Simon Nadel

Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine

Background:The Institute of Medicine calls for the use of clinical guidelines and practice parameters to promote “best practices” and to improve patient outcomes. Objective:2007 update of the 2002 American College of Critical Care Medicine Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock. Participants:Society of Critical Care Medicine members with special interest in neonatal and pediatric septic shock were identified from general solicitation at the Society of Critical Care Medicine Educational and Scientific Symposia (2001–2006). Methods:The Pubmed/MEDLINE literature database (1966–2006) was searched using the keywords and phrases: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, extracorporeal membrane oxygenation (ECMO), and American College of Critical Care Medicine guidelines. Best practice centers that reported best outcomes were identified and their practices examined as models of care. Using a modified Delphi method, 30 experts graded new literature. Over 30 additional experts then reviewed the updated recommendations. The document was subsequently modified until there was greater than 90% expert consensus. Results:The 2002 guidelines were widely disseminated, translated into Spanish and Portuguese, and incorporated into Society of Critical Care Medicine and AHA sanctioned recommendations. Centers that implemented the 2002 guidelines reported best practice outcomes (hospital mortality 1%–3% in previously healthy, and 7%–10% in chronically ill children). Early use of 2002 guidelines was associated with improved outcome in the community hospital emergency department (number needed to treat = 3.3) and tertiary pediatric intensive care setting (number needed to treat = 3.6); every hour that went by without guideline adherence was associated with a 1.4-fold increased mortality risk. The updated 2007 guidelines continue to recognize an increased likelihood that children with septic shock, compared with adults, require 1) proportionally larger quantities of fluid, 2) inotrope and vasodilator therapies, 3) hydrocortisone for absolute adrenal insufficiency, and 4) ECMO for refractory shock. The major new recommendation in the 2007 update is earlier use of inotrope support through peripheral access until central access is attained. Conclusion:The 2007 update continues to emphasize early use of age-specific therapies to attain time-sensitive goals, specifically recommending 1) first hour fluid resuscitation and inotrope therapy directed to goals of threshold heart rates, normal blood pressure, and capillary refill ≤2 secs, and 2) subsequent intensive care unit hemodynamic support directed to goals of central venous oxygen saturation >70% and cardiac index 3.3–6.0 L/min/m2.

Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery

BACKGROUND AND AIMS The case fatality rate from meningococcal disease (MD) has remained relatively unchanged in the post antibiotic era, with 20–50% of patients who develop shock still dying. In 1992 a new paediatric intensive care unit (PICU) specialising in MD was opened. Educational information was disseminated to local hospitals, and a specialist transport service was established which delivered mobile intensive care. The influence of these changes on mortality of children with MD was investigated. METHODS A total of 331 consecutive children with meningococcal disease admitted to the PICU between 1992 and 1997 were studied. Severity of the disease on admission was assessed using the paediatric risk of mortality (PRISM) score. Logistic regression analysis was used to correct for clinical severity, age, and sex; death was the outcome, and year of admission, a temporal trend variable, was the primary exposure. RESULTS The case fatality rate fell year on year (from 23% in 1992/93 to 2% in 1997) despite disease severity remaining largely unchanged. After adjustment for age, sex, and disease severity, the overall estimate for improvement in the odds of death was 59% per year (odds ratio for the yearly trend 0.41). CONCLUSIONS A significant improvement in outcome for children admitted with MD to a PICU has occurred in association with improvements in initial management of patients with MD at referring hospitals, use of a mobile intensive care service, and centralisation of care in a specialist unit.

Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease

Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D<E), P = 2.2 × 10−11) and in CFH-related protein 3 (CFHR3)(rs426736, P = 4.6 × 10−13). N. meningitidis is known to evade complement-mediated killing by the binding of host CFH to the meningococcal factor H–binding protein (fHbp). Our study suggests that host genetic variation in these regulators of complement activation plays a role in determining the occurrence of invasive disease versus asymptomatic colonization by this pathogen.

Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock

BACKGROUND Myocardial failure has a central role in the complex pathophysiology of septic shock and contributes to organ failure and death. During the sepsis-induced inflammatory process, specific factors are released that depress myocardial contractile function. We aimed to identify these mediators of myocardial depression in meningococcal septic shock. METHODS We combined gene-expression profiling with protein and cellular methods to identify a serum factor causing cardiac dysfunction in meningococcal septic shock. We identified genes that were significantly upregulated in blood after exposure to meningococci. We then selected for further analysis those genes whose protein products had properties of a myocardial depressant factor--specifically a 12-25 kDa heat-stable protein that is released into serum shortly after onset of meningococcal infection. FINDINGS We identified 174 significantly upregulated genes in meningococcus-infected blood: six encoded proteins that were of the predicted size and had characteristics of a myocardial depressant factor. Of these, interleukin 6 caused significant myocardial depression in vitro. Removal of interleukin 6 from serum samples of patients with meningococcaemia and from supernatants of inflammatory cells stimulated by meningococci in vitro abolished the negative inotropic activity. Furthermore, concentrations in serum of interleukin 6 strongly predicted degree of myocardial dysfunction and severity of disease in children with meningococcal septic shock. INTERPRETATION Interleukin 6 is a mediator of myocardial depression in meningococcal disease. This cytokine and its downstream mediators could be a target for future treatment strategies.

Emergency management of meningococcal disease

Meningococcal disease remains a major cause of mortality in children in the UK. Aggressive early volume resuscitation, meticulous attention to the normalisation of all physiological and laboratory parameters, and prompt referral to specialist paediatric intensive care may lead to a sharp reduction in mortality. Application of the management algorithm described in this article may be helpful to those involved in the early part of management of critically ill patients with meningococcal disease.

The role of healthcare delivery in the outcome of meningococcal disease in children: case-control study of fatal and non-fatal cases

Abstract Objective To determine whether suboptimal management in hospital could contribute to poor outcome in children admitted with meningococcal disease. Design Case-control study of childhood deaths from meningococcal disease, comparing hospital care in fatal and non-fatal cases. Setting National statistics and hospital records. Subjects All children under 17 years who died from meningococcal disease (cases) matched by age with three survivors (controls) from the same region of the country. Main outcome measures Predefined criteria defined optimal management. A panel of paediatricians blinded to the outcome assessed case records using a standardised form and scored patients for suboptimal management. Results We identified 143 cases and 355 controls. Departures from optimal (per protocol) management occurred more frequently in the fatal cases than in the survivors. Multivariate analysis identified three factors independently associated with an increased risk of death: failure to be looked after by a paediatrician, failure of sufficient supervision of junior staff, and failure of staff to administer adequate inotropes. Failure to recognise complications of the disease was a significant risk factor for death, although not independently of absence of paediatric care (P = 0.002). The odds ratio for death was 8.7 (95% confidence interval 2.3 to 33) with two failures, increasing with multiple failures. Conclusions Suboptimal healthcare delivery significantly reduces the likelihood of survival in children with meningococcal disease. Improved training of medical and nursing staff, adherence to published protocols, and increased supervision by consultants may improve the outcome for these children and also those with other life threatening illnesses.

Emergency management of children with severe sepsis in the United Kingdom: the results of the Paediatric Intensive Care Society sepsis audit

Objective: To audit current UK practice of the management of severe sepsis in children against the 2002 American College of Critical Care Medicine/Pediatric Advanced Life Support (ACCM-PALS) guideline. Design: Prospective observational study. Setting: 17 UK paediatric intensive care units (PICUs) and two UK PICU transport services. Participants: 200 children accepted for PICU admission within 12 h of arrival in hospital, whether or not successfully transported to a PICU, with a discharge diagnosis of sepsis or suspected sepsis. Main outcome measures: Medical interventions, physiological and laboratory data to determine the presence or absence of shock, inter-hospital transfer times, predicted mortality (using the Paediatric Index of Mortality, version 2 (PIM2) scoring system) and observed mortality. Results: 34/200 (17%) children died following referral. Although children defined as being in shock received significantly more fluid (p<0.001) than those who were not in shock, overall fluid and inotrope management suggested by the 2002 ACCM-PALS guideline was not followed in 62% of shocked children. Binary logistic regression analysis demonstrated that the odds ratio for death, if shock was present at PICU admission, was 3.8 (95% CI 1.4 to 10.2, p = 0.008). Conclusions: The presence of shock at PICU admission is associated with an increased risk of death. Despite clear consensus guidelines for the emergency management of children with severe sepsis and septic shock, most children received inadequate fluid resuscitation and inotropic support in the crucial few hours following presentation.

Morbidity and severity of illness during interhospital transfer: impact of a specialised paediatric retrieval team.

Abstract Objective: To evaluate the morbidity and severity of illness during interhospital transfer of critically ill children by a specialised paediatric retrieval team. Design: Prospective, descriptive study. Setting: Hospitals without paediatric intensive care facilities in and around the London area, and a paediatric intensive care unit at a tertiary centre. Subjects: 51 critically ill children transferred to the paediatric intensive care unit. Main outcome measures: Adverse events related to equipment and physiological deterioration during transfer. Paediatric risk of mortality score before and after retrieval. Therapeutic intervention score before and after arrival of retrieval team. Results: Two (4%) patients had preventable physiological deterioration during transport. There were no adverse events related to equipment. Severity of illness decreased during stabilisation and transport by the retrieval team, suggested by the difference between risk of mortality scores before and after retrieval (P<0.001). The median (range) difference between the two scores was 3.0 (−6 to 17). Interventions during stabilisation by the retrieval team increased, demonstrated by the difference between intervention scores before and after retrieval, median (range) difference between the two scores being 6 (−8 to 38) (P<0.001). Conclusions: Our study indicates that a specialised paediatric retrieval team can rapidly deliver intensive care to critically ill children awaiting transfer. Such children can be transferred to a paediatric intensive care unit with minimal morbidity and mortality related to transport. There was no deterioration in the clinical condition of most patients during transfer.

Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children

ObjectiveMeningococcal sepsis invariably is associated with coagulopathy. We have previously reported an association between mortality rate in meningococcal disease and the functional 4G/5G promoter polymorphism of the plasminogen-activator-inhibitor (PAI)-1 gene in a small patient cohort. In a much larger cohort, we aimed to confirm these results and further investigate the role of the 4G/5G polymorphism in determining susceptibility, outcome, and complications of disease. DesignSusceptibility was investigated in two separate studies, a case-control study and a family-based transmission study, each test using a separate patient cohort. Severity was investigated using clinical diagnosis, the presence of vascular complications, Pediatric Risk of Mortality (PRISM)-predicted morality, and actual mortality. SettingUniversity hospital and laboratories. SubjectsSubjects were 510 UK pediatric patients, 210 parents of patients, and 155 UK Caucasian controls. InterventionsDNA extraction and 4G/5G PAI-1 genotyping was carried out using published techniques. Measurements and Main ResultsPredicted mortality distribution differed significantly between genotypes (p = .05) with a significantly higher median PRISM in the 4G/4G (41.1%) than the 4G/5G (23.4%) and 5G/5G (19.0%) genotyped patients combined (p = .02). Actual mortality rate was significantly associated with both genotype (chi-square = 14.8, p = .001) and allele frequencies (chi-square = 14.0, p < .0001), with more deaths in the 4G/4G (28.4%) than the 4G/5G and 5G/5G genotyped patients combined (14.9%; chi-square = 7.9; p = .005; risk ratio, 1.9; 95% confidence interval, 1.2–3.0). Logistic regression indicated a 40% and 91% reduction in the odds of dying if a patient was either 4G/5G or 5G/5G, respectively, in comparison to a 4G homozygous patient. When analyzed by clinical diagnosis, the association with death was found only in the sepsis group (chi-square = 18.7, p < .0001; risk ratio, 2.7; 95% confidence interval, 1.6–4.6). In survivors of disease, a significantly higher proportion of 4G/4G patients suffered from vascular complications (chi-square = 6.7, p = .03; risk ratio, 2.4; 95% confidence interval, 1.1–5.0). The 4G/5G polymorphism was not associated or linked with susceptibility (case-control result, p = .6; family-based transmission study results, p = .2). ConclusionsThis study confirms that Caucasian pediatric patients carrying the functional PAI-1 4G/4G genotype are at an increased risk of developing vascular complications and dying from meningococcal disease.

Effect of the Factor V Leiden mutation on the severity of meningococcal disease

BACKGROUND One of the most serious complications of meningococcal disease is the syndrome of purpura fulminans, which is characterized by intravascular thrombosis and hemorrhagic infarction of skin, limbs and digits. The reasons why some patients with meningococcal disease develop purpura fulminans while others have minimal thrombotic and skin involvement despite having profound septic shock are not yet understood. The Factor V Leiden mutation (FV(L)) is associated with thrombotic events, and we hypothesized that children carrying FV(L) who develop meningococcal disease may be at increased risk of purpura fulminans. METHODS We determined the FV(L) genotype by PCR and restriction enzyme digestion (Mnl1) in 259 children with meningococcal disease and 80 healthy controls. In addition 79 parents of children with fatal meningococcal disease were studied. RESULTS There was no significant increase in the frequency of FV(L) in patients with meningococcal disease (10%) as compared with healthy controls (9%) or with the parents of children who died of meningococcal disease (12%). Although the mortality was not increased in patients heterozygous for FV(L), they had increased complications of purpura fulminans, as assessed by requirement for skin grafting, referral to plastic surgeon and/or amputation. Among survivors 5 of 24 (21%) of those heterozygous for FV(L) had complications, compared with 14 of 233 (7%) who were wild type [P < 0.03; relative risk, 3.1 (95% confidence intervals, 1.2 to 7.9)]. CONCLUSIONS FV(L) exacerbates purpura fulminans in meningococcal disease but does not have a significant effect on mortality.