Neonatal and Paediatric Pharmacist's Group (NPPG)

Newsletter No. 9

September 1998

Editor:

Peter Mulholland
Pharmacy Department Southern General Hospital
1345 Govan Road
GLASGOW G51 4TF
Tel: +44 (0)141 201 1382    Fax: +44 (0)141 201 2996
email:pmulholland@sghpharmacy.demon.co.uk

NPPG 4^th ANNUAL CONFERENCE Dublin 2^nd - 4^th October 1998

An article covering the conference will be submitted to the Irish Pharmaceutical Journal and the Hospital Pharmacist after the conference. Workshop leaders will be contacted to provide a 200 word abstract on the workshop intentions and the leaders will submit a report of the key points from the workshop to the editor for inclusion as a supplement to the next newsletter. The 'clinical pearls' presented at the conference will be reproduced in future newsletters.

The 1999 conference has been booked for October 1^st to 3^rd at the Midland Hotel, Derby.

OTHER UPCOMING CONFERENCES

The 1999 meeting of the International Society of Neonatal Screening, which is of broad interest to groups from fields such as paediatrics, genetics, clinical biochemistry, public health etc., has a web page at http://www.stocon.se/ins

Further information can be obtained from

Henrik Simonsen MD
Statens Serum Institut
5 Artillerivej
DK-2300 Copenhagen S
Denmark
Tel: +45 3268 3489   Fax: +45 3268 3878

Email: hss@ssi.dk

COMMITTEE DETAILS

Steve Tomlin, Royal Free Hospital, London, Email: druginfo@rfhpharmacy.demon.co.uk

NPPG COMMITTEE MEETING

2^nd JULY 1998

Andy Fox is progressing the design of a logo for the group.

Sharon Conroy has been asked to comment on key paediatric issues in the Pharmacy In A New Age document 'Drug Therapy and Pharmacy'. Malcolm Partridge will respond on behalf of NPPG.

Astra are sponsoring a study day in February 1999 entitled 'Introducing Medicines Into Paediatric Practice'. Details will be announced shortly.

NEWS FROM THE REGIONS & SUB-GROUPS

POP Group

Meeting held in Liverpool, 15^th May 1998

The pilot study and audit on chemotherapy standardisation is ongoing and results are awaited before extending use of standard prescriptions to other centres. Vicky Holden is co-ordinating the production of a standard prescription for ALL-97.

Work by the Palliative Care Working Group has been presented to the UKCCSG palliative Care Working Party and will be shown to the MacMillan nurses for comment.

The next meeting of the group will be on Friday 2^nd October in Dublin prior to the annual conference.

DRUG INFORMATION ADVISORY LINE (dial)

The information provided here is a summary of the full answer and in some cases may represent experience at Alder Hey or other Children's hospitals rather than evaluated clinical studies. More detailed information should be sought before acting on the information presented.

MIDAZOLAM

The single drug to generate the highest number of enquiries to dial over the last 8 months is midazolam. Listed below are some of the questions and summarised answers.

Q Information on the indications formulation and stability of oral midazolam?

Midazolam is a potent imidazobenzodiazepine, forming water soluble salts, which are stable and well tolerated by injection. Midazolam possesses hypnotic, anxiolytic, muscle-relaxant and anti-convulsant activity. The summary of product characteristics for midazolam (Hypnovel) includes the following paediatric indications: sedation by continuous intravenous infusion in intensive care and intravenous induction of anaesthesia in children over 7 years of age.

There are a number of reports in the literature describing the use of midazolam orally in children as an anxiolytic/sedative premedication^(1-5). Midazolam possesses many desirable properties of a pre-medicant for children undergoing day case surgery and painful procedures in the A&E⁽⁶⁾ department. Its elimination half life is short (1.5-2 hours), it exerts a reliable dose dependent anxiolytic effect without oversedation and produces minimal cardiovascular and respiratory effects. In addition the anterograde amnesia produced by the midazolam should help to reduce the psychological trauma of anaesthesia and surgery.

Doses of between 0.2 mg/kg and 1 mg/kg of oral midazolam have been studied in children aged 6 months to 10 years of age^(1-5). Midazolam 0.2mg/kg, in combination with analgesic doses of paracetamol was reported to be effective in children aged 6 months to 6 years attending the A&E department of Leeds General Infirmary⁽⁶⁾ UK. Doses of midazolam used as a pre-medicant for day case surgery have ranged from 0.25mg/kg to 1mg/kg, with the most effective dose about 0.5mg/kg. McMillan et al⁽³⁾ reported that doses greater than 0.5mg/kg offer no additional benefit and may cause more side effects (e.g. loss of balance and head control, blurred vision and dysphoric reactions). A dose of 0.5mg/kg (maximum 20mg) has been adopted for use in the day case surgery unit at Alder Hey Children's Hospital. The dose is administered 30mins before the procedure.

There are no licensed preparations of oral midazolam in the UK. However a licensed tablet (15mg) preparation is available in some other European countries and can be imported via IDIS. A number of formulae for liquid preparations of midazolam (based on the use of the injection solution) and relevant stability studies can be found in the literature^(7-10). Specials manufacturers such as Boots and Special Products also have preparations available, and many hospitals have their own standard formulae and stability data. With the exception of the Boots product, which has a 12 month expiry, the majority of formulae have relatively short expiry dates.
The following formula is prepared at Alder Hey Children's Hospital, Liverpool:

  
The product has a 2 week expiry at room temperature.

Q Any experience of sublingual administration of midazolam in children?

No experience of this route at Alder Hey Children's Hospital, but Hackett⁽¹¹⁾ describes the use of sublingual midazolam in children aged 15months to 6 years old, as an alternative to the intranasal or oral route for pre-medication. Onset of sedation occurred almost as quickly as with the intranasal route and the children were judged ready to enter the operating room in under 10 minutes. The bad taste associated with midazolam was circumvented by mixing the dose with a small amount of very sweet cherry syrup. The solution was placed under the tongue and patients were allowed to swish it around their mouths and swallow it if desired. The dose used was between 0.3-0.4mg/kg midazolam injection in 0.5-1ml of cherry syrup.

In a similar study Khalil et al⁽¹²⁾ described the safety and efficacy of sublingual midazolam in 80 children aged 2-10 years. Doses of 0.25mg/kg, 0.5mg/kg and 0.75mg/kg mixed with grape juice were evaluated. The investigators concluded that sublingual midazolam at a dose of 0.5 or 0.75mg/kg mixed in grape juice was acceptable, effective and safe in sedating patients in 10-15 minutes

Q Any information on the availability of midazolam lollipops?

Twenty years ago formulae for various medications in the form of ice lollies or lollipops were included in paediatric formularies and more recently, fentanyl has been presented in this formulation. No formulation for midazolam lollipops was found. The unpleasant taste of midazolam would require masking with a strong flavouring agent and it is unlikely that a child would continue to suck a lollipop if the taste was unpleasant. A lollipop formulation would not offer any real advantage over the oral solution.

Q What is the dose and method of administration of intranasal midazolam as a pre-medication in children?

The intranasal administration route for midazolam has been investigated in children (aged 6 months to 18years) as an alternative to the intravenous, oral and rectal routes of administration^(13-18). Doses of 0.2-0.3mg/kg are reported in the literature. No intranasal preparation is available and the injection solution is used. Half the volume is instilled into each nostril dropwise over 1-2 minutes; too rapid administration may result in "loosing" part of the dose down the back of the throat. Intranasal medications can irritate the nasal mucosa and may cause crying. The volume associated with the higher dose of 0.3mg/kg has been reported to cause coughing and sneezing and hence expulsion of the drug, possibly leading to a delayed onset of action⁽¹³⁾.

This method of administration of midazolam was used for pre-medication prior to cardiac catheterisation at Alder Hey Children's Hospital some years ago, but because of the unpleasantness of the administration process it is no longer used.

Q Has midazolam been used intranasally for the management of status epilepticus?

See NPPG newsletter issue 6

Q Information the use of intravenous midazolam in status epilepticus?

The role of intravenous midazolam in the management of refractory status epilepticus has been described in adults⁽¹⁹⁾ and more recently in children ^(20-22). Doses reported in the literature suggest a loading dose of 0.15mg/kg followed by a continuous infusion of between 0.1-0.5 microgram/kg/minute. The initial infusion dose of 0.1 microgram /kg/min is increased every 15 minutes until complete control of seizures is achieved.

In addition dosage recommendations can be found in paediatric dosage reference texts. The Guy's, St. Thomas' and Lewisham Paediatric Formulary (4th Edition)⁽²³⁾ suggests a dose of 100-200 microgram/kg as a slow IV injection. Lexicomp "Paediatric Dosage Handbook" (4th Edition 97/98)⁽²⁴⁾ suggests a loading dose of 0.15mg/kg in infants and children over 2 months of age, followed by a continuous infusion of 1 microgram/kg/min titrated upwards to achieve control every 5 minutes.

A potential disadvantage from the use of the use of midazolam in this way is the cost in relation to other benzodiazepines e.g. diazepam. In addition the lack of comparative data demonstrating superiority over diazepam does not justify the routine use of midazolam in this way.

Q Any information on the use of midazolam as an induction agent in young children?

Dr Andrew Bowhay (Consultant Paediatric Anaesthetist, Alder Hey) advised that Midazolam was not used as an induction agent in children, because of the very high doses required to achieve an adequate effect and the likely long recovery time. This is borne out by two early references^(25,26) which reported that doses of 0.6 mg/kg midazolam intravenously were unreliable in inducing anaesthesia in children but effective enough to cause significant falls in systolic blood pressure after induction.

This is not an exhaustive review of the paediatric literature relating to midazolam, but a selection of relevant reports to answer the enquiries received by DIAL.

REFERENCES

ORAL MIDAZOLAM

1. Saarnivaara L et al. Br. J Anaesth. 1998; 61: 390 - 396
2. Payne K A et al. SAMT. 1991; 79: 372 - 375
3. McMillan C.O. et al. Can J Anaesth. 1992; 39(6): 545-550
4. Parnis S J et al. Anaesth Intens Care. 1992; 20: 9 - 14
5. McClusky A and Meakin G.H. Anaesthesia. 1994; 49: 782 - 785
6. Taiwo B et al. Archives of Emergency Medicine. 1992; 9: 306 - 309
7. Steedman S.L. et al. AJHP 1992; 49: 615 - 618
8. Gregory DF et al. Southern Medical Journal. 1993; 86(7): 771 - 772
9. Bhatt-mehta V et al. AJHP. 1993; 50: 472 - 475
10. Mehta AC et al. Hospital Pharmacy Practice. 1993; April 224 - 225

SUBLINGUAL MIDAZOLAM

1. Hackett AE. Anaesth Analg. 1993; 77: 197 - 201 (letter)
2. Khalil S et al. Anaesth Analg. 1994; 78: S206

INTRANASAL MIDAZOLAM IN PREMEDICATION

1. Wilten NCT et al. Anaesthesiology 1988; 69: 972 - 975
2. Saint-Maurine C et al. Acta Anaesthesist Scand. 1990; 34: 39 - 41
3. Karl H et al. Anaesthesiology. 1992; 76(2)
4. Malinovsky J M et al. Brit J Anaesthesia 1993; 70(6)
5. Malvisvsky I M et al. Anaesthesia. 1995, 50: 351 - 354
6. Davis PJ et al. Anaesthesiology 1995; 82(1): 1

IV MIDAZOLAM IN STATUS EPILEPTICUS

1. Denzel D and Burstein A. The Annals of Pharmacotheropy 1996; 30(Dec); 1481 - 1483
2. Rivera R et al. Critical Care Medicine. 1993; 21(7): 991 - 994
3. Jelinek G and Galvin. Critical Care Medicine. 1994; 22(8): 1340 - 1341
4. Kolul R L et al. Arch. Dis. Child. 1997; 76: 445 - 448
5. Guy's, St. Thomas and Lewisham Hospitals Paediatric Formulary 4th Edition 1997
6. Paediatric Dosage Handbook 4th Edition 1997 - 98. Taketomo CK Pub. Lexicomp

MIDAZOLAM AS AN INDUCTION AGENT IN PAEDIATRICS

1. Salonen M et al. Anaesth Analg 1987; 66: 625 - 628
2. Salonen M et al. Int J clin Pharmacol, Ther and Toxicol 1987; 25(11): 613 - 615

INFORMATION ON THE INTERNET

First of all apologies to those who may have tried to access the Orphanet site mentioned in the previous newsletter. It really does exist and I have printouts to prove it! I tried to access the site just after the newsletter went for distribution and experienced some problems. It can now be found at http://orphanet.infobiogen.fr/site/anglais/accueil.stm.

This appears to be a problem with sites as they develop or move to different servers. The ESCP web site is currently under reconstruction for a similar reason. The following sites do (did!) exist at the time of writing. If anyone tries to access any of the sites detailed in the newsletter and fails, please let me know.

If you are looking for information on diseases of known or suspected genetic origin the National Center for Biotechnology Information has a searchable site at http://www3.ncbi.nlm.nih.gov/Omim/searchomin.html

The American Pediatric Society and the Society for Pediatric Research have their home page at http://www.aps-spr.org.

The Paediatric and Neonatal links page mentioned in Newsletter 8 has moved to http://web.raex.com/~sroush/accp/prnlinks.html

Gauchers disease, the most prevalent glycolipid storage disorder caused by a deficiency in the enzyme, glucocerebrosidase, leading to the accumulation of glycolipid in a variety of organs was the subject of an article in the first SNAPP newsletter. There is a web site devoted to the disease. It can be found at http://www.gaucher.org.uk

The Neonatology on the Web site mentioned in a previous newsletter has moved to http://www.neonatology.org

Email ADDRESSES

CONFERENCE REPORTS

6th Congress of the European Society for Developmental Pharmacology,
Ajaccio, Corsica 4-6th June 1998.

Sharon Conroy reports:
I was very lucky to be given the opportunity to attend this conference which was held in a fabulous hotel close to Ajaccio, the capital of the beautiful island Corsica. Travelling to and from the conference was very eventful since we were caught up in the middle of the Air France strike, however, that's another story!

The Society has about 70 members. Membership is open to scientific workers permanently resident in Europe who either have been or are engaged in basic or clinical research connected with developmental pharmacology as a major part of their professional careers. To become a member, an original scientific paper of a standard acceptable to the Society has to be presented as either an oral communication or a poster at a Society conference. I am pleased to report that I was successful in doing this and am now a member of this esteemed organisation! The object of the Society is the promotion of developmental pharmacology, whether fetal, perinatal or paediatric.

The meeting was a good combination of educational and social activities with a lot of opportunities for networking with other workers from across the world.

Symposia were held on:

Haematopoietic growth factors
Anticancer drugs
New arrangements for licensing of medicines in children
New methodologies in drug evaluation
Antibiotics

State of the art lectures were given entitled:

Fluid volume regulation in the perinatal period: recent advances
P-glycoprotein and first-pass metabolism
A non-conventional transmissible agent related to subacute spongiform encephalities

An interesting poster session was held with posters on a wide variety of subjects from pharmacokinetic studies of several drugs to excretion of drugs in breast milk to animal experiments - something for everyone! Each presenter was given a couple of minutes to summarise their poster which had been displayed all day and answer questions on it.

A series of free oral communications were also presented in several sessions throughout the conference. Again a wide variety of subjects were covered such as:

SIDS in infants and DTP status
Monitoring azathioprine therapy
Ibuprofen pharmacokinetics in premature infants with PDA
Drug treatment of migraine attacks in children

And many more!

I very nervously presented a retrospective study of unlicensed and off label use of drugs in a neonatal intensive care unit which received a reasonable amount of comment.

All in all the conference was an exciting opportunity to meet people whose names I had seen in print but had not imagined meeting in the flesh as it were! Some parts were very pure science and less interesting from a clinical perspective, but there were many very high quality and interesting sessions which I have abstracts and handouts from if anyone is interested in seeing them.

Paediatric Prescribing outside the licence: Is there a problem?

Sharon Conroy reports on a half day seminar organised by the Drug and Therapeutics Bulletin at the Medical Society of London on 10th June 1998

This included four presentations:

• Regulatory Aspects by Dr Julia Dunne, head of the New Chemical Entities Unit of the Medicines Control Agency. This talk covered the licensing process and the reasons why children are given unlicensed and off label drugs, including the reluctance of the pharmaceutical industry to conduct clinical trials in children. She also discussed the European guidance on testing of medicinal products in children which came into operation in September last year.

• Issues facing the pharmaceutical industry were addressed by Dr Richard Tiner, Medical Director of the ABPI. He went through the new guidelines mentioned by Dr Dunne but did not really convince the audience that the industry would bite the bullet and follow them. He mentioned the International Conference on Harmonisation which involves meetings of regulatory bodies from across the world with the intention of making recommendations for the licensing of medicines for children to be used on a world wide basis - their next meeting is in the year 2000.

• Issues facing the hospital paediatrician were presented by Professor Terence Stephenson, Professor of Child Health, University of Nottingham (my boss!). He described the aim of the licensing process, gave examples of studies showing the incidence of off label/unlicensed drug use in children, and raised the problem of the confusion of hospital staff and Trusts regarding the local position of prescribing outside the licence.

• Issues facing the general practitioner were described by Dr David Murfin, a London GP. He highlighted issues of GPs being expected to continue to supply medicines commenced by hospital consultants, these may be unlicensed/off label since about 25% of the average GP's work is with children under 15 years old. Many GPs are rightly concerned about this issue, particularly when being asked to do it with little knowledge or information. He highlighted the importance of the role of shared care policies in such situations.

Much discussion followed these presentations from an audience from a variety of areas. The issue of whether informed consent should be obtained prior to prescribing of an unlicensed/off label medicine was discussed, as was the problem of patient information leaflets which are inappropriate to the use of the medicine in the circumstances in which they are prescribed. A lively and interesting debate!

PAEDIATRIC and NEONATAL INFORMATION SHARING - REQUESTS

Kingsley Coulthard (Director of Pharmacy, Univ. of South Australia, Fax (08) 8204 6049 Email: coulthardk@wch.sa.gov.au is interested in the use of Lansoprazole in paediatrics and would be grateful to learn of anyone using this drug instead of omeprazole in children.

Chris Cutts, Pharmacy Dept, Leicester Royal Infirmary (Tel:0116 254 1414 bleep 5374) is looking for protocols, policies or experience in unblocking Hickman lines in children receiving long term parenteral nutrition. Assuming the cause is fibrin or lipid, we have used Urokinase and alcohol with varying success.

If you use alcohol, what volume or concentration do you use and how long do you leave it in the line. Has anyone used hydrochloric acid?. Does anyone have a strategy for preventing the lines from blocking after prolonged use?

RESPONSE TO QUERIES

In response to Sharon Conroy's query regarding Sedation for children Margaret Dolan writes:

I would like to notify members of my involvement in a SIGN guideline Development Group on Safe Sedation in Children. The Scottish Intercollegiate Guidelines Network (SIGN) was established in 1993 by the Conference of Royal Colleges and their faculties. SIGN is a network of clinicians and other health care professionals including pharmacy. Patient views are represented through the Scottish Association of Health Councils.

The objectives of SIGN are to sponsor and co-ordinate the development and appraisal of evidence based guidelines and recommendations which are then published and disseminated throughout the NHS in Scotland. The national guideline should then be tailored and implemented to local circumstances.

The SIGN development group is being chaired by Dr Neil Morton, Consultant in Paediatric Anaesthesia and Intensive Care, Yorkhill, Glasgow. The first meeting of the group was held on 3^rd June where the terms of reference for the guideline and literature search strategy were agreed. The remit is wider than sedation for procedures as it includes sedation in the primary care setting. The guideline is expected to be available in approximately 18 month's time.

In response to Alenka Pecar's query about Indomethacin Catherine Hall (Royal Victoria Infirmary, Newcastle) writes:

We do not supply indomethacin in pre-filled syringes. It is prepared when required on the ward by the nursing staff. When the dose has been given the remainder of the vial is discarded. We sometimes use the injection orally, particularly if only one dose is required and the cannula has tissued at the end of a treatment course. Alternatively we prepare an in-house suspension.

NEW PUBLICATIONS

Pediatrics - An Interactive Program CD-ROM (Windows) 1^st Edition - Braner (WB Saunders ISBN 072167612X)
An interactive, multimedia CD that simulates actual patient evaluations using text, graphics, pictures and real-time audio and video, allowing users to 'see and hear' patients as the truly present… covers over 100 disorders

Drugs in Pregnancy & Lactation 5^th Edition - Briggs, Freeman and Yaffe, 1200 pages (William & Wilkins ISBN 0683302620)
Information on more than 800 drugs, with 100 new and 80 completely revised drug monographs.

Paediatric toxicology: Handbook of poisoning in children - Bates, Edwards, Roper and Volans (Macmillan Reference ISBN 0333609154)

Textbook of Paediatric Infectious Diseases 4^th Edition - Feigin and Cherry 3195 pages 480 illustrations (ISBN 0721664482)
The new edition reflects the latest findings and the newest techniques in molecular biology, genetics and more. Clinical manifestations as well as step-by-step diagnosis and treatment guidelines are provided.

Kendig's Disorders of the Respiratory Tract in Children 6^th Edition - Chernick and Boat (WB Saunders ISBN 0721665411)
Explores the basic aspects of physiology, lung development and developmental biochemistry as well as the management of those clinical disorders that affect children)

DID YOU SEE? AUGUST 98

Compiled by Andy Fox (Portsmouth Hospitals).

Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and pre-school children: a double blind controlled trial Sazawal S et al Pediatrics, 1998, 102(1), 1-5

Practice guideline for the diagnosis and management of attention deficit hyperactivity disorder Baumgaertel A, Wolraich ML Ambulatory Child Health, 1998, 4, 24-58

Standardising the care of bronchiolitis Adcock PM et al, Arch Pediatr Adolesc Med, 1998, 152, 739 - 744

A study of the effectiveness of an educational intervention on the management of infants with bronchiolitis in hospital

A Phase I/II study of the protease inhibitor Indinavir in children with HIV infection Mueller BNU et al, Pediatrics, 1998, 102(1), 101-109

Central venous catheters vs peripheral veins for sampling blood levels of commonly used drugs J Parenteral and Enteral Nutrition, 1998, 22, 234-237

A study to compare accuracy of blood levels from different catheters in paediatric patients. For most drugs similar levels were obtained but the investigators suggest caution with cyclosporin levels particularly IV cyclosporin.

A randomized placebo-controlled trial of G-CSF administration to newborn infants with neutropenia and clinical signs of early onset sepsis Schibler KR et al, Pediatrics, 1998, 102(1), 6 - 13

A study of 20 infants given 3 days G-CSF or placebo within the first 3 days of life. No differences were seen in clinical markers between the two groups. There were no adverse events in the treatment group.

Neonatal and Paediatric Pharmacists Group

Membership fee for 1998 - 99 is £15 (GBP)
and should be sent with your application form, made payable to 'NPPG'

Membership Form : 1^st Nov 1998 - 31^st Oct 1999

The form is on a separate page for ease of printing

NPPG Newsletter No. 8

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