasma) blood glucose level <5.5 mmol/L a 1 hour postprandial capillary (venous plasma) blood glucose level <8.0 mmol/L a 2 hour postprandial capillary (venous plasma) blood glucose level <7.0 mmol/L. These minimum goals have been set on the basis of informed consensus opinion in Australasia and vary little from those of the American Diabetes Association clinical practice recommendations on gestational diabetes (fasting glucose ≤5.8 mmol/L and 2 hour postprandial plasma glucose ≤6.7 mmol/L).29 The setting of minimal goals for glycaemic control is controversial, however, as some, but not all, studies show benefit from tight glycaemic control in women with GDM.27,28,30-32 The reasons for the variance in results between studies may relate to differences in the underlying rates of GDM complications from one study population to another. The recommended fasting glycaemia goal of <5.5 mmol/L is supported by Langer et al, who have shown that rates of large-for-gestational-age (LGA) infants are increased in diet-treated GDM pregnancies if the fasting glucose level is between 5.3 and 5.8 mmol/L (28.6% LGA) compared with ≤5.3 mmol/L (5.35% LGA).32 Insulin treatment was shown to reduce the rates of LGA infants to 10.3% in GDM pregnancies with fasting glucose levels between 5.3 and 5.8 mmol/L.32 In support of the 1 and 2 hour postprandial glycaemic goals of <8.0 and <7.0 mmol/L, respectively, it has been shown that glycohaemoglobin (HbA1c) levels, birth weight, and rates of macrosomia, neonatal hypoglycaemia and caesarean section (for cephalopelvic disproportion) can all be significantly reduced in insulin-treated GDM subjects if insulin therapy is adjusted according to 1 hour postprandial, rather than preprandial, glucose measurements, aiming for <7.8 mmol/L.27 HbA1c levels may be used as an ancillary test, as assurance that the self monitored blood glucose results are appropriate. Fructosamine levels are reduced during pregnancy because of the dilutional effect of pregnancy on plasma proteins. HbA1c and fructosamine are not reliable substitutes for self monitoring of blood glucose level. Insulin therapy: Insulin therapy should be considered if the blood glucose goals are exceeded on two or more occasions within a 1 to 2 week interval, particularly in association with clinical or investigational suspicion of macrosomia. However, the benefit of instituting insulin therapy after 38 weeks' gestation is unproven. Human insulin should be used. No insulin preparations have a pregnancy category listing, except for the new, rapidly acting insulin analogue lispro, which is Category B2 (Australian medicines in pregnancy category). Two cases of congenital malformations were recently noted in women with insulin-dependent diabetes treated in pregnancy with lispro.33 The number of women treated with lispro in pregnancy is small to date, but no causative relationship between lispro and teratogenicity has been documented. In general, the insulin preparations and dosage schedules should be tailored to the abnormalities present in the glycaemic profile (eg, postprandial and/or fasting hyperglycaemia) and patient acceptability. The doses may be higher than those required in non-pregnant subjects and should be reviewed frequently so that adequate glycaemic control is achieved rapidly. Care should be taken to minimise the risk of hypoglycaemia, especially nocturnal episodes. Oral hypoglycaemic agents have no place in treatment of GDM under normal circumstances. Fetal surveillance The timing of commencement and the frequency of fetal monitoring in pregnancies complicated by GDM depend on the presence of other pregnancy complications such as pre-eclampsia, hypertension, antepartum haemorrhage and intrauterine growth retardation. The regimen chosen should be dictated by the severity of the obstetric complication. Monitoring may be by either Doppler umbilical bloodflow measurement or cardiotocograph (CTG). Although CTG surveillance is commonly undertaken routinely from around 36 weeks' gestation, there is no objective evidence that fetal monitoring in uncomplicated GDM affects fetal outcome.34 Common practice in the United States is to commence CTG monitoring after 40 weeks' gestation, while awaiting spontaneous onset of labour in uncomplicated GDM pregnancies,35 but again there is no evidence-based medicine to support or refute this practice. Ultrasonography should be considered at around 34 weeks' gestation to detect abnormalities of fetal growth and polyhydramnios. It may be indicated earlier in some women, for example for women unsure of their dates, or those with morbid obesity or suspected undiagnosed non-insulin-dependent diabetes. Ultrasonography may need to be repeated if any abnormality is detected. Timing of delivery The possibility that diagnosis of GDM may lead to increased obstetric intervention, including induction of labour and caesarean section,36 is a concern. Delivery before full term is not indicated unless there is evidence of macrosomia, polyhydramnios, poor metabolic control or other obstetric indications (eg, pre-eclampsia or intrauterine growth retardation).37 Continuation of the pregnancy in uncomplicated GDM to 10 days beyond term is acceptable provided that indications from fetal monitoring are reassuring. Delivery During labour, good glycaemic control needs to be maintained while avoiding hypoglycaemia. Lower insulin requirements are common during labour (often no insulin is necessary). Fetal surveillance is needed, as it is for any high risk pregnancy. A paediatrician should be present at the delivery if significant neonatal morbidity is suspected. The maternal blood glucose level should be monitored for 24 hours postpartum and, if indicated, continued for longer. Neonatal management The neonates of mothers with GDM are at risk of all the complications of infants born to mothers with overt diabetes, particularly those infants born macrosomic (birth weight >4000 g).38 The neonates should be observed closely after delivery for respiratory distress. Capillary blood glucose should be monitored at 1 hour of age and before the first four feeds (and for up to 24 hours in high risk neonates). Currently, some amperometric blood glucose meters are acceptable for use in neonates, provided that suitable quality control procedures and operator training are in place. A neonatal blood glucose level <2.0 mmol/L needs to be verified by repeat testing (laboratory verification is preferred but should not delay the initiation of treatment). Levels <2.0 mmol/L should be considered abnormal and treated. If the baby is obviously macrosomic, calcium and magnesium levels should be checked on Day 2. Breastfeeding is actively encouraged. Maternal follow-up It is important that women with GDM be counselled with regard to their increased risk of developing permanent diabetes. They should be made aware of the symptoms of hyperglycaemia. Advice should be given about the importance of healthy eating and exercise patterns. Contraceptive advice should be given in the puerperium, and women should be advised to plan future pregnancies and be reviewed medically by their general practitioner before conception (a pre-conception OGTT should be considered). An OGTT, using WHO criteria for the non-pregnant population, should be performed at 6-8 weeks' postpartum to exclude permanent diabetes. Repeat OGTTs should be performed at least every two years (possibly at the same time as the cervical cancer screening). Impaired glucose tolerance merits careful follow-up, which should include at least twice-yearly checks for frank diabetes in addition to assessment of other risk factors for macrovascular disease. The rates of development of permanent diabetes are much higher in several non-European ethnic groups. For example, the prevalence of type 2 diabetes in Polynesian women having a postpartum OGTT has been reported to be 30%.39 Life-table analysis in a cohort of Latino women shown to have normal glucose tolerance in the postpartum period after pregnancy complicated by GDM revealed a 47% cumulative incidence of type 2 diabetes 5 years after delivery.40 Similarly, 62% of women in Trinidad have been reported to develop type 2 diabetes after 3.6-6.5 years of follow-up.41 Follow-up OGTTs, therefore, should be more frequent than every two years in those groups at highest risk. Directions for future research ADIPS emphasises that, due to a lack of good quality randomised controlled clinical trials in the area of GDM, these guidelines are based on what is a reasonable consensus of informed opinion in Australasia. They are designed as a guide to practical management rather than a strict protocol. It is expected that the guidelines will not be static but will evolve as the results of clinical trials become available. Carefully designed, randomised controlled clinical trials are needed in order to determine: Whether universal screening programs are warranted; The optimal criteria for diagnosis of GDM; The costs v. benefits of the team approach; Optimal management (eg, clarification of the indications for insulin therapy); The role of follow-up programs for affected mothers and babies; and Possible interventions to reduce the rates of development of permanent diabetes in the mother. One such trial is the prospective Australasian Carbohydrate Intolerance Study in Pregnancy (ACHOIS), which aims to clarify what degree of maternal hyperglycaemia results in specific adverse outcome. In the design of these trials consideration needs to be given not only to perinatal outcome, but also to the potential long term benefits of diagnosis and treatment for both the baby and the mother. Acknowledgements The assistance of all members of ADIPS who contributed to the consensus statement is gratefully acknowledged. Valerie Arnol's assistance is also gratefully acknowledged. References Metzger BE, editor. Proceedings of the third international workshop-conference on gestational diabetes mellitus. Diabetes 1991; 40 Suppl 2: 1-201. O'Sullivan JB, Charles D, Mahan CM, Dandrow RV. Gestational diabetes and perinatal mortality rate. Am J Obstet Gynecol 1973; 136: 901-904. Pettitt DJ, Knowler WC, Baird HR, Bennett PH. Gestational diabetes: infant and maternal complications of pregnancy in relation to third trimester glucose tolerance in Pima Indians. Diabetes Care 1980; 3: 458-464. Oats JN, Beischer NA. Gestational diabetes. Aust N Z J Obstet Gynaecol 1986; 26: 2-10. Hod M, Merlob P, Friedman S, et al. Gestational diabetes mellitus: a survey of perinatal complications in the 1980s. Diabetes 1991; 40 (Suppl 2): 74-78. Van Asche FA, Aerts L, Holemans K. The effects of maternal diabetes on the offspring. Baillieres Clin Obstet Gynaecol 1991; 5: 485-492. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers: relationship to fetal hyperinsulinism. Diabetes Care 1995; 18: 611-617. Pettitt DJ. Diabetes in subsequent generations. In: Dornhurst A, Hadden DR, editors. Diabetes and pregnancy: an international approach. Chichester: J Wiley and Sons, 1996: 367-376. Simmons D, Robertson S. Influence of maternal insulin treatment on the infants of women with gestational diabetes. Diabet Med 1997; 14: 762-765. O'Sullivan JB. The Boston Gestational Diabetes Studies: review and perspectives. In: Sutherland HW, Stowers JM, Pearson DWM, editors. Carbohydrate metabolism in pregnancy and the newborn. London: Springer-Verlag, 1989: 287-294. Greene MF. Screening for gestational diabetes. N Engl J Med 1997; 337: 1625-1626. Jarrett RJ. Should we screen for gestational diabetes? BMJ 1997; 315: 736-737. Soares J de AC, Dornhurst A, Beard RW. The case for screening for gestational diabetes. BMJ 1997; 315: 737-739. Moses RG, Colagiuri S. The extent of undiagnosed gestational diabetes mellitus in New South Wales. Med J Aust 1997; 167: 14-16. Beischer NA, Oats JN, Henry OA, et al. Incidence and severity of gestational diabetes mellitus according to country of birth in women living in Australia. Diabetes 1991; 40: 35-38. Beischer NA, Wein P, Sheedy MT, Steffen B. Identification and treatment of women with hyperglycaemia diagnosed during pregnancy can significantly reduce perinatal mortality rate. Aust N Z J Obstet Gynaecol 1996; 36: 239-247. Moses R, Griffiths R, McPherson S. The incidence of gestational diabetes in the Illawarra area of New South Wales. Aust N Z Obstet Gynaecol 1994; 34: 425-427. Martin FIR, Ratnaike S, Wootton A, et al. The 75 g oral glucose tolerance in pregnancy. Diabetes Res Clin Pract 1995; 27: 147-151. Yue DK, Molyneau LM, Ross GP, et al. Why does ethnicity affect prevalence of gestational diabetes? The underwater volcano theory. Diabet Med 1996; 13: 748-752. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997; 20: 1183-1197. Naylor CD, Sermer M, Chen E, Farine D. Selective screening for gestational diabetes mellitus. N Engl J Med 1997; 337: 1591-1596. Martin FIR. The diagnosis of gestational diabetes. Med J Aust 1991; 155: 112. O'Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes 1964; 13: 278-285. World Health Organization Study Group, Diabetes Mellitus. World Health Organ Tech Rep Ser 1985; 727: 13-14. McCance DR, Pettitt DJ, Hanson RL, et al. Birth weight in non insulin dependent diabetes. Thrifty genotype, thrifty phenotype or surviving small baby genotype? BMJ 1994; 308: 942-945. Jovenovic-Peterson L, Peterson CM. Is exercise safe or useful for gestational diabetic women? Diabetes 1991; 40 Suppl 2: 179-181. De Veciana M, Major CA, Morgan MA, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995; 333: 1237-1241. Langer O, Rodriguez DA, Xenakis EMJ, et al. Intensified versus conventional management of gestational diabetes. Am J Obstet Gynecol 1994; 170: 1036-1047. American Diabetes Association: clinical practice recommendations 1997. Diabetes Care 1997; 20 Suppl 1: S1-S70. Hare JW. Gestational diabetes mellitus. Levels of glycemia as management goals. Diabetes 1991; 40 Suppl 2: 193-196. Garner P, Okun N, Keely E, et al. A randomized controlled trial of strict glycemic control and tertiary level obstetric care versus routine obstetric care in the management of gestational diabetes: a pilot study. Am J Obstet Gynecol 1997; 177: 190-195. Langer O, Berkus M, Brustman L, et al. Rationale for insulin management in gestational diabetes mellitus. Diabetes 1991; 40 Suppl 2: 186-190. Diamond T, Kormas N. Possible adverse effect of insulin lispro. N Engl J Med 1997; 337: 1009-1010. Landon MB, Langer O, Gabbe SG, et al. Fetal surveillance in pregnancies complicated by insulin-dependent diabetes mellitus. Am J Obstet Gynecol 1992; 167: 617-621. Carr DB, Gabbe S. Gestational diabetes: detection, management and implications. Clin Diabetes 1998; 16: 4-11. Hunter DJS, Keirse MJNC. Gestational diabetes. In: Chalmers I, Enkin M, Keirse MJ NC, editors. Effective care in pregnancy and childbirth. Vol 1. Oxford: Oxford University Press, 1989: 403-410. Rasmussen MJ, Firth R, Roley M, Stronge JM. The timing of delivery in diabetic pregnancy: a 10-year review. Aust N Z J Obstet Gynaecol 1992; 32: 313-317. Maresh M, Beard RW, Bray CS, et al. Factors predisposing to and outcome of gestational diabetes. Obstet Gynaecol 1989; 74: 542-546. Simmons D, Conroy C, Thompson C. Diabetes in pregnancy in South Auckland. Proceedings of the Australasian Diabetes in Pregnancy Society Annual Scientific Meeting, Melbourne, 1995. Melbourne: ADIPS, 1995: 55. Kjos SL, Peters RK, Xiang A, et al. Predicting future diabetes in Latino women with gestational diabetes. Utility of early postpartum glucose tolerance testing. Diabetes 1995; 44: 586-591. Ali Z, Alexis SD. Occurrence of diabetes mellitus after gestational diabetes mellitus in Trinidad. Diabetes Care 1990; 13: 527-529. Authors' details Department of Diabetes and Endocrinology, Royal Hobart Hospital, Hobart, TAS. Linda Hoffman, MD, FRACP, Visiting Specialist. School of Nutrition and Public Health, Deakin University, and Geelong Hospital, Geelong, VIC. Chris Nolan, PhD, FRACP, Postdoctoral Research Fellow, and Visiting Specialist. Department of Endocrinology, The Canberra Hospital, Canberra, ACT. J Dennis Wilson, MD, FRACP, Director of Endocrinology. Master Misericordiae Mothers' Hospital, South Brisbane, QLD. Jeremy J N Oats, DM, FRACOG, Director, and Clinical Professor of Obstetrics and Gynaecology. Department of Medicine, Middlemore Hospital, University of Auckland, Auckland, New Zealand. David Simmons, MD, FRACP, Senior Lecturer in Medicine. Reprints: Associate Professor L Hoffman, Department of Diabetes and Endocrinology, Royal Hobart Hospital, 48 Liverpool Street, Hobart, TAS 7001. - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Linda Hoffman · Chris Nolan · David Simmons

Tuberculosis in children in Australia: strategies for control David Isaacs and Craig M Mellis, on behalf of the Paediatric Special Interest Group of the Australasian Society for Infectious Diseases* and the Australasian Paediatric Respiratory Group** MJA 1998; 168: 121-124 Introduction - Epidemiology - Childhood tuberculosis - Child advocacy - Control of tuberculosis - Acknowledgements - References - Paediatric Special Interest Group of ASID - Australasian Paediatric Respiratory Group - Authors' details - - ©MJA1998 Introduction Globally, tuberculosis (TB) is responsible for more deaths per year than any other infection. The World Health Organization estimated that in 1990 there were 7.5 million new cases of TB; 1.3 million were in children under 15 years of age, of whom 450 000 died.1 TB is relatively rare in Australian children, but, because of the associated high morbidity and mortality and the risk of later reactivation of disease, it should not be neglected. This paper outlines strategies to control paediatric TB. Tuberculosis in childhood is different from that in adults, and requires different expertise. This position paper, a consensus by paediatric infectious disease and respiratory specialists, outlines strategies for managing childhood TB in Australia. A companion paper, in preparation, will address strategies applicable to New Zealand. A further paper will deal with specific details of management of paediatric tuberculosis, including diagnosis and treatment. Epidemiology While the incidence of TB in industrialised countries has fallen to very low levels with improving living conditions, in the United States the steady decline in incidence of TB has halted. From 1985 to 1992 there was a 20% increase in reported cases in both adults and children1-4 (although this situation has now improved5 ). Further, the US has experienced an increase in the prevalence of infection with multidrug-resistant strains of TB.2,4 This increase was the result of an association of HIV infection and TB, increasing poverty, immigration from countries with high TB prevalence, and decreased public health funding.4,5 The re-emergence of TB as a problem in the USA has caused other industrialised countries to re-examine policies for the prevention and management of this disease. Tuberculosis is not presently a major problem in Australia. Its incidence has remained stable since 1986 at 5.5-6.0 cases per 100 000 population per year.6-9 The number of notified cases in children aged 0-14 years has fallen from 70 in 1991, to 45 in 1992, 37 in 1993, and 33 in 1994.7-9 Two childhood deaths from TB were notified in 1992; none have been notified since. While most TB notifications are made from New South Wales and Victoria, the rate of notifications is highest in the Northern Territory. The notification rate is lowest in non-indigenous Australian-born people (1.5-2.0 per 100 000), while Aboriginality is associated with a higher incidence (10-13 per 100 000).8,9 However, being born overseas is associated with an even higher incidence, which has been consistently reported at around 15 per 100 000 for the past three years.7-9 Childhood tuberculosis Starke10 has emphasised the differences between paediatric and adult tuberculosis. Children generally have a much smaller bacterial population and there is less secondary resistance. Cavitary lesions are very rare, but children have a greater propensity for extrapulmonary disease. While children tolerate higher doses of medication relative to body weight, with lower rates of adverse reactions, paediatric formulations (syrups or soluble powders) are not always available. Paediatric tuberculosis is usually acquired from contact with an infected adult, and children with TB are generally at low risk of infecting others. Child advocacy In Australia, children with suspected or proven tuberculosis may be managed by paediatricians, at adult chest clinics, or by specialists in paediatric or adult infectious diseases.9 Given the low incidence of childhood cases, this variety of attending specialists is not surprising and does not necessarily mean that current management of paediatric TB is inappropriate. In large cities there may be enough children with TB or receiving preventive therapy to warrant specialised paediatric TB clinics that combine both paediatric and public health expertise. However, in many parts of Australia, children with TB or TB contact are managed in chest clinics by chest physicians who are expert in tuberculosis, but may lack paediatric knowledge and skills. On the other hand, the regional paediatrician, with experience in examining and managing children, may have little knowledge and experience of childhood tuberculosis. Although paediatric TB is rare, child contacts of adults with TB are much less rare, and preventive therapy of children requires expert knowledge and supervision.3,10 Guidelines on tuberculosis concentrate on adult aspects of TB, and tend to neglect paediatric aspects.11-13 As paediatricians are child advocates and experts in child health, they should be more involved in the care of children with TB,14 not necessarily as sole carers, but at least in consultation. Paediatricians can provide clinical expertise and advice in areas such as compliance with medication, particularly for very young children. Recommendation: Paediatricians should be consulted and involved in the management of TB in children whenever possible. [Consensus view, not addressed by the NHMRC TB Working Party.11] Control of tuberculosis The most critical aspect of control of tuberculosis is the existence of appropriate public health programs. The important strategies in TB control are: BCG vaccination; Screening of children at high risk; Contact tracing; and Appropriate duration of drug therapy. BCG vaccine Bacille Calmette-Guerin (BCG) vaccine was first used in humans in 1921, and few attempts have been made since then to develop improved vaccines against TB. BCG vaccine is moderately effective: a recent meta-analysis15 gave its protective efficacy as 50% against any TB disease, 64% against TB meningitis, and 71% against death from TB. Occasional cases of TB meningitis occur in children in Australia6-9 and might be prevented by BCG vaccination. The NHMRC TB Working Party currently recommends BCG vaccination for three groups of children:11 Aboriginal and Torres Strait Islander neonates in regions of high incidence; Neonates born to patients with leprosy (because of cross-protection by BCG against leprosy); and Children under the age of five years who will be travelling to live in countries of high TB prevalence for long periods. The NHMRC TB Working Party11 states that BCG vaccine should be considered for: Neonates who will be living in a household which includes immigrants or visitors recently arrived from countries of high TB prevalence (and neonates in families who have returned to visit the homes of relatives in countries of high prevalence); and Children and adolescents aged less than 16 years who continue to be exposed to a patient with active TB, and where the child or adolescent cannot be given preventive isoniazid therapy, or the person with active disease has organisms resistant to both rifampicin and isoniazid. We believe these latter two "considerations" should be changed to "recommendations" to prevent occasional, but devastating, cases of tuberculosis in these children. In particular, neonates whose parents are from South-East Asia or the Indian subcontinent should be given BCG at birth. There is currently no information on how many children receive BCG vaccine in Australia each year, either as an absolute number or as a proportion of those eligible. Clearly, such information would be a great advantage in analysing BCG vaccine efficacy, and thus in evaluating the current NHMRC recommendations. The Australian Childhood Immunisation Register, implemented in 1996, monitors compliance with some vaccines, but not with BCG as yet. Studies are needed on the proportion of eligible children who receive BCG vaccine, and on side effects of BCG vaccination. Recommendations: We support the indications for BCG vaccination as recommended by the NHMRC TB Working Party, but feel that BCG should be recommended in all five situations detailed above. [Consensus opinion based on the high rate of TB in children exposed to adults with TB. This recommendation has also been made in the Australian immunisation procedures handbook,16 but not by the NHMRC TB Working Party,11 in 1989.] We strongly urge the Federal Government to put in place mechanisms to audit the number of children vaccinated with BCG vaccine each year. [Consensus opinion.] Mantoux screening In Australia, Mantoux skin testing is usually performed with 10 tuberculin units of purified protein derivative (PPD), although one unit only may be used if there is a high risk of TB.16 In the United States,17 Mantoux skin testing is performed with five tuberculin units of PPD. US authorities' interpretation of a positive Mantoux skin test is shown in the Box; there is currently no recognised Australian interpretation of skin test positivity. At present, the Committee on Infectious Diseases of the American Academy of Pediatrics (the "Red Book" committee)17 recommends annual tuberculin testing of children at high risk, but not of children at low risk. Six months of isoniazid preventive therapy is recommended for children who are Mantoux positive without disease,12 as this is as effective as nine months' duration of therapy18 and has a better risk-benefit analysis.19 While Australian children are not routinely tested with tuberculin, two recent surveys of the Mantoux status of 13-year-old20 and six-year-old21 Sydney schoolchildren showed t hat being born overseas was the major risk factor for being Mantoux-positive. In addition, the later the child left the country of birth, the greater the risk of being Mantoux- positive. Australian-born children with one or both parents born overseas were not at increased risk of being Mantoux- positive compared with Australian-born children of Australian-born parents. As most Mantoux-positive children in Australia were born overseas, it is important to screen children who are migrating to Australia from countries with a high prevalence of TB. Short visits (e.g., holidays) overseas are associated with a low risk of becoming infected with TB. Although short term visitors to Australia occasionally transmit TB, screening them would be extremely difficult, and this is not done routinely. However, screening might be indicated in special circumstances (e.g., a visitor from a high endemic area with chronic respiratory symptoms). Routine annual Mantoux screening is not justified by the available data. Recommendations: Children born overseas who are migrating to Australia from a country with a high prevalence of tuberculosis should be screened by Mantoux testing with or without a chest x-ray on entry into Australia. [Based on evidence,20,21 but not currently recommended by the NHMRC TB Working Party.11] Children born in Australia should not be screened annually by Mantoux testing. [Based on evidence20,21 and consistent with NHMRC TB Working Party recommendations.11] Visitors to Australia from areas of high TB incidence should not be routinely screened, but neonates exposed to such visitors should be vaccinated with BCG. [Consensus opinion, consistent with Australian immunisation procedures handbook.16] Mantoux-positive children with no evidence of TB disease should be given preventive therapy with isoniazid for six months. [Based on evidence18,19 and consistent with NHMRC TB Working Party recommendations.11] Contact tracing Diligent tracing of the adult source of paediatric TB infection through public health networks continues to be an important step in preventing the spread of TB. Appropriate duration of drug therapy The emergence of highly resistant and multiply resistant strains of M. tuberculosis has re-emphasised the importance of good management of TB, and the development of innovative management and control strategies. The emergence of resistant strains is thought to be the result of failure of patients with TB to complete courses of chemotherapy. In New York, this was a consequence of failure to supervise patients' therapy as a result of cuts in health funding in the 1980s.4,5 In Australia, some States supervise all antituberculous therapy, while others use targeted supervision of patients considered to be at risk of being non-compliant. In general, there are insufficient public health staff to ensure supervision of preventive therapy with isoniazid. Continued supervision of therapy (either full or targeted supervision) is important to prevent the emergence of resistant strains in Australia, and requires funding. Recommendation: Specifically funded TB control programs need to be maintained in each State and Territory in Australia. [Consensus opinion.] This document has been discussed by the Writing Panel of the Paediatric Special Interest Group of the Australasian Society for Infectious Diseases (ASID), circulated to all members, and ratified by the ASID Council. It was discussed at the 1996 meeting of the Australasian Paediatric Respiratory Group, and circulated to all members for comment. It was sent to Dr Greg Stewart, Chair of the NHMRC Working Party on Towards elimination of tuberculosis II. Guidelines and protocols for controlling tuberculosis disease in Australia, and to the Public Health Association of Australia. Acknowledgements Helpful comments were received from Dr T Konstantinos, Dr Graeme Oliver, Dr Graham Simpson and Professor Louis Landau. References Raviglione MC, Snider DE, Kochi A. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 1995; 273: 220-226. Report from the Centers for Disease Control and Prevention: tuberculosis morbidity, United States, 1992. JAMA 1993; 270: 1525. Starke JR, Jacobs RF, Jereb J. Resurgence of tuberculosis in children. J Pediatr 1992; 120: 839-855. Drucker E, Alcabes P, Bosworth W, Schell B. Childhood tuberculosis in the Bronx, New York. Lancet 1994; 343: 1482-1485. Frieden TR, Fujiwara PI, Washro RM, Hamburg MA. Tuberculosis in New York City -- turning the tide. N Engl J Med 1995; 333: 229-233. Cheah D. Tuberculosis notification rates, Australia, 1991. Commun Dis Intell 1992; 16: 398-400. Hargreaves J. Tuberculosis notifications in Australia, 1992. Commun Dis Intell 1994; 18: 330-337. Hargreaves J. Tuberculosis notifications in Australia, 1993. Commun Dis Intell 1995; 19: 332-341. Oliver G. Tuberculosis notifications in Australia, 1994. Commun Dis Intell 1996; 20: 108-115. Starke JR. Multidrug therapy for tuberculosis in children. Pediatr Infect Dis J 1990; 9: 785-793. National Health and Medical Research Council. Tuberculosis in Australia and New Zealand into the 1990s. Canberra: AGPS, 1989. Grossman M, Hopewell PC, Jacobs RF, et al. Consensus: management of tuberculin-positive children without evidence of disease. Pediatr Infect Dis J 1988; 7: 243-246. NSW Health Department. Controlling tuberculosis in New South Wales. Sydney: NSW Health, 1993. Forfar JO. Child health in a changing society. Oxford: Oxford University Press, 1988. Colditz GA, Brewer TF, Berkey JCS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis. JAMA 1994; 271: 698-702. National Health and Medical Research Council. The Australian immunisation procedures handbook. 6th ed. Canberra: AGPS, 1997. American Academy of Pediatrics. Report of the Committee on Infectious Diseases. 23rd ed. Illinois: The Academy, 1994. Comstock GW, Baum G, Snider DE Jr. Isoniazid prophylaxis among Alaskan Eskimos. Am Rev Respir Dis 1979; 119: 827-830. International Union Against Tuberculosis, Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis. Five years of follow-up in the IUAT trial. Bull World Health Organ 1982; 60: 555-564. Alperstein G, Fett MJ, Reznik R, et al. The prevalence of tuberculosis infections among Year 8 school children in inner Sydney in 1992. Med J Aust 1994; 160: 197-201. Alperstein G, Morgan K, Fett MJ, et al. Prevalence of tuberculosis infection among primary school entry children in Sydney. Aust J Pub Health 1996; 20: 123-128. *Paediatric Special Interest Group of ASID R Benn, MA Burgess, D Burgner, D Caplan, J Carapetis, P Collignon, R Doherty, G Eagles, J Faoagali, M Ferson, K Forsyth, S Garland, GL Gilbert, D Gordon, K Grimwood, J Hanna, D Hansman, G Hogg, D Holdaway, M Holloway, D Isaacs, H Jeffery, C Jones, A Kakakios, A Kesson, D Lennon, D McCrossin, P McIntyre, A McGregor, D McIntosh, M Nissen, D Roberton, R Robins-Brown, J Robson, J Royle, L Voss, S Wesselingh, J Whitson, B Wild, A Yung. The writing panel of the Paediatric Special Interest Group of ASID comprised GL Gilbert, MA Burgess, M Ferson, S Garland, K Grimwood, G Hogg, D Isaacs, and P McIntyre. **Australasian Paediatric Respiratory Group H Allen, I Asher, P Van Asperen, G Bowes, B Clements, D Cooper, P Cooper, K Dawson, P Field, P Francis, N Freezer, J Gillies, M Haifer, M Harris, R Henry, A Isles, A Kemp, D Kennedy, L Landau, J Martin, CM Mellis, S Sawyer, B Masters, J Morton, T Olinsky, P Pattemore, P Phelan, C Robertson, P Robinson, P Sly, G Smith, P Le Souef, R Staugas, S Stick. Authors' details Australasian Society for Infectious Diseases, Sydney, NSW. David Isaacs, FRACP, Member of the Paediatric Special Interest Group; Craig M Mellis, FRACP, Member of the Australasian Paediatric Respiratory Group. Reprints will not be available from the authors. Correspondence: Associate Professor D Isaacs, Department of Immunology and Infectious Diseases, Royal Alexandra Hospital for Children, Westmead, NSW 2145. E-mail: davidi AT rich.edu.au - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Adult domiciliary oxygen therapy Position statement of the Thoracic Society of Australia and New Zealand Iven H Young, Alan J Crockett and Christine F McDonald Evidence shows that patients with chronic obstructive pulmonary disease and a stable daytime PaO2 of 55 mm Hg or less will have longer life expectancy if given supplemental oxygen to keep the PaO2 above 60 mm Hg, preferably for longer than 15 hours a day, including sleep. There is some evidence for improved quality of life. It is reasonable to offer this therapy for other lung diseases which cause chronic hypoxaemia, and there are also less well defined indications for supplemental oxygen during exercise, sleep and air travel. (MJA 1998; 168: 21-25) → This position statement has been superseded by a new statement published in 2005. Click here for the new statement. Introduction - Indications - Contraindications - Investigations - Reassessment - Dangers - Quality of life - Methods of domiciliary oxygen delivery - Authorisation of oxygen therapy - References - Authors' details - - ©MJA1997 Introduction Domiciliary oxygen therapy is an effective but potentially expensive therapy that should be prescribed to those in whom there is evidence for benefit. This position paper is a consensus statement based on evidence from English-language publications up to 1996 obtained by search of MEDLINE with keywords domiciliary oxygen, home oxygen and LTOT (long term oxygen therapy). The paper is an update of the position statement published in the Journal in 1991.1 Supplementary oxygen may benefit patients whose disability is related to decreased oxygen concentration in arterial blood. The most common cause of chronic hypoxaemia in Australia is chronic obstructive pulmonary disease (COPD), and there is more substantial information about use of domiciliary oxygen in this condition than in any other. In COPD, domiciliary oxygen is the only therapy (apart from smoking cessation) shown to reduce mortality.2,3 There is also evidence that it alleviates right heart failure caused by cor pulmonale, enhances neuropsychological function, and improves exercise performance and capacity to undertake the activities of daily living.4 Although long term oxygen therapy has been best studied in COPD, other possible indications include hypoxaemia associated with cyanotic congenital heart disease, severe congestive cardiac failure, diffuse interstitial lung disease, advanced lung cancer or cystic fibrosis,5 and, in general, any illness with chronic hypoxaemia as an important feature. In the absence of hypoxaemia, oxygen therapy is unlikely to contribute usefully to relief of dyspnoea, heart failure or angina. Indications Continuous (at least 15 hours/day) oxygen therapy: Long term continuous oxygen therapy should be considered for patients with stable chronic lung disease, particularly COPD, who have an arterial PO2 (PaO2) consistently less than or equal to 55 mm Hg when breathing air, at rest and awake. At assessment (see Investigations), the patient's condition must be stable and all reversible factors (such as anaemia) should be remediated.6 Because gas exchange may improve substantially on ceasing cigarette smoking, assessment should be made at least a month after the patient has stopped smoking. Polycythaemia (Hb > 170 gm/L), clinical or electrocardiographic (ECG) evidence of pulmonary hypertension, as well as episodes of right heart failure, are consistent with the systemic effects of chronic hypoxaemia and strengthen the case for therapeutic use of oxygen. Patients with these complications should be prescribed continuous oxygen if their stable PaO2 is 55-59 mm Hg. In COPD, continuous oxygen therapy is of most benefit for patients with increased arterial PCO2 ( >45 mm Hg).3 As the benefit has been shown to increase with increasing daily use of oxygen for up to 19 hours per day,3 patients should be advised to use oxygen whenever the physical restriction imposed by the oxygen therapy is not onerous. Intermittent oxygen therapy: The use of intermittent oxygen may be considered for: Patients with fibrotic or obstructive lung diseases during exercise, as supplementary oxygen may improve exercise capacity. Benefit cannot be predicted by a resting test and may occur irrespective of resting or exercise hypoxaemia. Benefit should be established by comparing exercise endurance when breathing oxygen and when breathing air (using a treadmill, stationary bicycle or six-minute walk test). Room air is probably adequate for this comparison, as there appears no difference in exercise endurance between breathing room and cylinder air.7 The Society's position on the controversal use of oxygen during exercise is summarised in Box 1. Patients with acute asthma living in isolated areas or prone to sudden life-threatening episodes while they are awaiting medical attention or evacuation by ambulance. During air travel, particularly long distance flights out of Australia. Commercial passenger aircraft operate at cabin pressures between about 1500 and 3000 metres above sea level, with the lowest pressure likely to be experienced for a significant time being equivalent to 2500 metres above sea level. This is analogous to breathing 15% oxygen at sea level. Sufficient supplementary oxygen should be given during flight to keep the PaO2 above 50 mm Hg, which is commonly achieved by increasing the usual flow by 1-2 L/min. Patients who qualify for continuous oxygen at home will require this supplementation. Others can be tested for the effects of 15% oxygen in the laboratory before the flight. Further, those travelling to high-altitude destinations may need an increase in their oxygen prescription during their sojourn.4 Patients with late stage interstitial or neoplastic lung disease with significant hypoxaemia. Supplementary oxygen may provide symptomatic relief. Patients in the latter category will generally have a life expectancy of three months or less. Duration of use may be extended as long as necessary to relieve symptoms. The prescription of home oxygen for patients with chronic heart failure and/or angina is not well supported by evidence of efficacy, and a decrease in mortality with this therapy has not been verified. A high inspired oxygen concentration of 50% may modestly improve exercise duration in heart failure,8 but concentrations this high are difficult to attain with current home delivery systems. Nocturnal oxygen therapy: This may be indicated in patients with hypoxaemia during sleep. This diagnosis should be considered in patients whose arterial gas tensions are acceptable when awake, but who have daytime somnolence, polycythaemia or right heart failure. The clinical importance of isolated nocturnal hypoxaemia (i.e., without daytime hypoxaemia or obstructive sleep apnoea) was recently established.9 In patients with this condition, nocturnal oxygen at 3 L/min over three years was found to reduce pulmonary hypertension, but not to alter mortality, in comparison with a control group over this relatively short period. Although data are insufficient to make rigorous recommendations for this group, and further studies are needed, the current consensus is that those whose nocturnal arterial oxygen saturation falls to 88% or less should be treated with nocturnal oxygen. Hypoxaemia during sleep should be distinguished from sleep apnoea caused by upper airway obstruction, which requires other forms of therapy (such as continuous positive airway pressure and nocturnal ventilation). The diagnosis is by formal sleep studies. These are essential if obstructive sleep apnoea is suspected in a patient with chronic airflow limitation; this combination is suggested by daytime hypercapnia. Contraindications Supplementary oxygen is not indicated for: Patients with severe airflow limitation whose main complaint is dyspnoea, but who maintain a PaO2 greater than 60 mm Hg and who show no secondary effects of chronic hypoxia; Patients who continue to smoke cigarettes, because of the increased fire risk and the probability that the poorer prognosis conferred by smoking will offset treatment benefit; Patients who have not received adequate therapy of other kinds (e.g., inhaled and oral bronchodilators, treatment of right ventricular failure and of any respiratory infection); and Patients who are not sufficiently motivated to undertake the discipline required in oxygen therapy. Investigations Establish the nature and severity of the pulmonary disorder responsible for hypoxaemia (usually obstructive or fibrotic lung disease) by appropriate tests, including objective tests of pulmonary function. Undertake clinical, ECG, echocardiographic and radiological assessment of right heart failure and pulmonary hypertension. Measure haemoglobin level. Polycythaemia, the usual response to chronic hypoxaemia in otherwise healthy people, is not always seen in those with hypoxaemia of chronic lung disease. The degree to which it is adaptive or adds to the burden of disordered function through increased blood viscosity is controversial. Anaemia is always a burden and should be investigated and corrected. Undertake other appropriate tests, according to clinical findings, for other major diseases which might be expected to seriously limit survival. As noted above, it is appropriate to prescribe oxygen for symptomatic relief in patients with a very limited prognosis. Before introducing oxygen therapy, undertake optimal treatment of the pulmonary disorder while monitoring improvement with objective tests (usually simple tests of ventilatory capacity such as FEV1 and vital capacity).6 Treatment may include maximum therapy of airway obstruction, attention to nutrition and body weight, an exercise rehabilitation program, control of infection and treatment of cor pulmonale. When the patient's condition has been stabilised and drug therapy optimised over about four weeks, the degree of hypoxaemia should be determined by measurement of arterial blood gases while the patient is breathing air at rest. This should include measurements of PaO2 at rest on at least two occasions and, when indicated, measurements of PaO2 or arterial oxygen saturation during sleep. In patients selected for oxygen therapy, assess the adequacy of relief of hypoxaemia (PaO2 > 60 mm Hg, SaO2 > 90%) and/or improvement in exercise capacity or nocturnal arterial oxygen saturation while using a practical oxygen delivery system. Reassessment Patients should be reassessed a month after starting continuous or nocturnal oxygen therapy, both clinically and by measurement of PaO2 and PaCO2 with and without supplementary oxygen. It should then be decided whether the treatment has been properly applied and whether it is worthwhile or should be abandoned. This one-month review is particularly important to confirm that the low entry PaO2 was not spurious because the patient was unstable at the time of sampling. Subsequent review should be undertaken at least annually, or more often according to the clinical situation. Some patients will show a sustained rise in PaO2 to > 60 mm Hg when breathing air, but current thinking is that this represents the reparative effects of supplementary oxygen and should not be a rationale for stopping therapy.4 This recommendation may change with further evidence. A patient having intermittent oxygen therapy should also undergo periodic reassessment, but this may be unnecessary and undesirably disruptive for those with a limited prognosis. Dangers Pulmonary oxygen toxicity has not been seen at the low rates of flow used for long-term oxygen therapy. However, supplementary oxygen in patients with increased arterial PCO2 may depress ventilation, increase physiological deadspace, and further increase arterial PCO2. This is suggested by an obvious decrease in respiratory rate and depth, as well as the development of somnolence and disorientation. In long-term oxygen therapy, the increase in arterial PCO2 is usually small and well tolerated. It was not a practical problem in two large trials, probably because patients were in a stable condition.2,3 However, serious hypercapnia may occasionally develop, making continued oxygen therapy impractical. Risk appears greater during acute exacerbations of disease. Sedatives (particularly benzodiazepines), narcotics, alcohol and other drugs which impair the central regulation of breathing should not be used in patients with hypercapnia receiving oxygen therapy. Quality of life With the potential restriction of movement imposed by long-term continuous oxygen therapy, it is possible that the treatment may only prolong suffering rather than improve quality of life. However, for patients who qualify according to the above criteria, the improvement in quality of life will mostly outweigh the restriction imposed. There is some evidence that women experience more improvement than men in several quality-of-life dimensions.10 Whether oxygen therapy is worthwhile for a particular individual must be determined by a comprehensive clinical assessment rather than solely, or mainly, by the increase achieved in PaO2. Methods of domiciliary oxygen delivery There are three methods of oxygen supply for the home: Cylinders: These contain compressed pure oxygen gas and deliver 100% oxygen at the outlet. Sizes and contents vary (see Box 2), and a regulator, flow meter, spanner and key wheel are needed to connect the tubing to the cylinder. These components are mostly interchangeable for the different cylinder sizes, although cylinder C requires a specific regulator. Several portable light-weight cylinders are available which allow the patient to leave home for several hours. Cylinders are available from Medical Gases Australia, BOC Gases and Sunrise Medical. Oxygen concentrators: These are floor-standing electrically driven devices that entrain room air, extract the nitrogen in molecular sieves and deliver oxygen at the outlet. They run off the domestic electricity supply, and, as they do not store significant amounts of gas, they must run all the time that oxygen is needed. Most of these units deliver 90%-95% oxygen at the outlet when operating at a flow rate of 2 L/min; the percentage falls with increasing flow rate (to about 78% oxygen at 5 L/min), depending on the model. All units currently available in Australia are imported, and there are several distributing agents (including Medical Gases Australia, BOC Gases, Anaesthetic Supplies, and Sunrise Medical). Rental fees are about $100 per month. A back-up standard D-size oxygen cylinder is recommended in case of concentrator breakdown or power failure. Liquid oxygen systems: These systems, now available in Australia, conserve space by storing oxygen in liquid form at 2 1831/4C (30 L of liquid oxygen is equivalent to 25 800 L of gaseous oxygen). The oxygen is delivered through coils, where it vaporises. Two tanks are needed: a large storage tank, which is filled by the supplier as required (e.g., one unit has a 25 800 L gaseous capacity, equivalent to seven E-size cylinders), and a portable unit filled from the larger tank for ambulatory use. Comparisons between supply methods There is no significant difference in the quality of oxygen delivery among the above methods. Advantages and disadvantages of each are compared in Box 3. For patients receiving intermittent oxygen, D-size cylinders or concentrators are the most appropriate mode of supply, while for most patients receiving continuous or nocturnal oxygen concentrators are favoured. Further aspects of concentrators to be considered are: Concentrators are cheaper than cylinders if use is equivalent to three E-size cylinders per month, but electricity costs must be considered (council rebates may apply). Concentrators can be wheeled around the home but are heavy (about 21-26 kg) and difficult to move upstairs and in and out of cars. Concentrators cannot be used for nebulisation, as the pressure delivered is too low (35-63 kPa, compared with 140 kPa for nebuliser pumps). If the anticipated need is for longer than two years, then it is cheaper to buy than to rent a unit. On the other hand, rental is not affected by the hours per day the machine is used and includes maintenance costs (about $180 annually). Regular maintenance of concentrators, including changing and cleaning of filters and checking of alarm systems, is essential. Conservation devices These are small devices introduced between the oxygen source and the patient to ensure that oxygen is delivered only during inspiration and not wasted during expiration. They are useful cost- and time-conserving devices for cylinders and liquid oxygen systems, especially portable units, and can prolong the use of a C-size cylinder from two to 10 hours. As many conservation devices switch on the flow by sensing negative pressure at the nares via the nasal cannula, they may not trigger if the patient mouth-breathes (unless the cannula is transferred to the mouth); many breathless patients become mouth breathers when they are more distressed. These devices are of no value with concentrators and should not be used with transtracheal delivery systems. Delivery to the patient All patients should receive careful and detailed instruction on how to operate and obtain optimal benefit from their oxygen equipment. Flow rate should be set in the range 1-5 L/min, at the lowest rate needed to maintain a resting PaO2 of 60 mm Hg (in practice, most often 2 L/min). It should be increased by 1 L/min during exercise and sleep. Humidifiers are not needed as flow rates are low, and ambient air entrainment supplies sufficient humidification for the total inspired gas. Extrasoft nasal prongs are recommended for continuous oxygen use, but may become uncomfortable at flow rates over 2-3 L/min and in the long term. Facemasks may be preferred for at least some of the time. Simple masks are adequate; complex Venturi masks are not necessary; the appropriate mask should be selected using measurements of arterial oxygen tension. Both nasal prongs and masks are also acceptable for intermittent oxygen use. In selected patients needing 24-hour oxygen therapy, transtracheal delivery systems may have advantages.12 These allow substantially lower flow rates, as the tracheal cannula fills the tracheal and upper airway deadspace with oxygen during each expiration. This may be a crucial advantage in patients needing high flow rates. In addition, portable systems become more useful with this conserving effect, and the delivery tubing can be hidden under clothing. However, care of this relatively invasive appliance is demanding -- the patient must learn to clean and replace the cannula often, as it may become obstructed by formation of "mucous balls" at the tip -- and it will be attractive to only a few. Authorisation of oxygen therapy Current guidelines for prescription through the Program of Aids for Disabled People specify that respiratory physicians and cardiologists are authorised prescribers. It could be argued that other groups should be authorised as long as the guidelines are adhered to. At present, any medical practitioner may order home oxygen if the patient meets the costs. References Breslin AB, Colebatch HJ, Engel LA, Young IH. Adult domiciliary oxygen therapy. Med J Aust 1991; 154: 474-477. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980; 93: 391-398. Report of the Medical Research Council Working Party. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1: 681-686. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. ATS Official Statement. Am J Respir Crit Care Med 1995; 152 Suppl: 77-120. Recommendations for long term oxygen therapy (LTOT). Report of a European Society of Pneumology Task Group. Eur Respir J 1989; 2: 160-165. Cooper CB, Waterhouse J, Howard P. Twelve year clinical study of patients with hypoxic cor pulmonale given long term domiciliary oxygen therapy. Thorax 1987; 52: 105-110. McKeon JL, Tomlinson JC, Tarrant PE, Mitchell CA. Portable oxygen in patients with severe chronic obstructive pulmonary disease. Aust N Z J Med 1988; 18: 125-129. Restrick LJ, Davies SW, Noone L, Wedzicha JA. Ambulatory oxygen in chronic heart failure. Lancet 1992; 340: 1192-1193. Fletcher EC, Luckett RA, Goodnight-White S, et al. A double-blind trial of nocturnal supplemental oxygen for sleep desaturation in patients with chronic obstructive pulmonary disease and a daytime PaO2 above 60 mm Hg. Am Rev Respir Dis 1992; 145: 1070-1076. Crockett AJ, Cranston JM, Moss JR, Alpers JH. Initial trends in quality of life and survival in CAL patients on domiciliary oxygen therapy. Monaldi Arch Chest Dis 1996; 51: 64-71. Kampelmacher MJ, van Kesteren RG, Deenstra M, et al. Long-term oxygen therapy. Neth J Med 1994; 44: 141-152. Christopher KL, Spofford BT, Petrun MD, et al. A program for transtracheal oxygen delivery. Assessment of safety and efficacy. Ann Intern Med 1987; 107: 802-808. (Received 8 Apr, accepted 18 Sep, 1997) Authors' details Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, NSW. Iven H Young, PhD, FRACP, Head. Department of Respiratory Medicine, Flinders Medical Centre, Adelaide, SA. Alan J Crockett, MPH, Senior Hospital Scientist. Austin and Repatriation Medical Centre, Melbourne, VIC. Christine F McDonald, PhD, FRACP, Respiratory Physician. Reprints: The Thoracic Society of Australia and New Zealand, 145 Macquarie Street, Sydney, NSW 2000. E-mail: iveny AT mail.med.usyd.edu.au Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Iven H Young · Alan J Crockett · Christine F McDonald

Specific allergen immunotherapy for asthma A Position Paper of the Thoracic Society of Australia and New Zealand and the Australasian Society of Clinical Immunology and Allergy MJA 1997; 167: 540-544 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/MJA/>". Introduction - Atopy, allergens and asthma - Rationale for using immunotherapy for asthma - Clinical trials - Allergen extracts and route of administration - Adverse effects - Practical aspects of administering immunotherapy - References - Authors' details Make a comment - - ©MJA1997 Introduction Specific allergen immunotherapy (desensitisation, hyposensitisation) is the technique of treating IgE-mediated disease with increasing doses of an allergen in order to decrease sensitivity to that allergen. First used early this century, 60 million patients annually are now treated with immunotherapy throughout the world. The only absolute indication for immunotherapy is a life-threatening reaction after a Hymenoptera (bee or wasp) sting; all other indications are relative (see indications and contraindications for immunotherapy). Many randomised controlled trials have shown that hayfever caused by airborne pollens and house dust mite responds to this therapy.1 The use of specific allergen immunotherapy in asthma remains controversial. Despite this, the Thoracic Society of Australia and New Zealand and the Australasian Society of Clinical Immunology and Allergy believe that all strategies which may impact on the morbidity and mortality of asthma should be assessed. The cost-effectiveness of this therapy also needs to be addressed in the context of the total cost of asthma in Australia, the mid-estimate of which in 1991 was $652 million (National Asthma Campaign, 1992). We present an overview and do not cover all aspects of this subject. Interested readers are referred to recent reviews.1-9 Atopy, allergens and asthma Allergy is best defined as an exaggerated response on exposure to an allergen following prior exposure, and mediated by an immune reaction involving IgE. The same clinical picture may result from non-immune mechanisms. Atopy is an increased tendency to IgE-based sensitivity resulting in production of specific IgE antibody to common environmental allergens, such as house dust mite, pollens, moulds or animal danders. This sensitisation occurs in genetically predisposed people after exposure to low concentrations of allergen; cigarette smoke and viral infections may assist in the sensitisation process. About 40% of the population is atopic, and about half of this group develop clinical disease ranging from trivial rhinitis to life-threatening asthma. After sensitisation, continuing exposure to allergens leads to a significant increase in the prevalence of asthma.10 Ninety per cent of children and 80% of adults with asthma are atopic.10 Once sensitisation has occurred, re-exposure to allergen is a risk factor for exacerbations of asthma.11 Effective management of allergic asthma includes pharmacological therapy and allergen avoidance. For example, avoiding dust mite allergen can reduce symptoms and the need for medication. Rationale for using immunotherapy for asthma Asthma is an inflammatory disease characterised by the presence of cells such as eosinophils, mast cells, basophils, and CD25+ T lymphocytes in the airway walls. There is close interaction between these cells, because of the activity of cytokines which have a variety of communication and biological effector properties. Chemokines attract cells to the site of inflammation and cytokines activate them, resulting in inflammation and damage to the mucosa.12 With chronicity of the process, secondary changes occur, such as thickening of basement membrane and fibrosis.13 An immunological reaction to allergen is the initiating event of airway inflammation in many cases of asthma.14 Continued exposure to allergen results in chronic inflammation. Current therapy aims to suppress this inflammation with inhaled corticosteroids, sodium cromoglycate, or nedocromil sodium, all of which interfere with the cellular and cytokine interactions by diverse mechanisms, but do not address the initiating event in allergic asthma. By withdrawing the allergen or altering the immune response to allergen, it is theoretically possible to control the allergic trigger of asthma. Immunological changes have been described after immunotherapy. These include an initial rise in specific serum IgE, followed by a fall, and a rise in specific IgG ("blocking antibody"). Specific IgG titres correlate poorly with the degree of protection. Immunotherapy leads to a reduction in mediator release from mast cells in vitro, alterations in lymphocyte subsets, and a downregulation of IL-4 production from T cells.15 Several studies have shown a reduction in inflammation and a decrease in bronchial hyperresponsiveness after immunotherapy.1,16,17 There are strong theoretical arguments why immunotherapy should be used early in the course of the disease, before irreversible secondary changes such as fibrosis have occurred. Further, data are emerging to suggest that immunotherapy may also influence the progression of clinical disease.3,7 Immunotherapy should not be regarded as an alternative to established forms of preventive therapy, as recommended by the National Asthma Campaign.18 A systematic cost-benefit analysis of immunotherapy has not yet been undertaken. Clinical trials There have been numerous randomised placebo- controlled double-blind trials of immunotherapy for asthma. Comparison of these trials is difficult, not only because of the inherent problems of trials involving asthma (such as standardisation of inclusion and outcome criteria), but also because of differences in allergen extracts and dosage regimens. A meta-analysis can address some of these difficulties, and has recently been applied to 20 randomised controlled trials of immunotherapy for asthma in both adults and children.19 This meta-analysis found a clinically useful improvement from immunotherapy with house dust mite and with other allergens (see Box below). It concluded that immunotherapy is a treatment option in highly selected patients (discussed more fully below) with allergic asthma. The reviews cited in this position paper,1-9 the meta-analysis19 and further controlled studies published in the last five years20-24 provide references to the most important trials of immunotherapy. Allergen extracts and route of administration Although several routes of allergen delivery have been used in immunotherapy, only subcutaneous injection has been studied in detail and shown to be effective. Giving allergen extract sublingually is not recommended as studies have failed to show long-term efficacy.25 Trials with giving birch pollen orally appeared promising, but large doses were required and there was a high incidence of side effects. Further studies of oral immunotherapy using modified preparations are under way. Intranasal administration of pollen extracts resulted in an unacceptable level of side effects. Local bronchial immunotherapy with mite extract in patients with asthma has been studied in a controlled trial but failed to produce significant clinical improvement.26 Most allergen extracts used in Australia for immuno therapy of inhalant allergy are alum-precipitated. Such preparation slows the absorption of allergen, reducing the risk of serious anaphylaxis and providing sustained immune stimulation. There is no reliable standardisation of biological activity for many allergen extracts used in Australia. Mass and concentration of active material are not useful guides to biological activity. The concentrations of the slow-release (alum-precipitated) preparations are expressed in "protein nitrogen units" and not biological activity. Aqueous preparations of some allergens, including Dermatophagoides pteronyssinus, are standardised against a WHO standard and are extremely potent. Their use in asthma should be restricted to specialist centres. Adverse effects Local reactions Mild swelling and erythema at the site of the injection is to be expected. It may persist for 24 hours or more and is not a cause for concern. A more severe reaction over 50 mm in diameter is an indication for reduction in the subsequent dose. Systemic reactions These include sneezing, bronchospasm, urticaria and, in more severe cases, anaphylaxis with hypotension and collapse. They must always be regarded seriously. Although they usually occur within 30 minutes of the injection, they may be delayed for several hours with the use of alum-precipitated preparations. Recent data from the UK estimate that the incidence of severe systemic reactions was 1 in 500 injections,1 but most occurred with aqueous extracts, and alum-precipitated extracts appeared to be much safer. The incidence of anaphylaxis with Allpyral (Bayer, Pymble, NSW), the alum-precipitated material available in Australia, was reported to be 1 in 27 854 courses of treatment, and of anaphylaxis and/or bronchospasm, 1 in 14 998 courses of treatment.27 The Committee on the Safety of Medicines, in the United Kingdom, reported in 1986 that in the 29 years from 1957 to 1986 during which 1 459 273 courses of treatment were given, there were 29 deaths from immunotherapy -- 16 in patients where the indication for therapy was asthma.27 Highly purified and potent aqueous extracts were involved in most of these deaths, and no deaths were reported with the Allpyral extract. Subsequent reports indicated a much lower incidence of anaphylaxis and deaths in France and the US,28,29 where one major difference in practice is that treatment is administered by specialists with expertise in the area. In Australia, five deaths from immunotherapy were reported to the Adverse Drug Reactions Advisory Committee in the 21 years from 1972 to 1993. Four were in patients with asthma, and in each case there was a divergence from recommended procedure. Long term adverse effects There is no increase in the prevalence of vasculitis, autoimmune disease or monoclonal gammopathies during or after immunotherapy.30 Further, there is no evidence that long term worsening of asthma occurs with immunotherapy. Practical aspects of administering immunotherapy These guidelines relate to specific allergen immunotherapy for the treatment of asthma in patients with clinical manifestations and/or need for treatment of ongoing bronchial hyperreactivity. The decision to prescribe immunotherapy is based on appropriate patient selection, appropriate antigen selection, and whether potential benefits outweigh associated risks. Only a practitioner or team with training and experience in the management of both asthma and immunotherapy should make the decision. Suitably qualified practitioners include thoracic physicians with training and expertise in allergy, or clinical immunologist/allergists with training and expertise in asthma. It is the responsibility of the supervising consultant to (a) decide whether a patient needs to be treated in a hospital, and (b) ensure that the medical practitioner giving immunotherapy receives written instructions on patient assessment and immunotherapy protocol. Informed consent according to currently accepted guidelines must be obtained from patients before starting immunotherapy. Immunotherapy should be given only by a medical practitioner familiar with immunotherapy, conversant with resuscitative procedures, and in a setting where the following resuscitation equipment is immediately available: adrenaline 1:1000 for intramuscular use (adrenaline is the drug of choice for the immediate management of systemic reactions to immunotherapy), oxygen, an inflatable bag and mask ventilator, a nebuliser and bronchodilator nebuliser solution, needles and tubing for intravenous access, intravenous fluids suitable for volume replacement, parenteral antihistamine, and parenteral corticosteroid. The practitioner and a second appropriately trained health care professional should be present during immunotherapy to assist if resuscitation is required. Each patient requires an individual dosage schedule according to the degree of sensitivity and clinical reaction to the injections. The principle of therapy is to start with a small dose and gradually increase it as tolerated. Supervising consultants will have the training and experience necessary to determine the starting dose and appropriate schedule. Flexibility in dosage is essential and rigid adherence to predetermined dosage schedules is inappropriate. Extracts should be stored in a refrigerator at 4°C , clearly marked with the patient's identifier(s) and replaced in the refrigerator immediately after use. Before injection, the extract should be examined visually and discarded if its appearance has changed. The contents of the bottle should be mixed well to avoid variation in dosage. When changing to a new batch of unstandardised extract (such as Allpyral), the first dose should be reduced by 25% to take account of possible variation in biological activity of the preparations. Each patient should have his or her own individual vial of extract -- laws in some States forbid multiple use of vials for different patients. Every patient should be assessed clinically on each occasion before an injection is given , with particular attention to stability of asthma as indicated by peak flow charts, intercurrent illness, reaction to the last injection and any change in medication. Spirometry or peak flow meter readings must be taken before injection and, if more than 20% below the best recent recorded reading for that patient, the injection should not be given. The readings should be repeated 30 minutes after the injection and immediately any lower respiratory symptoms arise during the period of observation -- a fall of 10% or more is an indication for reducing the dose of the next injection. The medical practitioner must be responsible for selecting the dose and having it checked by a second health professional. Injections are given subcutaneously, a suitable site being the tissue overlying the triceps muscle group. After introducing the needle, and before starting the injection, the plunger should be withdrawn gently to ensure that the needle is not placed intravenously. There is no consensus about the optimal time that a patient must remain under observation . However, we recommend 45 minutes, as serious reactions after that time are rare. Reactions may be delayed with alum-precipitated preparations but they are usually minor. Before discharge patients should be examined to record the size of the local reaction, ensure that there are no signs of a systemic reaction, and to repeat spirometry or peak flow readings. Patients must not engage in strenuous physical exercise or take hot baths or saunas for six hours after the injection. Patients should monitor their peak flow at home ; excessive variability would indicate a need for re-evaluation of asthma and immunotherapy. A local swelling larger than 50 mm requires a reduction in dosage. Patients should be instructed to measure the diameter of any local reaction should it increase in size after leaving medical supervision, and report this before the next injection. Some practitioners "cover" therapy by giving prophylactic antihistamines to reduce the local reactions. This practice may make it difficult to judge the effects of therapy, both locally and systemically, and to modify dosage accordingly. It may also block the initial manifestations of an anaphylactic reaction. Use of this practice is a matter of judgement, but if prophylactic drugs are used use must be consistent. Injection schedules vary with individual patients, but the Allpyral preparations are administered every 1-2 weeks until a maintenance dose is reached. Maintenance injections are administered every 2-4 weeks. It should be re-emphasised that immunotherapy schedules are individualised and fixed schedules are not recommended, particularly when aqueous extracts, which are becoming more readily available in Australia, are used. The duration of therapy for optimal management is unknown at present. With bee and wasp venom immunotherapy, there is evidence that five years of maintenance injections will provide long term protection in almost all patients. There is no corresponding evidence in inhalant allergy and practice varies. Dust mite injections are often continued for 2-3 years if there is a response, and preseasonal immunotherapy with grass pollen is repeated for 2-3 years. References Position paper on allergen immunotherapy. Report of a BSACI Working Party. Clin Exp Allergy 1993; 23 Suppl 3: 1-44. WHO/IUIS Working Group Report. Current status of allergen immunotherapy. Lancet 1989; 1: 259-261. Position paper: immunotherapy. The European Academy of Allergology and Clinical Immunology (EAACI). Allergy 1993; 48 (14 Suppl): 9-35. Platts-Mills TAE. Allergen-specific treatment for asthma. Am Rev Respir Dis 1993; 148: 553-555. Lockey RF, Bukantz SC, editors. Allergen immunotherapy. New York: Marcel Dekker, 1991. Walls RS. Desensitisation injections: do they have a role? Aust Prescriber 1989; 12: 90-92. Bousquet J, Michel F-B. Specific immunotherapy in asthma: is it effective? J Allergy Clin Immunol 1994; 94: 1-11. Malling H-J. Immunotherapy in Europe. Clin Exp Allergy 1994; 24: 515-521. Greenberger PA, editor. Immunotherapy of IgE-mediated disorders. Immunol Allergy Clin North Am 1992; 12: 1-203. Sporik RB, Chapman MD, Platts-Mills TAE. House dust mite exposure as a cause of asthma. Clin Exp Allergy 1992; 22: 897-906. Gelber LE, Seltzer LH, Bouzoukis JK, et al. Sensitization and exposure to indoor allergens as risk factors for asthma among patients presenting to hospital. Am Rev Respir Dis 1993; 147: 573-578. Corrigan CJ, Kay AB. T cells and eosinophils in the pathogenesis of asthma. Immunol Today 1992; 13: 501-506. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989; 1: 520-524. Lenfant C. Global initiative for asthma: global strategy for asthma management and prevention. NHLBI/WHO Workshop Report. Bethesda, Md.: National Institutes of Health, January 1995. (Publication No. 95-3659.) O'Brien RM, Byron KA, Varigos GA, Thomas WR. House dust mite immunotherapy results in a decrease in Der p2-specific IFN- g and IL-4 expression by circulating T lymphocytes. Clin Exp Allergy 1997; 27: 46-51. Rak S, Bjornson A, Hakanson L, et al. The effect of immunotherapy on eosinophil accumulation and production of eosinophil chemotactic activity in the lung of subjects with asthma during natural pollen exposure. J Allergy Clin Immunol 1991; 88: 878-888. Nagata M, Shibasaki M, Sakamoto Y, et al. Specific immunotherapy reduces the antigen-dependent production of eosinophil chemotactic activity from mononuclear cells in patients with atopic asthma. J Allergy Clin Immunol 1994; 94: 160-166. Asthma management handbook. 2nd ed. Melbourne: National Asthma Campaign, 1996. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-analysis of randomised controlled trials. Am J Resp Crit Care Med 1995; 151: 969-974. Bousquet J, Hejjaoui A, Soussana M, Michel F. Double-blind placebo-controlled immunotherapy with mixed grass-pollen allergoids. IV. Comparison of the safety and efficacy of two dosages of a high-molecular-weight allergoid. J Allergy Clin Immunol 1990; 85: 490-497. Haugard L, Dahl R. Immunotherapy in patients allergic to cat and dog dander. I. Clinical results. Allergy 1992; 47: 249-254. Alvarez-Cuesta EJ, Cuesta-Herranz J, Puyana-Ruiz J, et al. Monoclonal antibody-standardised cat extract immunotherapy: risk-benefit effects from a double-blind placebo study. J Allergy Clin Immunol 1994; 93: 556-566. Creticos PS, Reed CE, Norman PS, et al. Ragweed immunotherapy in adult asthma. N Engl J Med 1996; 334: 501-506. Adkinson NF, Eggleston PA, Eney D, et al. A controlled trial of immunotherapy for asthma in allergic children. N Engl J Med 1997; 336: 324-331. Bjšrksten B. Local immunotherapy is not documented for clinical use. Allergy 1994; 49: 299-301. Crimi E, Voltolini S, Troise C, et al. Local immunotherapy with Dermatophagoides extract in asthma. J Allergy Clin Immunol 1991; 87: 721. Committee on Safety of Medicines. CSM update. Desensitising vaccines. BMJ 1986; 293: 948. Warner JO, Kerr JW. Hyposensitisation. BMJ 1987; 294: 1179-1180. Stewart GE, Lockey RF. Systemic reactions from allergen immunotherapy. J Allergy Clin Immunol 1992; 90: 567-578. Katelaris CH, Walls RS. A study of possible ill effects from prolonged immunotherapy in treatment of allergic diseases. Ann Allergy 1984; 53: 257-261. Authors' details The Thoracic Society of Australia and New Zealand, Melbourne, VIC. Reprints: Dr P I Field, Honorary Secretary, 145 Macquarie Street, Sydney, NSW 2000. Australasian Society of Clinical Immunology and Allergy, Melbourne, VIC. No reprints will be available. Correspondence: Dr D Gillis, Honorary Secretary, PO Box 204, Mt Albert, VIC 3127. <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.

Consensus Statement Glycohaemoglobin: a crucial measurement in modern diabetes management Progress towards standardisation and improved precision of measurement* Peter G Colman, G Ian Goodall, Peter Garcia-Webb, Paul F Williams and Marjorie E Dunlop MJA 1997; 167: 96-98 Introduction - What is glycohaemoglobin and why should we measure it? - Types of assays available - Importance of reproducible measurement - How reliable are assays in Australia? - Progress towards standardisation - References - Authors' details - - More articles on Endocrinology Abstract Synopsis There are currently four principal glycohaemoglobin assay techniques (ion-exchange chromatography, electrophoresis, affinity chromatography and immunoassay) and about 20 different methods that measure different glycated products and report different units. Standardisation will lead to all assays reporting results in a standard unit, the HbA1c percentage of total serum haemoglobin, and should be in place within the next one to three years. In the interim, clinicians using glycohaemoglobin assays should be aware that the ranges indicating good and poor glycaemic control can vary markedly between different assays. The reproducibility of some assays may be insufficient to provide definitive evidence of changes in glycaemic control. Some assays may be so imprecise that they are unable to separate patients with good and poor control. Interim recommendations The terminology to be used for the assay is glycohaemoglobin (GHb) assay (recommendation from the combined meetings of the International Federation of Clinical Chemistry [IFCC] Working Group on HbA1c standardisation and the American Association of Clinical Chemistry [AACC] Subcommittee on Glycohemoglobin). The unit of measurement for GHb assays should be reported as %HbA1c (Diabetes Control and Complications Trial equivalent). Other units, such as % total GHb or %HbA1, should not be used. Assays producing these units should be converted to %HbA1c reporting units. Assays with high precision are highly desirable. The IFCC/AACC are currently recommending between-run coefficients of variation of less than 5% for manufacturers of kits and instruments. However, between-run coefficients of variation of less than 3% are far more clinically useful and therefore desirable. Introduction The landmark Diabetes Control and Complications Trial (DCCT)1 has focused increased attention on the importance of glycaemic control in preventing or retarding the progression of complications in patients with diabetes.2 Regular measurement of glycohaemoglobin is now recognised as an essential adjunct to self-measurement of blood glucose in achieving the best possible glycaemic control. However, clinicians using glycohaemoglobin assays should be aware of several potential problems which can confound the interpretation of the glycohaemoglobin result. What is glycohaemoglobin and why should we measure it? Glycohaemoglobin (GHb) is formed by a non-enzymatic interaction between glucose and the amino groups of the valine and lysine residues in haemoglobin. Formation of glycohaemoglobin is irreversible and the level in the red blood cell depends on the blood glucose concentration. Thus, measuring glycohaemoglobin provides a measurement of glycaemic control over time, and its use has been proven to evoke changes in diabetes treatment, resulting in improved metabolic control.3 First introduced in the 1970s, it is now accepted as a unique and important index of metabolic control and was a major outcome measure in the DCCT.1In the DCCT, 1441 patients with insulin-dependent diabetes were randomly allocated to intensive treatment and monitoring (usually with four insulin injections a day or pump treatment) with the aim of achieving normoglycaemia or to conventional treatment (usually with one or two injections a day). The effectiveness of intensive therapy was reflected in clear differences in mean blood glucose and glycohaemoglobin levels between the two groups. The intensive treatment group achieved a mean daily blood glucose level of 8.6 mmol/L and a median HbA1c value of 7.2% compared with the conventional treatment group, which achieved a mean blood glucose level of 12.8 mmol/L and a median HbA1c of 8.9%. These differences in glycaemic control were maintained over a mean period of 6.5 years and were associated with a 35%-76% reduction in retinopathy, nephropathy and neuropathy. Using the knowledge gained in the DCCT, doctors caring for patients with diabetes can now establish targets for glycaemic control that are based on observed outcomes, and which, if met, should minimise the development of complications. Inevitably, because glycohaemoglobin measurements reflect an integrated view of glycaemic control over time, the patients and their carers will place increasing reliance on the glycohaemoglobin result. So it is timely to evaluate the types of assays available, the moves toward standardisation of the reporting units and the precision and reproducibility of current assays. In the DCCT all glycohaemoglobin measurements were performed using the same closely standardised method. Unfortunately, in Australia there are currently four principal glycohaemoglobin assay techniques and about 20 different specific methods, most of which are not standardised between laboratories. Types of assays available The four principal techniques used to measure glycohaemoglobin are ion-exchange chromatography, electrophoresis, affinity chromatography and immunoassay. The techniques measure slightly different glycated products and use at least three different units for reporting the results (%HbA1c, %HbA1 and % total GHb). They can produce different values for the same patient specimen. This was demonstrated in a recent study in which four whole blood samples with HbA1c levels of 5.1% (representing non-diabetes), 6.7% (representing excellent glycaemic control), 8.5% (representing moderate glycaemic control) and 11.4% (representing poor glycaemic control) were distributed to 29 laboratories in Victoria for glycohaemoglobin determinations.4 The range of values obtained for the non-diabetic (4.1%-6.8%), good control (5.1%-9.3%), moderate control (6.7%- 11.9%) and poor control (10.1%-17.3%) specimens demonstrated extensive overlap between measurements of samples from patients with markedly different degrees of glycaemic control (Box 1). At present it is impossible to compare the results from two different laboratories; this can be confusing not only for patients but also for their carers. Laboratory- specific reference ranges are a means by which results from different laboratories can be compared, but the data used to derive such ranges are arbitrary and the categories into which different glycohaemoglobin levels are divided may be misleading. Importance of reproducible measurement A major use of the glycohaemoglobin assay is to assess changes in metabolic control that follow an alteration in treatment. The ability of any assay to reliably detect a change depends on its reproducibility (the ability of the assay and laboratory to get the same answer for the same sample each time). Reproducibility is normally expressed as the coefficient of variation (CV) of an assay. The CV is obtained by measuring the same sample at least 20 times in different assay runs and calculating the mean and standard deviation (SD) of the measurements; the CV is calculated by dividing the SD by the mean and expressing the result as a percentage. An assay with a high CV suffers from poor reproducibility and cannot demonstrate whether glycohaemoglobin levels have changed in different samples. Laboratories normally accept an assay for reporting purposes if the result for quality control samples falls within three SDs of the mean (3SD range). The imprecision of measurement of patient samples will be similar to that of the quality control samples. For example, if the result of an HbA1c assay with good precision (3% CV) was 7%, the 3SD range would be 6.37%-7.63%; for a result of 9%, the 3SD range would be 8.19%-9.81%. These two results can clearly be separated. In contrast, the same results of an assay with poor precision (6% CV) would have 3SD ranges of 5.74%-8.26% (for the 7% level) and 7.38%-10.62% (for the 9% level), and could not be differentiated. How reliable are assays in Australia? The Royal College of Pathologists of Australasia/Australasian Association of Clinical Biochemists Chemical Pathology Quality Assurance Programme provides external quality control samples for Australian laboratories that report glycohaemoglobin levels.5 The program runs on a six-monthly cycle, in which participating laboratories analyse two random samples per month, drawn from lyophilised whole blood samples representing six levels of glycohaemoglobin. The use of lyophilised samples can lead to minor variations in assay values for some methods. However, a recent study has excluded this as a complicating factor.6When measuring control samples with the value of 7.2% HbA1c (the mean outcome of intensive treatment in the DCCT), Australian laboratories reported HbA1c assay results between 6% and 9% HbA1c, while the range of values reported for all units (percentage of HbA1c, HbA1 and total GHb) was between 6% and 12.6%. When measuring control samples with the value of 8.9% HbA1c (the mean outcome level for conventional treatment in the DCCT trial), laboratories reported HbA1c values between 7.4% and 11%, while the range of values for all glycohaemoglobin units was 7.4% to 16.4%. The overlap between values obtained for these samples epitomises the problems currently facing clinicians in interpreting glycohaemoglobin levels and changes in levels reported by different laboratories. The interlaboratory CV obtained varied between 1.6% and 8.9% for the most common assays. To critically evaluate changes in HbA1c, the precision of individual laboratory assays for glycohaemoglobin must be known. For example, the difference in mean HbA1c value between the intensive and the conventional treatment groups in the DCCT was only 1.7%, and any assay used should at least be able to detect a difference of this order. With most laboratories using the 3SD range to accept or reject assay runs, glycohaemoglobin assays with CVs close to 3% are necessary to differentiate the two DCCT group means (Box 2). At 3% CV, the 3SD range of values for a patient with a true HbA1c level of 8.05 %HbA1c would be 7.33 to 8.77 %HbA1c. This range is less than ideal, but, realistically, only high pressure liquid chromatography assays currently achieve such precision. We recommend that the CV of the assay currently being used by the reporting laboratory be made available to carers who use glycohaemoglobin measurements. This will allow them to determine if the assay has the ability to differentiate between reported levels. Reference laboratories in the International Federation of Clinical Chemistry (IFCC)/American Association of Clinical Chemistry (AACC) International Standardization Programme must be able to achieve a CV below 3% at HbA1c levels of 6% and 9%.7 Manufacturers' assays should be able to achieve a CV below 5%. Currently, some GHb assays are unable to achieve these limits. Progress towards standardisation Standardisation is crucial to allow comparison of results obtained in different laboratories. A working party of the IFCC and AACC is coordinating an international effort by which all methods will be standardised to a designated method. This will be performed at the manufacturer level. Glycohaemoglobin analyser and kit manufacturers will have their assays standardised by reference laboratories established and monitored monthly by the IFCC/AACC working party. Thus, ultimately all laboratory methods will report their results in %HbA1c units which have been standardised against the DCCT method.8 Patients and carers will then be able to directly compare their level of glycaemic control against the enormous amount of data obtained by the DCCT trial on the onset and incidence of diabetes-related complications. References Larsen ML, Horder M, Mogensen EF. Effect of long-term monitoring of glycosylated hemoglobin levels in insulin-dependent diabetes mellitus. N Engl J Med 1990; 323: 1021-1025. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent diabetes mellitus. N Engl J Med 1993; 329: 977-986. Yue DK, Colagiuri S, McElduff A, Silink M. Diabetes Control and Complications Trial. Position Statement of the Australian Diabetes Society. Med J Aust 1993; 159: 803-804. Gilbert RE, Goodall I, Young V, Jerums G. Interlaboratory variation of GHb assays in Victoria, Australia. Diabetes Care 1996; 19: 730-734. Goodall I, Gill J, Penberthy L, Gilbert R. Interlaboratory variability of glycohaemoglobin. The Australian experience. In: Proceedings of the International Congress of Clinical Chemistry, 8-12 July, 1996 (editors: Martin SM, Halloran SP). Association of Clinical Biochemists, London, UK. July C 493 (ISSN 0959-9029), London, UK. Weykamp CW, Penders TJ, Muskiet FAJ, van der Slik W. Evaluation of reference material for glycated haemoglobin. Eur J Clin Chem Clin Biochem 1996; 34: 67-72. National Glycohemoglobin Standardization Program (NGSP) (Web site) http://www. missouri.edu/,diabetes/ngsp.html Hoelzel W, Miedema K. Development of a reference system for the international standardisation of HbA1c/glycohemoglobin determinations. J Int Fed Clin Chem 1996; 9: 62-67. * Consensus statement from the Australian Diabetes Society, the Royal College of Pathologists of Australasia and the Australasian Association of Clinical Biochemists Authors' details Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, VIC. Peter G Colman, FRACP, MD, Director. Special Chemistry Unit, Austin and Repatriation Medical Centre, Melbourne, VIC. G Ian Goodall, BSc, FAACB, Unit Manager. St John of God Pathology, Perth, WA. Peter Garcia-Webb, MD, FRCPA, Clinical Pathologist. Royal Prince Alfred Hospital, Sydney, NSW. Paul F Williams, MSc, PhD, Principal Hospital Scientist. University of Melbourne Department of Medicine, Melbourne, VIC. Marjorie E Dunlop, MSc, PhD, Principal Research Fellow. Reprints: Dr P G Colman, Department of Diabetes and Endocrinology, Royal Melbourne Hospital, PO Box 3050, Parkville, VIC 3050. E-mail: petercATnursing.medrmh.unimelb.edu.au Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> 1: Results of glycohaemoglobin assays of four samples in 29 Victorian laboratories4 The four samples were from patients with differing degrees of diabetes control. The closed circles represent individual laboratory results for each sample and the open circles represent the notional target value. The notional target value was set by the Biorad Diamat (Biorad Laboratories, Hercules, California) in a laboratory where the assay was referenced against the DCCT method.2 Six methods of measuring glycohaemoglobin were used by the laboratories: High pressure liquid chromatography (cation exchange, measuring HbA1c)Immunoassay (measuring HbA1c)Ion exchange chromatography (manual assay, measuring HbA1c or HbA1)Affinity chromatography (measuring total GHb but expressed as either total GHb or %HbA1c)Electrophoresis (measuring HbA1c or HbA1)Low pressure liquid chromatography (measuring HbA1c and including HbF). Back to text Back to text

Peter G Colman · Peter Garcia-Webb · Paul F Williams · Marjorie E Dunlop

Position Statement Asthma in pregnancy and lactation A position paper for the Thoracic Society of Australia and New Zealand Christine F McDonald and Jonathan G W Burdon MJA 1996; 165: 485-488 Introduction - Literature search - Effects of pregnancy on asthma - Effects of asthma on pregnancy - Management of asthma in pregnancy - Pharmacological therapy - Labour - Breastfeeding - Patient education - Monitoring - References - Author's Details - - More articles on Respiratory medicine This position statement was developed as a consensus view between the two authors and was subsequently reviewed by the Education and Research Sub-Committee of the Thoracic Society of Australia and New Zealand, whose membership comprises six respiratory physicians with a broad range of interests in research and clinical respiratory medicine. This Committee also sought the opinion of an external reviewer with expertise in the subject. The following conclusions were reached: Physiological changes which occur during pregnancy may affect asthma control. Regular monitoring (monthly or every six weeks) of asthmatic women should occur throughout pregnancy. Regular therapy, including the use of inhaled steroids, is recommended. Well-controlled asthma should have no adverse effects on pregnancy, labour or breastfeeding. Medicines used to control asthma carry less risk to the mother and baby than a severe attack of asthma. Good asthma management will result in a birth outcome similar to that experienced by women without asthma. Introduction Pregnant women with asthma should be reassured that their asthma medication carries less risk to the fetus than a severe asthma attack. Inadequately treated asthma can cause maternal and fetal hypoxaemia, which leads to complications during pregnancy and poorer birth outcomes. Here, we outline the effects of asthma on pregnancy (and vice versa) and the management of asthma during pregnancy and the postpartum period. Literature search We searched the literature, using the MEDLINE database, for the period 1985-1995 and the keywords "asthma" and "pregnancy". Standard textbooks on asthma were also reviewed. A total of 146 papers were identified and other papers contained within their references were also reviewed. Thirty-three papers were found suitable. Effects of pregnancy on asthma Although bronchial hyperresponsiveness lessens during mid-pregnancy,1 studies reporting changes in asthma severity during pregnancy show widely differing results.2-5 Overall, the data indicate that the clinical severity of asthma during pregnancy improves in about 30% of women, remains stable in about 50% and worsens in about 20%.6Factors responsible for the variation in asthma severity during pregnancy include an increase in circulating free cortisol,7,8 a decrease in bronchomotor tone and an increase in serum concentrations of cyclic adenosine monophosphate.8 These changes would normally improve the asthma, but in pregnancy other competing factors, including exposure to fetal antigens and alterations in cell-mediated immunity, may worsen asthma symptoms.8 Asthma may be further complicated by sinusitis and rhinitis, which occur in about 35% of pregnant women, but vascular dilatation and congestion of the mucosa of the upper respiratory tract (vasomotor rhinitis of pregnancy) does not involve the lower airways.9 The physiological respiratory changes which occur during pregnancy may affect asthma control (Box). Changes in blood gases secondary to acute asthma will be superimposed on the physiological respiratory alkalosis of pregnancy. Therefore, a normal or elevated PCO2 associated with acute asthma will indicate respiratory compromise of greater severity in pregnancy than in the non-pregnant state. The dyspnoea of pregnancy must be differentiated from dyspnoea caused by asthma. Indeed, patients who develop asthma during pregnancy may wrongly attribute dyspnoea to the pregnancy, which can lead to undermedication and severe maternal and fetal hypoxaemia. It is difficult to predict which women will experience worsening of their asthma during pregnancy, but the severity of the condition before pregnancy,2,8 and an absence of the expected decrease in IgE concentration during pregnancy,8,13 should alert the clinician to this possibility. If asthma is going to worsen, it will usually do so between 24 and 36 weeks' gestation. Symptoms are likely to be less troublesome in the peripartum period. In most women, asthma severity returns to the prepregnant state within three months of delivery,1,5 but in rare cases it may be worse than before the pregnancy. Effects of asthma on pregnancy The fetus exists in a precarious state of oxygenation and is dependent for its oxygen supply on maternal arterial oxygen content, venous return and cardiac output, and uterine artery and placental bloodflow. Compensating mechanisms of the fetus to combat potentially adverse conditions of oxygenation include a haemoglobin level of at least 16 g/dL and a P50 of 22 mmHg (indicating a left shift in the oxyhaemoglobin dissociation curve). Poorly controlled asthma or severe asthma attacks further threaten the fetus because of increased maternal hypoxaemia and diminution of uterine artery bloodflow secondary to hypocapnic vasoconstriction. These women have an increased incidence of low birthweight and premature babies, neonatal hypoxia, complications during labour, and perinatal and maternal mortality.14-17 Hyperemesis gravidarum, maternal haemorrhage and pre-eclampsia are more common in this group.14 For these reasons, it has been argued that a pregnancy complicated by asthma should be regarded as a high risk pregnancy.16 However, the babies of most asthmatic women (i.e., those with well controlled asthma) show no difference in birthweight, Apgar scores or rates of congenital malformation when compared with those of non-asthmatic mothers.5,15,16 Management of asthma in pregnancy The management of asthma during pregnancy is similar to that at any other time: treatment should be aggressive, with the aim of eliminating symptoms and restoring and maintaining normal lung function. Guidelines for asthma management have been published by the National Asthma Campaign and are highly recommended.18 Cooperation between the respiratory physician and obstetrician is important throughout pregnancy for women with severe asthma. Pharmacological therapy Care should be taken with pharmacological therapy during pregnancy, particularly in the first trimester, when the risk of congenital defects is greatest. Fortunately, the medicines currently used in the treatment of asthma have been found in practice to have a good safety profile during pregnancy. The drug categories listed here are those of the Australian Drug Evaluation Committee's categorisation of risk of drug use in pregnancy.19 Bronchospasm relaxants β2-Agonists (category A): There is no evidence of a teratogenic risk with the commonly used inhaled β2-agonists salbutamol, terbutaline and fenoterol. Intravenous salbutamol may be used to delay the onset of labour in some circumstances and there is a theoretical risk that oral β2-agonists could also have this effect. Delayed labour does not occur with bronchodilators administered by metered-dose inhaler or wet nebulisation. Ipratropium bromide (category B1): Although there is less experience with this drug, it appears to be safe for use during pregnancy, as it is poorly absorbed when administered by the inhaled route and has not been identified as imparting an increased risk of fetal malformations. Salmeterol (category B3): These newer long-acting agents have not been tested extensively in pregnant women. Theopyllines (category A): The use of theophyllines remains controversial. They may aggravate the nausea and reflux suffered by some pregnant women and can cause transient neonatal tachycardia and irritability.20,21 Teratogenicity has been shown in animals,22,23 and there are occasional case reports of cardiovascular abnormalities in humans.24 However, larger human studies have not shown any significant increase in fetal abnormalities.25,26 It has been suggested that theophyllines be withheld during the first trimester.26 If they are used, serum theophylline levels should be measured as drug metabolism may alter during pregnancy. Preventive inhalations and aerosols Sodium cromoglycate (category A): This drug appears to have no adverse fetal effects. Nedocromil sodium (category B1): Animal studies have not shown any teratogenic effects, but, as with all new drugs, care should be exercised, especially in the first trimester. Inhaled corticosteroids Beclomethasone and budesonide (category B3): These are the mainstay of treatment in moderate to severe asthma and both appear to have a good safety profile in pregnancy. Although beclomethasone is a known animal teratogen, its use in pregnant women has not been associated with teratogenicity. The largest human experience of inhaled corticosteroids is with beclomethasone and it is therefore the inhaled steroid of choice in pregnancy.9 Less information is available on the use of budesonide in pregnancy as it is a newer drug. If moderate to severe asthma is well controlled with budesonide, the risks of destabilising the condition by changing from budesonide to beclomethasone must be weighed against the potential benefits of using a medicine which has been more extensively studied. Fluticasone (category B3): Experience with this drug in pregnancy is more limited. Oral corticosteroids (Category A) These are sometimes necessary for severe asthma in pregnancy but usually only for short periods. An increased risk of cleft palate and placental abnormalities has been reported in animals given huge doses of oral steroids.27,28 These abnormalities have not been reported in humans, and the results of animal studies should not deter the practising clinician from using oral corticosteroids if required. Methotrexate and other steroid-sparing agents have an occasional role in the treatment of some individuals with severe resistant asthma. However, these drugs are contraindicated in women of childbearing age who are trying to conceive or who are pregnant. Labour There is no increase in the induction of labour, use of forceps or emergency caesarean sections in women with asthma, but elective caesarean sections are more common. Women with very severe asthma may be advised to have an elective caesarean section at a time when their asthma control is good. Close cooperation between the respiratory physician, obstetrician and anaesthetist is particularly important at this time. Symptoms of asthma during labour are generally easily controlled with standard asthma therapy. Acute asthma attacks in labour are rare, but prostaglandin F2alpha (Dinoprost, UpJohn) and ergometrine cause bronchoconstriction. Their use in the induction of labour, the initiation of the third stage of labour and for placental separation should be avoided.29 There is no evidence that oxytocin causes bronchoconstriction. Breastfeeding Breastfeeding should be continued in women with asthma as breast milk confers some immunity to infection to the baby, especially to respiratory and gastrointestinal infections. Breast milk may contain very small amounts of the drugs used to treat asthma, but, in general, these are not known to be harmful to the infant. Corticosteroids are about 90% protein bound in the blood and are not secreted into breast milk in any significant quantity. However, the manufacturers of budesonide have recommended discontinuation of this drug during lactation because of an absence of information regarding its transmission into breast milk. The decision to alter a successful medication regimen that is controlling the mother's asthma must be weighed against any potential detrimental effects to the infant from continuation of the drug. Although less than 1% of maternal theophylline is transferred to the infant,30 it has been suggested that women breastfeed their baby before taking this drug to minimise its side effects.31 It is recommended that tetracycline antibiotics and iodine-containing mixtures be avoided in pregnant and lactating women as they may cause dental discoloration and goitre in the baby. Patient education Environmental trigger factors which cause deterioration in asthma control or may lead to acute asthma attacks must be avoided and pregnant women should be urged to stop smoking. Mothers should be advised about the importance of avoiding exposure to allergens and environmental tobacco smoke in the first years of their child's life to reduce the potential for later asthma development.32 Monitoring Women with asthma should be reviewed at least every four to six weeks (and more frequently if needed) so that early changes in respiratory function can be detected and treated expeditiously. Although formal spirometry may be indicated from time to time, lung function can be easily monitored at home with a peak flow meter.33 The doctor should formulate an asthma action plan with the patient, to be put into effect if her condition deteriorates.33If a woman with asthma is closely monitored, pregnancy outcomes approaching those of the general population can be expected.34 Well-controlled asthma should have no adverse effect on pregnancy, labour or breastfeeding. References Juniper EF, Daniel EE, Roberts RS, et al. Improvement in airway responsiveness and asthma severity during pregnancy. A prospective study. Am Rev Respir Dis 1989; 140: 924-931. Williams DA. Asthma and pregnancy. Acta Allergol 1967; 22: 311-323. Turner ES, Greenberger PA, Patterson R. Management of the pregnant asthmatic patient. Ann Intern Med 1980; 93: 905-919. Greenberger PA, Patterson R. Management of asthma during pregnancy. N Engl J Med 1985; 312: 897-902. Schatz M, Harden K, Forsythe A, et al. The course of asthma during pregnancy, post-partum and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988; 81: 509-517. Burdon JGW, Goss G. Asthma and pregnancy. Aust N Z J Med 1994; 24: 3-4. Nolten WE, Rueckert PA. Elevated free cortisol index in pregnancy: possible regulatory mechanisms. Am J Obstet Gynecol 1981; 139: 492-498. Gluck JC, Gluck PA. The effects of pregnancy on asthma: a prospective study. Ann Allergy 1976; 37: 164-168. National Heart, Lung and Blood Institute. Report of the Working Group on Asthma and Pregnancy. Executive Summary: Management of asthma during pregnancy. J Allergy Clin Immunol 1994; 93: 139-162. Prowse CM, Gaensler EA. Respiratory and acid-base changes during pregnancy. Anesthesiology 1965; 26: 381-392. Rees GB, Pipkin KB, Symonds EM, et al. A longitudinal study of respiratory changes in normal human pregnancy with cross sectional data on subjects with pregnancy-induced hypertension. Am J Obstet Gynecol 1990; 162: 826-830. Gee JBL, Packer BS, Millen JE, et al. Pulmonary mechanics in pregnancy. J Clin Invest 1967; 46: 945-952. Gazioglu K, Kaltreider NL, Rosen M, et al. Pulmonary function during pregnancy in normal women and patients with cardiopulmonary disease. Thorax 1970; 25: 445-450. Hernandez E, Angell CS, Johnson JW. Asthma in pregnancy: current concepts. Obstet Gynecol 1980; 55: 739-743. Gordon M, Niswander KR, Berendes H, et al. Fetal morbidity following potentially anoxigenic obstetric conditions. VII. Bronchial asthma. Am J Obstet Gynecol 1970; 106: 421-429. Bahna SL, Bjerkedal T. The course and outcome of pregnancy in women with bronchial asthma. Acta Allergol 1972; 27: 397-406. Fitzsimons R, Greenberger PA, Patterson R. Outcome of pregnancy in women requiring corticosteroids for severe asthma. J Allergy Clin Immunol 1986; 78: 349-353. National Asthma Campaign. Asthma Management Handbook. Melbourne: National Asthma Campaign Ltd, 1993. Australian Drug Evaluation Committee. Medicines in Pregnancy. 3rd ed. Commonwealth Department of Health and Family Services, 1996. 20. Yeh TF, Pildes RS. Transplacental aminophylline toxicity in a neonate [letter]. Lancet 1977; 1: 910. Labovitz E, Spector S. Placental theophylline transfer in pregnant asthmatics. JAMA 1982; 247: 786-788. Gilbert EF, Bruyere HJ, Ishikawa S, et al. The effect of methylxanthines on catecholamine-stimulated and normal chick embryos. Teratology 1977; 16: 47-52. Ishikawa S, Gilbert EF, Bruyere HJ, et al. Aortic aneurysms associated with cardiac defects in theophylline-stimulated chick embryos. Teratology 1978; 18: 23-30. Park JM, Schmer V, Myers TM. Cardiovascular anomalies associated with prenatal exposure to theophylline. South Med J 1990; 83: 1487-1488. Schatz M. Asthma during pregnancy: interrelationships and management. Ann Allergy 1992; 68: 123-133. Stenius-Aarniala B, Riikonen S, Teramo K. Slow-release theophylline in pregnant asthmatics. Chest 1995; 107: 642-647. Fainstat T. Cortisone-induced congenital cleft palate in rabbits. Endocrinology 1954; 55: 502-508. Blackburn WR, Kaplan HS, McKay DG. Morphologic changes in the developing rat placenta following prednisolone administration. Am J Obstet Gynecol 1963; 92: 234-246. Math AA, Hedqvist P. Effect of prostaglandins F2 and E2 on airway conductance in healthy subjects and asthmatic patients. Am Rev Respir Dis 1975; 111: 313-320. Yurchak AM, Jusko WJ. Theophylline secretion into breast milk. Pediatrics 1979; 57: 518-525. Berkowitz R, Coustan DR, Mochizuki TK. Handbook for prescribing medications during pregnancy. 2nd ed. Boston: Little, Brown and Co, 1986. Peak JK. Prevention of asthma. Eur Respir J 1996; 9: 1545-1555. The Thoracic Society of Australia and New Zealand. Peak flow meter use in asthma management. Med J Aust 1996; 164: 727-730. Stenius-Aarniala B, Piilrila P, Teramo K. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax 1988; 43: 12-18. Authors' details Department of Respiratory Medicine, Austin and Repatriation Medical Centre, Heidelberg, VIC. Christine F McDonald, PhD, FRACP, Consultant Respiratory Physician. Department of Respiratory Medicine, St Vincent's Hospital, Melbourne, VIC. Jonathan G W Burdon, MD, FRACP, Consultant Respiratory Physician. Reprints: Dr J G W Burdon, Director, Department of Respiratory Medicine, St Vincent's Hospital, 41 Victoria Parade, Fitzroy, VIC 3065. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> Physiological respiratory changes in pregnancy Dyspnoea Dyspnoea is experienced by 60%-70% of women at some time during pregnancy,10 most commonly in the first or second trimester. Mechanical factors do not seem to play a major role in its pathogenesis because it frequently occurs before any increase in abdominal girth. Early pregnancy: Dyspnoea may be caused by rising circulating maternal progesterone levels, which result in a progressive increase in minute ventilation of up to 40% by the end of the first trimester, largely as a result of increases in tidal volume.11 Late pregnancy: Dyspnoea later in pregnancy is (likely to be) caused by a combination of the hyperventilation of pregnancy and restriction due to uterine enlargement. The latter leads to a small reduction in both residual volume and functional residual capacity, while total lung capacity is maintained by an increase in inspiratory capacity.12,13 Changes in peak flow rates and forced expiratory volume in one second (FEV1) are small and of no clinical significance.1,13 Respiratory alkalosis Maternal gas exchange is mildly disordered as a result of the increase in minute ventilation.11 A slight rise in arterial oxygen tension, a change in carbon dioxide tension and pH changes are common and indicate a mild respiratory alkalosis. The changes in arterial blood gas tensions occur despite increases in oxygen consumption and carbon dioxide production in the last few months of pregnancy.11 Back to text

Christine F McDonald

Position Statement Paediatric advanced life support The Australian Resuscitation Council Guidelines The Advanced Life Support Committee of the Australian Resuscitation Council MJA 1996; 165: 199-206 Basic cardiorespiratory resuscitation - Advanced life support - Techniques in paediatric advanced life support - Medications and fluids used in paediatric advanced life support - Management after resuscitation - Cessation of cardiopulmonary resuscitation - Contributors - References - Register to be notified of new articles by email - These guidelines by the Australian Resuscitation Council (ARC) provide brief step-by-step outlines of the management of common life-threatening emergencies in infants and children. The guidelines are similar, but not identical, to guidelines published by the American Heart Association 1 and the European Resuscitation Council. 2 An international liaison committee (including representation from the ARC) is attempting to resolve differences and will in due course publish common advisory statements. The current guidelines are specifically for advanced life support, but some essential techniques of basic life support are presented. Further details of basic life support for infants and children 3 and specific guidelines for resuscitation of asphyxiated newborn infants have been published. 4,5 Basic cardiorespiratory resuscitation Cardiorespiratory arrest should be suspected when the infant or child loses consciousness, appears pale or cyanosed, or is apnoeic or pulseless (see definitions in Box 1). Assess airway and breathing by observing movement of the chest and feeling for expired breath. Position the head and neck to maintain an open airway. Movement of the chest without expiration implies an obstructed airway. If the obstruction is not relieved by backward head tilt and chin lift or by forward jaw thrust, the pharynx should be inspected with a laryngoscope and cleared of any secretions, vomitus or blood with a sucker (Yankauer). Forceps (Magill) may be needed to extract a foreign body. If spontaneous ventilation is not immediately resumed, artificial ventilation is commenced with mouth-to-mask expired air, a self-inflating resuscitation bag or an oxygen-inflated bag and mask circuit. Supplemental 100% oxygen should be added. Insertion of an oropharyngeal airway (Guedel) may facilitate ventilation. Assess the circulation by palpating the carotid, brachial or femoral pulse. Commence external cardiac compression (ECC) if a pulse is not palpable or it is: < 80 beats per minute (bpm) in a newborn or infant; < 60 bpm in a small child; < 40 bpm in a large child. Precede ECC with 2-5 slow breaths to reinflate the lungs. The patient should be placed on a firm surface, and compression directed to the lower sternum to a depth approximating a third of the anteroposterior diameter of the chest, or at a depth of 2-3 cm and rate of 100/min for a newborn or infant; depth of 3-4 cm and rate of 100/min for a small child; depth of 4-5 cm and rate of 80-100/min for a large child. ECC for a newborn or infant can be performed with two fingers, although a better technique is to encircle the chest with both hands, compressing the sternum anteriorly with the thumbs while stabilising the vertebral column posteriorly with the fingers. The rescuer's hands must encircle the chest freely and not restrict chest expansion. ECC for a small child can be performed with the heel of one hand and, for a large child or teenager, with two hands. A cycle should be 50% chest compression and 50% relaxation. Combine ECC and assisted ventilation in an infant or small child in a ratio of 5 : 1. For a large child or teenager in whom a two-handed technique of ECC is required, a single rescuer may achieve better circulation and ventilation with a ratio of compression to ventilation of 15 : 2. If a mask is used, breaths should be delivered between successive compressions to allow adequate expansion of the lungs, but if an endotracheal tube is used coordination is less crucial as effective ventilation can be given against the resistance imposed by ECC. For the asphyxiated newborn, ECC should be at a rate of 120/minute and ventilation at 40-60/min (i.e., in a ratio of 3 : 1). 5,6 Advanced life support Advanced life support implies a patent airway by endotracheal intubation, mechanical ventilation with oxygen, the treatment of cardiac arrhythmias, the treatment of the cause of cardiorespiratory arrest and of complications arising from its management. When several rescuers are in attendance, tracheal intubation and ventilation, display of the electrocardiograph (ECG) and access to the circulation should be attempted simultaneously. Thereafter treatment should be guided by the cardiac rhythm (see Flowchart in Box 2). Tracheal intubation is the first priority. This establishes and maintains a patent airway, facilitates mechanical ventilation with 100% oxygen, minimises pulmonary aspiration, enables suctioning of the trachea and provides a route for the administration of selected drugs. If intubation cannot be accomplished easily, ventilate and oxygenate the patient using a mask before reattempting intubation. Assess the cardiac rhythm by displaying the ECG via chest leads or the defibrillator paddles. Proceed with drug therapy or immediate direct current (DC) shock (Box 2), while maintaining ECC and mechanical ventilation with supplemental 100% oxygen. Secure access to the circulation with a peripheral intravenous (IV) cannula. If cannulation is difficult, do not waste time (more than 90 seconds) with repeated unsuccessful attempts -- instead use the intraosseous (IO) route or the (less effective) respiratory tract via the endotracheal tube (ETT). 7 All drugs and resuscitative fluids may be given via the IO route but only adrenaline, atropine and lignocaine may be given via the ETT. Central venous cannulation of the subclavian or internal jugular veins should not be attempted initially as it wastes time and is potentially hazardous. However, cannulation of an external jugular or femoral vein may be easily accomplished. Surgical cutdown onto a vein may be required. Intracardiac injection should not be attempted unless all alternative methods of access to the circulation are impossible. The doses of drugs, DC shock and fluid therapy are based on body weight, which may be estimated according to age if the weight is unknown: Newborn: 3.5 kg 1 year: 10 kg 1-9 years: (age in years x 2) + 8 kg 10 years and over: age in years x 3.3 kg. Doses may also be prescribed on the basis of height. 8,9 Drug doses according to the 50th percentiles of weight and height for age are given in Box 3. Asystole or severe bradycardia If the cardiac rate is unresponsive to ventilation with 100% oxygen, asystole or pulseless severe bradycardia ( < 80 bpm in an infant, < 60 bpm in a small child, < 40 bpm in a large child or teenager) should be treated with adrenaline (10 µg/kg IV or IO, or 100 µg/kg via the ETT). The subsequent dose of adrenaline by any route is up to 100 µg/kg. If sinus rhythm cannot be restored, sodium bicarbonate (1 mmol/kg IV or IO) and/or atropine (20 µg/kg IV, IO or ETT), with additional doses of adrenaline, may be successful. If facilities are available, cardiac pacing (via the oesophageal, transcutaneous, transvenous or epicardial routes) may be effective. Ventricular fibrillation and pulseless ventricular tachycardia The only effective treatment of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) is DC shock. If the onset of VF is recent or is observed, a precordial thump may be given (although its efficacy has not been proven) and defibrillation should be attempted before any other treatment. The initial DC shock treatment of VF or pulseless VT is 2 J/kg, increasing to a maximum of 4 J/kg 10,11 in a series of three shocks. If sinus rhythm does not occur, give adrenaline (10 µg/kg IV or IO, or 100 µg/kg ETT) and a further three shocks of 4 J/kg. Persistent or refractory VF or VT may be treated with lignocaine (1 mg/kg IV, IO or ETT) followed by another series of up to three shocks of 4 J/kg. If the VF or VT remains refractory, alternative agents (bretylium tosylate 5 mg/kg, sodium bicarbonate 1 mmol/kg, magnesium sulfate 0.05-0.1 mmol/kg) may be tried, in combination with adrenaline (100 µg/kg IV, IO or ETT) and a series of three shocks of 4 J/kg. However, no drug has been conclusively proven to improve the efficacy of DC shock. Electromechanical dissociation (pulseless electrical activity) Electromechanical dissociation exists if pulses are absent despite relatively normal coordinated electrical activity on the ECG. It may be due to poor intrinsic myocardial contractility or secondary to a number of remediable causes, including hypoxaemia, hypovolaemia, severe acidosis, tension pneumothorax, pericardial tamponade, hyperkalaemia, hypocalcaemia, poisoning with a calcium channel blocker or hypothermia. It may also be due to massive pulmonary embolism. Treatment is with adrenaline, 10 µg/kg IV or IO or 100 µg/kg ETT initially, with subsequent doses up to 100 µg/kg by any route. If the electromechanical dissociation is persistent, consider hypovolaemia or severe acidosis and give a bolus of crystalloid or colloid fluid (20 mL/kg IV or IO) and/or sodium bicarbonate (1 mmol/kg). An underlying cause should be sought by clinical examination and investigations, including a chest x-ray, 12-lead ECG and echocardiograph if possible. Supraventricular tachycardia Supraventricular tachycardia (SVT) may cause severe hypotension or pulselessness. Synchronised DC shock (0.5-1 J/kg) should be given immediately to a pulseless patient. If blood pressure is adequate, vagal stimulation or drug therapy may be used. Adenosine is the drug of first choice. Alternatives are digoxin, a beta-blocker or a calcium channel blocker. Calcium channel blockers should not be used to treat SVT in infants because their negative inotropic effect may be fatal. Techniques in Paediatric advanced life support are given in Box 4. Medications and fluids used in paediatric advanced life support are summarised in Box 5. Management after resuscitation The cause of cardiorespiratory arrest should be sought and specifically treated. Complications of the resuscitation procedure should also be sought, especially if secondary deterioration occurs. This includes a chest x-ray to check the position of the endotracheal tube, to exclude pneumothorax, lung collapse or aspiration and to check the cardiac silhouette, and a blood sample for estimation of the haemoglobin level, pH, gas tensions and electrolyte and glucose concentrations. Supportive therapy should be provided until there is recovery of function of vital organs. This may include oxygen therapy, mechanical ventilation, inotropic infusion and renal support for several days or longer. Recovery in infants and children is usually slow because cardiorespiratory arrest is often secondary to prolonged global hypoxaemia and ischaemia with prior damage of other organs. Particular care should be taken to ensure adequate cerebral perfusion with well oxygenated blood and adequate blood pressure. Cessation of cardiopulmonary resuscitation The decision to cease cardiopulmonary resuscitation should be based on a number of factors, including the patient's pre-arrest condition, response to resuscitation, remediable factors, likely outcome and the opinions of experienced medical personnel. References Emergency Cardiac Care Committee and Subcommittees of the American Heart Association. Guidelines for cardiopulmonary resuscitation and emergency cardiac care. JAMA 1992; 268: 2171-2302. Paediatric Life Support Working Party of the European Resuscitation Council. Guidelines for paediatric life support. BMJ 1994; 308: 1349-1355. Manual Australian Resuscitation Council. Policy Statements. Policies 12.1-12.9, November 1995. (Located at the Royal Australasian College of Surgeons, Spring Street, Melbourne.) Emergency Cardiac Care Committee and Subcommittee of the American Heart Association. Guidelines for cardio resuscitation and emergency cardiac care. JAMA 1992; 268: 2276-2281. Roy RN, Betheras FR. The Melbourne chart -- a logical guide to neonatal resuscitation. Anaesth Intens Care 1990; 18: 348-357. The Advanced Life Support Committee of the Australian Resuscitation Council. Adult advanced life support. The Australian Resuscitation Council Guidelines. Med J Aust 1993; 159: 616-621. Tibballs J. Endotracheal and intraosseous drug administration for paediatric CPR. Aust Fam Physician 1992; 21: 1477-1480. Lubitz SL, Seidel JS, Chameides L, et al. A rapid method for estimating weight and resuscitation drug dosages from length in the pediatric age group. Ann Emerg Med 1988; 17: 576-581. Oakley P, Phillips B, Molyneux E, Mackway-Jones K. Updated standard reference chart. BMJ 1993; 306: 1613. Chameides L, Brown GE, Raye JR, et al. Guidelines for defibrillation in infants and children. Report of the American Heart Association Target Activity Group: cardiopulmonary resuscitation in the young. Circulation 1977; 56 (suppl): 502A-503A. Gutgesell HP, Tacker HA, Geddes LA, et al. Energy dose for ventricular defibrillation of children. Pediatrics 1976; 58: 898-901. Rogers FB. Technical note: a quick and simple method of obtaining venous access in traumatic exsanguination. J Trauma 1993; 34: 142-143. Hornchen U, Schuttler J, Stoeckel H, et al. Endobronchial instillation of epinephrine during cardiopulmonary resuscitation. Crit Care Med 1987; 15: 1037-1039. Jasani MS, Nadkarni VM, Finkelstein MS, et al. Effects of different techniques of endotracheal epinephrine administration in pediatric porcine hypoxic-hypercarbic cardiopulmonary arrest. Crit Care Med 1994; 22: 1174-1180. Patterson M, Boenning D, Klein B. High dose epinephrine in pediatric cardiopulmonary arrest (CPA). Pediatric Emerg Care 1994; 10: 310. Goetting MG, Paradis NA. High-dose epinephrine improves outcome from pediatric cardiac arrest. Ann Emerg Med 1991; 20: 22-26. Contributors This document was drafted and revised by Dr James Tibballs at the request of the Australian Resuscitation Council. Submissions were received from members of the Advanced Life Support Committee of the ARC and from Dr R Henning, Dr F Shann, Ms S Kinney (Melbourne); Dr A Duncan (Perth); Dr J McEniery, Dr G Delbridge, Dr B Lister (Brisbane); Dr B Wilkins, Dr R Choong, Dr B Duffy, Dr T Gratten-Smith, Dr I Alexander, Dr M Schindler, Dr J Gillis, Dr A O'Connell, Dr D Schell, Dr O Miller (Sydney); Dr S R Keeley, Dr A J Slater, Dr G M Shaw, Dr J Raftos (Adelaide); Dr E R Segedin (Auckland); Dr L Quan (Seattle); and Dr D Zideman (London). Members of the Advanced Life Support Committee: Dr M Allen (ARC South Australian Branch). Dr R A Capps (Australian Defence Force). A/Prof V Callanan (ARC Chairman; and Australian and New Zealand College of Anaesthetists). Ms J Dennett (Confederation of Australian Critical Care Nurses). Mr M Draheim (ARC Tasmanian Branch). Ms J Finn (Royal College of Nursing, Australia). Dr L Grigg (Cardiac Society of Australia and New Zealand; and National Heart Foundation). Mr A Hadj (Royal Australasian College of Surgeons). Mr J Hall (Institute of Ambulance Officers, Australia). Mr K Hambrecht (Co-opted member). Prof G A Harrison (Chairman, ARC Advanced life Support Committee; and Australian and New Zealand College of Anaesthetists). Dr I Jacobs (ARC Western Australian Branch). Mr O Juul (ARC New South Wales Branch). Mr S Leahy (Surf Lifesaving Association of Australia). Ms J Maclean (Royal Lifesaving Society, Australia). Dr P Morley (ARC Victorian Branch). Dr J O'Callaghan (Co-opted member). Dr A Phillips (Royal Australian College of General Practitioners). Mr C Smith (ARC Queensland Branch). Dr J Taylor (Co-opted member). Dr J Tibballs (Australian and New Zealand Intensive Care Society). Mrs E P Tyler (Australian Red Cross Society). Dr J Wassertheil (Australasian College for Emergency Medicine). Dr J Williamson (St John Ambulance Australia). No reprints will be available. Correspondence: Dr J Tibballs, Intensive Care Unit, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, VIC 3052. ©MJA 1996 Home |