Hydrogen Sulfide in Exhaled Gases From Ventilated Septic Neonates and Children: A Preliminary Report.

OBJECTIVES: There is increasing interest in hydrogen sulfide as a marker of pathologic conditions or predictors of outcome. We speculate that as hydrogen sulfide is a diffusible molecule, if there is an increase in plasma hydrogen sulfide in sepsis, it may accumulate in the alveolar space and be detected in exhaled gas. We wished to determine whether we could detect hydrogen sulfide in exhaled gases of ventilated children and neonates and if the levels changed in sepsis. DESIGN: Prospective, observational study. SETTING: The study was conducted across three intensive care units, pediatric, neonatal and cardiac in a large tertiary children's hospital. PATIENTS: We studied ventilated children and neonates with sepsis, defined by having two or more systemic inflammatory response syndrome criteria and one organ failure or suspected infection. A control group of ventilated non-septic patients was also included. INTERVENTION: A portable gas chromatograph (OralChroma; Envin Scientific, Chester, United Kingdom) was used to measure H2S in parts per billion. MEASUREMENTS AND MAIN RESULTS: A 1-2 mL sample of expired gas was taken from the endotracheal tube and analyzed. A repeat sample was taken after 30 minutes and a further single daily sample up to a maximum of 5 days or until the patient was extubated. WBC and C-reactive protein were measured around the time of gas sampling. Each group contained 20 subjects. Levels of H2S were significantly higher in septic patients (Mann Whitney U-test; p < 0.0001) and trended to control levels over five days. C- reactive protein levels were also significantly raised (p < 0.001) and mirrored the decrease in H2S levels. CONCLUSION: Hydrogen sulfide can be detected in expired pulmonary gases in very low concentrations of parts per billion. Significantly higher levels are seen in septic patients compared with controls. The pattern of response was similar to that of C-reactive protein.

Selective decontamination of the digestive tract in critically ill children: systematic review and meta-analysis.

OBJECTIVE: We examined the impact of selective decontamination of the digestive tract on morbidity and mortality in critically ill children. DATA SOURCES: We searched MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and previous meta-analyses. STUDY SELECTION: We included all randomized controlled trials comparing administration of enteral antimicrobials in selective decontamination of the digestive tract with or without a parenteral component with placebo or standard therapy used in the controls. DATA EXTRACTION: The primary end point was the number of acquired pneumonias. Secondary end points were number of infections and overall mortality. Odds ratios were pooled with the random effect model. DATA SYNTHESIS: Four randomized controlled trials including 335 patients were identified. Pneumonia was diagnosed in five of 170 patients (2.9%) for selective decontamination of the digestive tract and 16 of 165 patients (9.7%) for controls (odds ratio 0.31; 95% confidence interval 0.11-0.87; p = .027). Overall mortality for selective decontamination of the digestive tract was 13 of 170 (7.6%) vs. control, 11 of 165 (6.7%) (odds ratio 1.18; 95% confidence interval 0.50-2.76; p = .70). In three studies (n = 109), infection occurred in ten of 54 (18.5%) patients on selective decontamination of the digestive tract and 24 of 55 (43.6%) in the controls (odds ratio 0.34; 95% confidence interval 0.05-2.18; p = .25). CONCLUSIONS: In the four available pediatric randomized controlled trials, selective decontamination of the digestive tract significantly reduced the number of children who developed pneumonia.

Should religious beliefs be allowed to stonewall a secular approach to withdrawing and withholding treatment in children?

Religion is an important element of end-of-life care on the paediatric intensive care unit with religious belief providing support for many families and for some staff. However, religious claims used by families to challenge cessation of aggressive therapies considered futile and burdensome by a wide range of medical and lay people can cause considerable problems and be very difficult to resolve. While it is vital to support families in such difficult times, we are increasingly concerned that deeply held belief in religion can lead to children being potentially subjected to burdensome care in expectation of 'miraculous' intervention. We reviewed cases involving end-of-life decisions over a 3-year period. In 186 of 203 cases in which withdrawal or limitation of invasive therapy was recommended, agreement was achieved. However, in the 17 remaining cases extended discussions with medical teams and local support mechanisms did not lead to resolution. Of these cases, 11 (65%) involved explicit religious claims that intensive care should not be stopped due to expectation of divine intervention and complete cure together with conviction that overly pessimistic medical predictions were wrong. The distribution of the religions included Protestant, Muslim, Jewish and Roman Catholic groups. Five of the 11 cases were resolved after meeting religious community leaders; one child had intensive care withdrawn following a High Court order, and in the remaining five, all Christian, no resolution was possible due to expressed expectations that a 'miracle' would happen.

Germline gain-of-function mutations of ALK disrupt central nervous system development.

Neuroblastoma (NB) is a frequent embryonal tumor of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harboring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes.

Does triage to critical care during a pandemic necessarily result in more survivors?

OBJECTIVE: The 2009 H1N1 pandemic reinforced the need for a planned response to increased demand for critical care. Triage protocols have been proposed incorporating the exclusion of specified subgroups of patients from critical care. There have been no studies that explore the theoretical underpinning of triage at referral, and it is not clear under what circumstances triage would confer the intended benefits. We sought to explore the mechanisms whereby triage could lead to fewer deaths across a critical care population in the context of a pandemic. DESIGN: We constructed a mathematical model based on queuing theory to compare the estimated short-term survival achieved by using a critical care service with and without triage at referral. Illustrative scenarios concerning a hypothetical critical care population were constructed to explore the roles of length of stay and critical care survival in determining the impact of triage and to identify "tipping points" of demand at which triage would result in more survivors. SETTING: Not applicable as this was a data-free mathematical modeling exercise. MAIN RESULTS: We identified circumstances in which triage would be expected to result in more survivors and circumstances in which it would not. In some scenarios, excluding patient groups solely on the basis of anticipated length of stay could be effective due to a more efficient use of critical care bed days. CONCLUSIONS: The impact of triage is dependent on the level of demand and on the scale of achievable differences between included and excluded groups in terms of anticipated length of stay and critical care survival. It cannot be assumed that triage can or will result in fewer deaths. It should be remembered that there are considerations other than population-level short-term survival when determining the objectives of triage and its ethical implementation.

Effect of patient- and team-related factors on stabilization time during pediatric intensive care transport.

OBJECTIVES: To examine the effects of patient- and transport-related factors on the time spent at the referring hospital by an intensive care retrieval team to stabilize critically ill children and to study the relationship between stabilization time and patient outcome. DESIGN: : Analysis of prospectively collected data during pediatric intensive care transport. SETTING: A dedicated regional pediatric intensive care retrieval service performing interhospital transports in England. PATIENTS: Critically ill children transported to intensive care units over a 2-yr period between April 1, 2006 and March 31, 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Factors related to the patient (age group, diagnostic category, and severity of illness) and transport (time of referral, team response time, and number of major and minor interventions performed) were analyzed for their effect on stabilization time in univariate and multivariate analyses. The relationship between stabilization time and patient outcome in the first 24 hrs post intensive care unit admission was also studied. Patient acuity was high in the transported population (84% invasively ventilated; 28% on vasoactive agents). Predicted mortality risk (Pediatric Index of Mortality 2 score), diagnostic category, team response time, and number of major interventions performed had an independent effect on stabilization time, whereas the length of stabilization itself did not influence early mortality on the intensive care unit. Each minor intervention prolonged the stabilization time by an average of 10 mins. CONCLUSIONS: Stabilization time during intensive care transport is influenced by a number of patient- and transport-related factors, and cannot be used in isolation as an indicator of team efficiency. Time spent undertaking intensive care interventions early in the course of patient illness at the referring hospital does not worsen patient outcome, suggesting that the "scoop and run" model can be safely abandoned in interhospital transport.

Emergency management of children with acute severe asthma requiring transfer to intensive care.

PURPOSE: Children presenting to emergency departments (ED) with acute severe asthma unresponsive to initial medical therapy may require endotracheal intubation and mechanical ventilation. There is little data on complications during the acute management of children with life-threatening asthma, particularly at hospitals where specialist paediatric staff are lacking. It was hypothesised that a better understanding of complications, particularly associated with intubation and mechanical ventilation, would improve acute management in ED, aid quality improvement initiatives at district general hospitals (DGH) and form the basis for educational interventions from regional paediatric critical care units. METHODS: A retrospective case note review was performed for all children referred to a regional intensive care retrieval service with status asthmaticus over a 2-year period. Initial treatment, patient-related factors, indication for endotracheal intubation and the type and occurrence of adverse events during acute management at the DGH were studied. Bivariate and multivariate analyses were undertaken to identify factors associated with the occurrence of complications. RESULTS: 51 (85%) of the 60 children transferred to a paediatric intensive care unit for acute severe asthma required intubation. 36 (70.5%) experienced one or more complications during intubation and in the early phase of mechanical ventilation. The most common complications were hypotension (requiring fluid resuscitation and/or inotropic support) and severe bronchospasm with acute hypercarbia. The indication for intubation significantly affected the chances of a complication occurring during stabilisation. CONCLUSIONS: There is considerable morbidity in asthmatic children who are referred to paediatric intensive care. The majority of complications may be anticipated and prevented resulting in improved management at DGH.

A pilot study of neonatal and pediatric esophageal pulse oximetry.

BACKGROUND: In this pilot study we explored the suitability of the esophagus as a new measuring site for blood oxygen saturation (Spo(2)) in neonates. METHODS: A new miniaturized esophageal pulse oximeter has been developed. Five patients (one child and four neonates) were studied. RESULTS: Spo(2) values were obtained in the esophagus of all patients. A Bland and Altman plot of the difference between Spo(2) values from the esophageal pulse oximeter and a commercial toe pulse oximeter against their mean showed that the bias and the limits of agreement between the two pulse oximeters were +0.3% and +1.7% to -1.0%, respectively. CONCLUSIONS: This study suggests that the esophagus can be used as an alternative site for monitoring blood oxygen saturation in children and neonates.

Inhaled nitric oxide in neonatal and paediatric transport.

Since the first reports of the use of inhaled nitric oxide in the early 1990s its applications have been refined to a number of specific conditions. Pre-term and term neonates benefit significantly in the improvement of oxygenation in conditions such as hypoxic respiratory failure and persistent pulmonary hypertension of the neonate and the reduction in referral rates to extra corporeal membrane oxygenation. Many neonatal units still do not have the ability to administer inhaled nitric oxide though an increasing number of neonatal units have acquired the capability to deliver inhaled nitric oxide in recent years with commercially available delivering devices. In either case if the neonate needs transfer for further management or extra corporeal membrane oxygenation the journey can be improved if inhaled nitric oxide is introduced during transport or could deteriorate if inhaled nitric oxide was discontinued during transport. Delivery of inhaled nitric oxide during transport can be technically challenging and the consequences of increased or interrupted delivery can be dangerous. The different modes of transport either by road or air can influence the method of delivery. We describe our method of delivering inhaled nitric oxide during the retrievals we undertake and how this changes depending upon the type of journey performed. We also suggest guidelines for its use during transport and outline the precautions we take to ensure safety of patient and carers during transport.

Effects of blood sample volume on hematocrit in critically ill children and neonates.

BACKGROUND: There are no studies correlating the volume of blood taken from children and hematocrit (Hct) stability, relating those changes to duration of stay, severity of illness or weight. Earlier studies in neonates suggest that repeated sampling results in a drop in Hct. AIM: To characterize the changes in Hct in children of all ages admitted to intensive care over a 5-day period following routine blood volume sampling. METHODS: We undertook an open prospective observational study. Eligible children were recruited sequentially and data recorded for 5 days following admission. The bedside nurse recorded the daily volume of blood samples taken and transfusions given. Daily Hct was noted from the routine full blood count. The relationship between changes in Hct and blood sample volume and transfusion requirement was studied. RESULTS: There were no differences in mean Hct on admission at end of the study (P = 0.69, n = 30) nor in the median blood volume sampled between transfused and nontransfused groups (7.5 ml.kg(-1) vs 7.9 ml.kg(-1), P = 0.88). The largest blood sample volumes were taken on admission and from the smallest patients. CONCLUSION: We have quantitated the change in Hct and size of blood volume taken for routine laboratory studies. We suggest that children can tolerate 0.25 ml.kg(-1).day(-1) blood sampling without a fall in Hct and sampling can be tailored to the individual child according to the admission Hct.

Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease.

BACKGROUND: Increased pulmonary vascular resistance (PVR) because of congenital heart disease (CHD) may be caused by a dysfunction in endogenous pulmonary endothelial nitric oxide (NO) production. In other forms of pulmonary vascular disease with increased PVR, an elevated activity of a phosphodiesterase type 5 (PDE-5), responsible for the degradation of cyclic guanidine monophosphate (cGMP), the second messenger of endothelially produced NO, has been demonstrated. This study compares the effects of inhaled NO before and after the specific inhibition of the PDE-5 by intravenous sildenafil (Viagra) in pre- and postoperative children with increased PVR because of CHD. METHODS AND RESULTS: 12 children with congenital heart disease (age 0.2 to 15.7 years, median 2.4 years) and increased mean pulmonary arterial pressure, and 12 postoperative children (age 0.11 to 0.65 years, median 0.32 years) with increased PVR (8.3+/-1.0 Wood Units*m2) were studied during cardiac catheterization ("cath laboratory"), or within 2 hours after return from cardiac surgery ("post op"), respectively. All were sedated, tracheally intubated and paralyzed. During alveolar hyperoxygenation (FiO2=0.65), the effects of inhaled NO (20 ppm) were compared before and after the stepwise infusion of sildenafil ("cath laboratory", 1 mg/kg; post op, 0.25 mg/kg). Intravenous sildenafil more effectively reduced PVR than NO (11.5% versus 4.3% in the "cath laboratory" patient group, P<0.05, and 25.8% versus 14.6% in the post op patient group, P=0.09. The increase in cGMP in response to NO was potentiated (2- to 2.4-fold) by PDE-5 inhibition. While the vasodilating effects of sildenafil showed pulmonary selectivity, its infusion was associated with increased intrapulmonary shunting in the postoperative patients (Qs/Qt=16.5+/-4.7% to 25.5+/-18.2% P=0.04). CONCLUSIONS: Intravenous sildenafil is as effective as inhaled NO as a pulmonary vasodilator in children with congenital heart disease. Although clinically insignificant in this study, increased intrapulmonary shunting with sildenafil may be disadvantageous in some patients after CHD surgery.

Comparison of the bispectral index monitor with the Comfort score in assessing level of sedation of critically ill children.

OBJECTIVE: To compare the value of bispectral index as a monitor of sedation in critically ill children with a validated sedation scoring system. DESIGN: Prospective convenience sample. SETTING: Paediatric intensive care unit in a tertiary paediatric centre. PATIENTS AND PARTICIPANTS: Forty-three critically ill children receiving sedation and mechanical ventilation. MEASUREMENTS AND RESULTS: Simultaneous recording of bispectral index (BIS) and assessment of depth of sedation using the Comfort score were performed at regular intervals. To determine if BIS could detect episodes of arousal, times of endotracheal suctioning and the corresponding BIS score were recorded. There was an overall moderate correlation between BIS scores and Comfort scores ( r=0.50, r(2)=0.25, p<0.0001). Children who had a neurological reason for their current admission ( n=25) showed a weaker correlation ( r=0.26, r(2)=0.06, p<0.007) than those ( n=15) with normal neurology ( r=0.51, r(2)=0.26, p<0.0001). There were no significant differences in the rise in BIS following endotracheal suctioning among any of the predefined depths of sedation. There was a correlation of r=0.84 ( r(2)=0.71) (SE of slope 0.49, CI(95) 1.79-3.88) for mean BIS values for each individual Comfort score from 8-23. Using Spearman's rank correlation of Comfort versus mean BIS, the correlation coefficient was r=0.92. CONCLUSIONS: Bispectral index scores correlate with Comfort scores to a moderate degree. BIS is able to discriminate between light and deep levels of sedation, but not between deep and very deep levels of sedation. The BIS monitor may provide a useful method for assessing sedation in critically ill children, especially those receiving neuromuscular blockers.

All great truths are iconoclastic: selective decontamination of the digestive tract moves from heresy to level 1 truth.

OBJECTIVE: The objective was to compare evidence of the effectiveness, costs and safety of the traditional parenteral antibiotic-only approach against that gathered from 53 randomised trials involving more than 8,500 patients and six meta-analyses on selective decontamination of the digestive tract (SDD) to control infection on the intensive care unit (ICU). PHILOSOPHY: Traditionalists believe that all infections are due to breaches of hygiene except those established in the first 2 days, and that all micro-organisms can cause death. In contrast, newer insights show that transmission via the hands of carers are responsible only for infections occurring after one week, and that only a limited range of 15 potential pathogens contribute to mortality. INTERVENTIONS TO PREVENT ICU INFECTION: The traditional approach is based on hand disinfection aiming at the prevention of transmission of all micro-organisms, to control all infections that occur after 2 days on the ICU. The second feature is the restrictive use of systemic antibiotics, only in cases of microbiologically proven infection. In contrast, SDD aims to control the three types of infection: primary, secondary endogenous and exogenous due to 15 potential pathogens. The classical SDD tetralogy comprises four components: (i) a parenteral antibiotic, cefotaxime, administered for three days to prevent primary endogenous infections typically occurring "early"; (ii) the oropharyngeal and enteral antimicrobials, polymyxin E, tobramycin and amphotericin B administered in throat and gut throughout the treatment on the ICU to prevent secondary endogenous infections tending to develop "late"; (iii) a high standard of hygiene to control transmission of potential pathogens; and (iv) surveillance samples of throat and rectum to monitor the efficacy of the treatment. ENDPOINTS: (i) Infectious morbidity; (ii) mortality; (iii) antimicrobial resistance; and (iv) costs. RESULTS: Properly designed trials on hand disinfection have never demonstrated a reduction in either pneumonia and septicaemia, or mortality. Two randomised trials using restrictive antibiotic policies failed to show a survival benefit at 28 days. In both trials the proportion of resistant isolates obtained from the lower ways was >60% despite significantly less use of antibiotics in the test group. A formal cost effectiveness analysis of the traditional antibiotic policies has not been performed. On the other hand, two meta-analyses have shown that SDD reduces the odds ratio for lower airway infections to 0.35 (0.29-0.41) and mortality to 0.80 (0.69-0.93), with a 6% overall mortality reduction from 30% to 24%. No increase in the rate of super infections due to resistant bacteria could be demonstrated over a period of 20 years of clinical research. Four randomised trials found the cost per survivor to be substantially lower in patients receiving SDD than for those traditionally managed. CONCLUSIONS: The traditionalists still rely on level 5 evidence, i.e. expert opinion, with a grade E recommendation, whilst the proponents of SDD are able to cite level 1 evidence allowing a grade A recommendation in their attempts to control infection on the ICU. The main reason for SDD not being widely used is the primacy of opinion over evidence.