Send letter to journal:
Re: Mortality in meningococcal disease: please report the figures accurately

Dear Editor,

We read with great interest the two recent articles on mortality in meningococcal disease.[1,2] Whilst we would agree with the message contained in both articles, namely that the mortality associated with this condition has decreased with time, we have serious concerns regarding the presentation of the data in the paper from the St Mary’s group.

Booy and colleagues report a crude mortality of 2% for the year 1997,[2] a figure that has generated considerable media interest. Several reasons are cited for this falling mortality: the provision of mobile intensive care, meticulous attention to stabilising the patient whilst in the district hospital, and the existence of a specialist "sepsis" intensive care unit. However the way in which the mortality data are presented demonstrate several contradictions.

Booy and colleagues purport that intensive care begins from the time the retrieval team is contacted, indeed they calculate PRISM mortality risk from this time, yet mortality is calculated only from those patients who physically arrive back in their own unit. It is well known that mortality from meningococcal disease is greatest in the first 6 hours, primarily from myocardial failure. [3] To cull non-survivors before PICU admission thus creates a self-fulfilling prophesy.

To illustrate this, we present data from our own unit (Guy’s Hospital), which covers a similar geographical catchment area to St Mary’s. The table shows mortality data for the period January 1998 to November 2001, illustrating time of death after arrival of the retrieval team. For completeness sake, we have also included the four deaths that occurred prior to arrival of the team. Over this period we have undertaken 183 retrievals on patients with severe meningococcal disease; 147 (80%) of these required mechanical ventilation and/or inotropic support. Twelve percent of these patients presented with meningitis alone, the remainder with septic shock. The overall crude mortality is 8.2% (15/183), which includes four patients who died before arrival of the retrieval team. Our death rate becomes comparable to that of St Mary’s if we exclude patients who die within 6 hours of the retrieval team’s arrival, producing a mortality of 4/176 (2.3%).

Our unit policy is one of rapid stabilisation before transfer, as evidenced by a median time spent out of the PICU (the sum of the time spent in the district general hospital and the transit time back to PICU) of 2 hours 35 minutes. This resulted in only one death in the district general hospital, none during transfer, but a considerable proportion in the early hours following PICU admission.

It is our impression that the St Mary’s retrieval process is a considerably longer one, which may artifactually reduce PICU mortality. We would therefore ask that the St Mary’s group present their data in a similar fashion, including retrieval times. Specifically, were the 29 deaths before physical admission to the PICU occurring whilst under the management of the retrieval team at the local hospital (and thus under PICU management, by their own definition)? If so, mortality should be adjusted accordingly. Second, has this trend continued in subsequent years? This disease attracts media and public attention par excellence. It is therefore vital that outcome data which are accessible to the public and may be used to influence service reorganisation be presented in a transparent manner.

Shane M Tibby
Ian A Murdoch
Andew Durward

Table. Mortality data for severe meningococcal patients retrieved to Guy’s Hospital January 1998 to November 2001.

References
(1) Thorburn K, Baines P, Thomson, Hart CA. Mortality in severe meningococcal disease. Arch Dis Child 2001;85:382-385
(2) Booy R, Habibi P, Nadel S, de Munter C, Britto J, Morrison A, et al. Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery. Arch Dis Child 2001;85:386-390
(3) Mercier JC, Beaufils F, Hartmann JF, Azema D. Hemodynamic patterns of meningococcal shock in children. Crit Care Med 1988 16:27-33

Send letter to journal:
Re: Inter-unit comparisons are flawed

Dear Editor

Mortality from meningococcal septic shock may be falling however it is difficult to be sure. Inter-unit comparisons of the sort precipitated by these articles and correspondence are inevitably distorted by confounding factors. These factors are not entirely removed by the use of mortality prediction models.

Historically mortality data for meningococcal septicaemia from the UK Public Health Laboratory Service Communicable Disease Surveillance Centre have always shown a lower mortality rate than that in many paediatric intensive care units. However the comparison is regarded as inappropriate because the surveillance data includes patients with positive blood cultures (septicaemia) who were not shocked and so would be expected to survive without intensive care. If one admits such patients to intensive care then both crude and standardised mortality are artificially reduced. Furthermore mortality rates from individual intensive care units or time periods are difficult to compare even using mortality prediction models, without reassurance that the same threshold for admission and/or intervention applies in each case.

The paper by Booy and Habbibi et al contains no reassurances on this issue and no information is given about the performance of the mortality prediction model (PRISM) on their data. Furthermore their series includes mortality rates that appear to exclude the deaths during retrieval. This despite the fact that the quality of retrieval is hailed as a potential cause of decreased mortality. Thorburn and Baines et al provide some reassurance by quoting a consistently high rate of ventilation in the reported cases and detailed information on the performnace of the mortality prediction model. Hence if there has been a decrease in the threshold for admission it has been accompanied by an increased use of ventilation and perhaps other interventions. It is not clear whether the data from the north west includes deaths during retrieval, prior to admission to the PICU.

Both series significantly outperform the expected mortality predicted by PRISM which is not surprising and calls into question the use of the model. Convincing evidence of a fall in mortality for meningococcal septic shock however requires a uniform definition of the illness and "all cause" mortality data from a geographically defined resident population. The regional arrangement for delivery of paediatric intensive care in the north west of england combined with the factors mentioned above make it far more likely that Thorburn and Baines have indeed detected a true improvement in survival for this condition. Since 1996 there has been a trend for more children to receive intensive care in lead centres[1,2] and this might be expected to reduce mortality across the board.

References
(1) Should Intensive Care be Centralised Trent vs Victoria G.A. Pearson, F. Shann, P. Barry, J. Vyas, D. Thomas, D. Field The Lancet 1997 349: 1213-1217
(2) Changes in the profile of paediatric intensive care associated with centralisation Gale Pearson, Peter Barry, Christopher Timmins, John Stickley, Michael Hocking Intensive Care Medicine (2001) 27: 1670-1673

Send letter to journal:
Re: Re: Mortality in meningococcal disease: please report the figures accurately

We thank Tibby and colleagues for their interest. We believe they and others would be interested in the accompanying figure.

It compares yearly case fatality rates on all referrals to St Mary's PICU, regardless of whether they died before a mobile intensive care team arrived or while the team was assisting with resuscitation. The 29 ‘outside’ deaths are included (3 in 1992/3, 8 in 1994,10 in 1995, 3 in 1996, 5 in 1997). As stated in our published paper, logistic regression analysis, controlling for disease severity, age and sex, and including these extra deaths, showed no change in the estimated odds ratio for the yearly reduction in death rate, namely 0.41. The overall case fatality rate for 1997 became 6% compared with the PICU admission rate of 2% and a predicted case fatality rate 34% using PRISM scores.

For the 5 deaths in 1997 outside St Mary’s PICU, response times between call to the unit and arrival of a team at the DGH varied between 100 and 185 minutes. One child died as the local hospital were telephoning us, two arrested within 90 minutes of St Mary’s being called and died within minutes of the team arriving, and the other two died between 2 and 7 hours after arrival.

Send letter to journal:
Re: Genuine reduction in meningococcal deaths results from teamwork

As paediatric intensivists in Lead Centres accredited for paediatric intensive care (PIC) training and responsible for the care of approximately 7000 cases per year, we read with concern the report from St Mary's Hospital which reported improved outcome of Meningococcal Disease (MD) in 1997 compared to previous years[1].

Their reported reduction in mortality must be seen in the context of an overall reduction of childhood mortality and a widespread improvement in the outcome for many conditions requiring PIC such as acute respiratory failure[2], persistent pulmonary hypertension[3] and complex congenital heart defects[4]. Overall UK PIC mortality rates have fallen to a standardised mortality ratio (SMR) of 0.87 as assessed by the Paediatric Index of Mortality[5] compared to the model generated in 1994[6]. An MRC prospective study of UK PIC outcomes is nearing completion with very detailed admission and follow-up data on >10,000 admissions from 21 Centres. It is regrettable that St Mary's are not contributing to these studies.

Their application of the severity of illness score (PRISM) is incorrect. No patient has a 100% predicted risk of mortality and therefore all deaths observed in any such study must increase the SMR. The exclusion of nearly half of the total deaths (29/62, 47%) who did not survive the long stabilisation and overall retrieval times must reduce SMR regardless of any other intervention. Whilst inclusion of these cases does not alter the direction of the relationship between SMR and year, it raises the overall mortality in the series towards 20% and more than doubles the headline mortality in 1997. Data from the last 4 years would be of interest. In addition, the lack of any data relating to the performance of the model in different risk groups fails to address the potential confounding factor of disease severity. Since all survivors will reduce SMR, one cause of apparent improvement in risk-adjusted survival is increased admission of low risk cases. Recent series from other institutions have followed the convention of presenting data by level of predicted risk[7 8;9].

The claim that their 'Mobile Intensive Care' service is the key element in improved survival is disingenuous at best when all the cases that died under the care of this service were excluded from both the analysis and the 'headline' figure of 2% mortality for MD.

However our greatest concern is the claim that these data support their particular 'model' of care of critically ill children. This is not consistent with their report, as St Mary's had been performing transports since 1992 but the fall in mortality occurred some 4-5 years later. It should be remembered that PICU retrievals have been performed in Liverpool and Glasgow since the late 1970's. Their claim that this 'model' has reduced mortality of meningococcal disease is also inconsistent with the similar improvements in outcome presented by other PICs [7 8;9].

We feel the narrow focus of the paper on the ICU care of MD is misleading. It ignores the important contribution of many others including parents, charities and healthcare workers. Their role in education, early identification, treatment and immediate high quality resuscitation is discounted. To imply that ICU management after the initial resuscitation is the key factor in improved survival undermines the vital contributions of these groups. The media headlines should perhaps have read ‘The Meningitis Trust, GPs, parents and UK PICUs save lives in meningococcal disease’ rather than just St Mary’s.

References

(1) Booy R, Habibi P, Nadel S, De Munter C, Britto J, Morrison A et al. Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery. Arch.Dis.Child 2001;85:386-90.

(2) Peters MJ, Tasker RC, Kiff KM, Yates R, Hatch DJ. Acute hypoxemic respiratory failure in children: case mix and the utility of respiratory severity indices. Intensive.Care Med. 1998;24:699-705.

(3) UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. Lancet 1996;348:75-82.

(4) Andrews R, Tulloh R, Sharland G, Simpson J, Rollings S, Baker E et al. Outcome of staged reconstructive surgery for hypoplastic left heart syndrome following antenatal diagnosis Arch.Dis.Child 2001;85:474-7.

(5) Pearson GA, Stickley J, Shann F. Calibration of the paediatric index of mortality in UK paediatric intensive care units. Arch.Dis.Child 2001;84:125-8.

(6) Shann F, Pearson G, Slater A, Wilkinson K. Paediatric index of mortality (PIM): a mortality prediction model for children in intensive care. Intensive Care Med. 1997;23:201-7.

(7) Thorburn K, Baines P, Thomson A, Hart CA. Mortality in severe meningococcal disease. Arch.Dis.Child 2001;85:382-5.

(8) Peters MJ, Ross-Russell RI, White D, Kerr SJ, Eaton FEM, Keengwe IN et al. Early severe neutropenia and thrombocytopenia identifies the highest risk cases of acute meningococcal disease. Ped.Crit, Care Med 2001;2:225-31.

(9) Tibby, S. M. Mortality in meningococcal disease: please report the figures accurately. http://adc.bmjjournals.com/cgi/eletters/archdischild;85/5/386#224. 26-10-2001.

Dr Mark Peters
Consultant Intensivist
Great Ormond St Hospital

Dr Paul Baines
Consultant Intensivist
Royal Liverpool Childrens’ Hospital

Dr Paul Loan
Consultant Intensivist
Royal Belfast Hospital for Sick Children

Dr Pauline Cullen
Consultant Intensivist
Royal Hospital for Children, Glasgow

Dr Charles Ralston
Consultant Intensivist and Medical Director
Birmingham Children’s Hospital

Dr Robert Yates
Director of Intensive Care
Manchester Children’s Hospital

Dr Michael Marsh
Director of Intensive Care
Southampton General Hospital

Dr Patrica Weir
Consultant Intensivist
St Michael’s Hospital, Bristol

Send letter to journal:
Re: Reduction in Case Fatality Rate From Meningococcal Disease Is due to Genuine Teamwork

Dear Editor

We read with disappointment the response of Dr Petros and colleagues [1] to our article "Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery" [2]. It is unfortunate that there appears to be a misunderstanding of the message of our study which demonstrated a significant improvement in the mortality of children with meningococcal disease (MD) over a period of time. Contrary to their concerns those results were achieved through "genuine teamwork" as stated in our paper.

In answer to the specific points they raised: We and other intensivists are also aware that mortality in conditions other than MD is also improving. In our paper we did not state that MD was the only condition in which there is an improvement in mortality. Our paper referred to a study published in Critical Care Medicine which also showed improving survival rates of paediatric patients (with various diseases) over time in another paediatric intensive care (PIC) setting. [3]

Regarding the participation of St. Mary’s PICU in the PICOS study, our unit along with several others were not able to participate from the outset due to restricted funding from the MRC.

With reference to the patients who died at the referring hospital and their exclusion from the study. Our paper clearly states “Logistic regression analysis, controlling for disease severity, age and sex, showed that over the study period (1992-97) the overall estimate for the reduction in the odds of death was 59% per year (odds ratio for the yearly trend 0.41, 95% CI 0.27-0.62, p=0.000001). This estimate and significance remained the same after inclusion of the 29 deaths that occurred at local hospitals”.

We did not claim that mobile intensive care is the key element in improved survival. What we stated was: “Considerable changes in the management of patients with MD have occurred over the study period. While no single factor alone is likely to explain the reduction in mortality, several factors might have contributed to the improved outcome. In the past, few centres, including those with PICUs, admitted more than a small number of patients with MD annually. Furthermore, patients were often considered too sick to transfer to a specialist centre and were treated in the A&E department, paediatric ward or adult ICU of the local district general hospital. Establishment of a mobile intensive care team allowed the centralisation of care of children with MD at a specialist clinical and research unit, which in turn enabled extensive experience in the management of MD to be developed; this may be the most important reason for the improved outcome..... In other words, it was the increased experience in dealing with meningococcal disease that was the critical factor.

The role of mobile intensive care was more directly addressed when we stated that it ''has probably been another important factor in improved outcome'', not the key factor.

The conclusions of our paper clearly state the multiple factors responsible for the results of the study, which have shown that a notable reduction in the case fatality rate for MD has been achieved.

The purpose of presenting our data was to emphasise the improvements in mortality in a particular group of patients brought about by a change in health care delivery. The key point being early intervention by a multi-disciplinary team with a major research interest in the care of the critically ill child with infectious disease, who have the benefit of a “critical mass” experience.

The PICU at St. Mary’s Hospital, London was established in 1992, at the time primarily to facilitate the enrolment of children with meningococcal disease into clinical trials. As a large number of critically ill children were referred to our unit, we were subsequently able to record high-quality data regarding clinical status, severity of illness and outcome. We began to demonstrate a reduction in mortality from 1994 onwards, as it takes time to establish the clinical experience which can have a significant impact on the disease process.

The unit at St. Mary’s has been greatly involved in the development of a model of care involving 'genuine teamwork' with the aim of improving the healthcare of children with MD. To this end we have been working with the meningitis charities (which are acknowledged on the paper) and other agencies to develop guidelines, publish treatment algorithms and improve policies. In addition our research unit has played a key role in the design and implementation of clinical trials of adjunctive treatments in meningococcal disease, which has lead to the publication of the only two large randomised, double-blind, placebo-controlled studies in childhood septic shock. [4,5]

Finally we are humbled by the magnitude of response from many other colleagues who have applauded our efforts. We believe, and have repeatedly stated, that what has been widely accepted as a major advance in the outcome of children with MD, could only have been achieved by multi -disciplinary effort involving all sectors of health care delivery.

References

(1) Petros AJ, Weir P, Marsh M, Yates R, Ralston C, Cullen P, Loan P, Baines P, Peters M. Genuine reduction in meningococcal deaths results from teamwork. (Arch Dis Child e.letters 7 March 2002)

(2) R Booy, P Habibi, S Nadel, C de Munter, J Britto, A Morrison, M Levin, and the Meningococcal Research Group. Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery. Arch Dis Child 2001; 85: 386-390

(3) Tilford JM, Robertson PK, Lensing S, Finer DH. Differences in paediatric ICU mortality risk over time. Crit Care Med 1998;26:1737-43

(4) Derkx B, Wittes J, McCloskey R and the European Pediatric Meningococcal Septic Shock Trial Study Group. Randomized Placebo- Controlled Trial of HA-1A, a Human Monoclonal Antibody to Endotoxin, in Children with Meningococcal Septic Shock. Clin Infect Dis 1999;28:770-7

(5) Levin M, Quint PA, Goldstein B, Barton P, Bradley JS, Shemie SD, Yeh T, Kim SS, Cafaro DP, Scannon PJ, Giroir BP. Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group. Lancet. 2000;356:961-7.

From Simon Nadel, Robert Booy*, Parviz Habibi, Claudine de-Munter, Joseph Britto and Michael Levin.
Department Of Paediatrics, St. Mary’s Hospital, London W2 1NY, and *Department of Child Health, Queen Mary’s School of Medicine and Dentistry, University of London