Antifibrinolytic Drugs for the Prevention of Bleeding in Pediatric Cardiac Surgery on Cardiopulmonary Bypass: A Systematic Review and Meta-analysis.

BACKGROUND: Bleeding is one of the commonest complications affecting children undergoing cardiac surgery on cardiopulmonary bypass. Antifibrinolytic drugs are part of a multifaceted approach aimed at reducing bleeding, though sufficiently sized pediatric studies are sparse, and dosing algorithms are heterogeneous. Our objective was to evaluate the efficacy and safety of antifibrinolytic agents as well as the effectiveness of different dosing regimens in pediatric cardiac surgery using cardiopulmonary bypass. METHODS: We performed a systematic review and meta-analysis evaluating randomized controlled trials published between 1980 and 2019, identified by searching the databases MEDLINE, EMBASE, PubMed, and CENTRAL. All studies investigating patients <18 years of age without underlying hematological disorders were included. The primary outcome was postoperative bleeding; secondary end points included blood product transfusion, mortality, and safety (thromboses, anaphylaxis, renal or neurological dysfunction, and seizures). Different dosing regimens were compared. Studies were dual appraised, outcomes were reported descriptively and, if appropriate, quantitatively using the Review Manager 5 (REVMAN 5) software (The Cochrane Collaboration). RESULTS: Thirty of 209 articles were included, evaluating the following drugs versus control: aprotinin n = 14, tranexamic acid (TXA) n = 12, and epsilon-aminocaproic acid (EACA) n = 4. The number of participants per intervention group ranged from 11 to 100 (median, 25; interquartile range [IQR], 20.5) with a wide age span (mean, 13 days to 5.8 years) and weight range (mean, 3.1-26.3 kg). Methodological quality was low to moderate.All agents reduced mean 24-hour blood loss compared to control: aprotinin by 6.0 mL/kg (95% confidence interval [CI], -9.1 to -3.0; P = .0001), TXA by 9.0 mL/kg (95% CI, -11.3 to -6.8; P < .00001), and EACA by 10.5 mL/kg (95% CI, -21.1 to 0.0; P = .05). Heterogeneity was low for TXA (I2 = 29%; P = .19), moderate for aprotinin (I2 = 41%; P = .11), and high for EACA (I2 = 95%; P < .00001). All agents also reduced 24-hour blood product transfusion. There was no clear dose-response effect for TXA nor aprotinin. Studies were underpowered to detect significant differences in mortality, thromboses, anaphylaxis, and renal or neurological dysfunction. CONCLUSIONS: The available data demonstrate efficacy for all 3 antifibrinolytic drugs. Therefore, the agent with the most favorable safety profile should be used. As sufficient data are lacking, large comparative trials are warranted to assess the relative safety and appropriate dosing regimens in pediatrics.

Strategies for Prevention and Management of Bleeding Following Pediatric Cardiac Surgery on Cardiopulmonary Bypass: A Scoping Review.

OBJECTIVE: We aimed to systematically describe, via a scoping review, the literature reporting strategies for prevention and management of mediastinal bleeding post pediatric cardiopulmonary bypass surgery. DATA SOURCES: MEDLINE, EMBASE, PubMed, and Cochrane CENTRAL Register. STUDY SELECTION: Two authors independently screened publications from 1980 to 2016 reporting the effect of therapeutic interventions on bleeding-related postoperative outcomes, including mediastinal drain loss, transfusion, chest re-exploration rate, and coagulation variables. Inclusions: less than 18 years, cardiac surgery on cardiopulmonary bypass. DATA EXTRACTION: Data from eligible studies were extracted using a standard data collection sheet. DATA SYNTHESIS: Overall, 299 of 7,434 screened articles were included, with observational studies being almost twice as common (n = 187, 63%) than controlled trials (n = 112, 38%). The most frequently evaluated interventions were antifibrinolytic drugs (75 studies, 25%), blood products (59 studies, 20%), point-of-care testing (47 studies, 16%), and cardiopulmonary bypass circuit modifications (46 studies, 15%). The publication rate for controlled trials remained constant over time (4-6/yr); however, trials were small (median participants, 51; interquartile range, 57) and overwhelmingly single center (98%). Controlled trials originated from 22 countries, with the United States, India, and Germany accounting for 50%. The commonest outcomes were mediastinal blood loss and transfusion requirements; however, these were defined inconsistently (blood loss being reported over nine different time periods). The majority of trials were aimed at bleeding prevention (98%) rather than treatment (10%), nine studies assessed both. CONCLUSIONS: Overall, this review demonstrates small trial sizes, low level of evidence, and marked heterogeneity of reported endpoints in the included studies. The need for more, higher quality studies reporting clinically relevant, comparable outcomes is highlighted. Emerging fields such as the use of coagulation factor concentrates, goal-directed guidelines, and anti-inflammatory therapies appear to be of particular interest. This scoping review can potentially guide future trial design and form the basis for therapy-specific systematic reviews.

The relationship among thromboelastography, hemostatic variables, and bleeding after cardiopulmonary bypass surgery in children.

BACKGROUND: Mediastinal bleeding is common after pediatric cardiopulmonary bypass (CPB) surgery. Thromboelastography (TEG) may predict bleeding and provide insight into likely mechanisms. We aimed to (a) compare perioperative temporal profiles of TEG and laboratory hemostatic variables between patients with significant hemorrhage (BLEED) and those without (CONTROL), (b) investigate the relationship between TEG variables and routine hemostatic variables, and (c) develop a model for prediction of bleeding. METHODS: TEG and laboratory hemostatic variables were measured prospectively at 8 predefined times for 50 children weighing <20 kg undergoing CPB. RESULTS: Patients who bled demonstrated different TEG profiles than those who did not. This was most apparent after protamine administration and was partly attributable to inadequate heparin reversal, but was also associated with a significantly lower nadir in mean (sd) fibrinogen for the BLEED group compared with CONTROL group: 0.44 (0.18) and 0.71 (0.40) g/L, respectively (P = 0.01). Significant nonlinear relationships were found between the majority of TEG and laboratory hemostatic variables. The strongest relationship was between the maximal amplitude and the platelet-fibrinogen product (logarithmic r(2) = 0.71). Clot strength decreased rapidly when (a) fibrinogen concentration was <1 g/L, (b) platelets were <120 x 10(9)/L, and (c) platelet-fibrinogen product was <100. A 2-variable model including the activated partial thromboplastin time at induction of anesthesia and TEG mean amplitude postprotamine discriminated well for subsequent bleeding (C statistic 0.859). CONCLUSIONS: Hypofibrinogenemia and inadequate heparin reversal are 2 important factors contributing to clot strength and perioperative hemorrhage after pediatric CPB. TEG may be a useful tool for predicting and guiding early treatment of mediastinal bleeding in this group.

The influence of hyperchloraemia on acid base interpretation in diabetic ketoacidosis.

OBJECTIVES: During the acute treatment of diabetic ketoacidosis we (a) determined the temporal incidence of hyperchloraemia, and (b) quantified the influence of hyperchloraemia on interpretation of common blood gas derived acid base parameters, namely base deficit and bicarbonate. DESIGN AND SETTING: Retrospective chart review in two regional paediatric intensive care units. MEASUREMENTS AND RESULTS: Stewart's physicochemical theory was used to develop regression equations quantifying the acidifying effect of hyperchloraemia on both base deficit and bicarbonate. These were then applied retrospectively to blood chemistry results from 18 children (median age 12.7 years, weight 43 kg) with diabetic ketoacidosis. Plasma ketonaemia was estimated using the albumin-corrected anion gap. The incidence of hyperchloraemia, as documented by a ratio of plasma chloride to sodium of greater than 0.79, increased from 6% at admission to 94% after 20 h of treatment. Correction for chloride produced a dramatic improvement in the relationship between changes in the anion gap vs. both base deficit (from R(2)=0.55 to R(2)=0.95) and bicarbonate (from R(2)=0.51 to R(2)=0.96) during treatment. After 20 h of treatment the mean base deficit had decreased from 24.7 mmol/l to 10.0 mmol/l however, the proportion that was due to hyperchloraemia increased from 2% to 98%. CONCLUSIONS: It is now possible using a simple correction factor to quantify the confounding effect of hyperchloraemia on both base deficit and bicarbonate in diabetic ketoacidosis. This bedside tool may be a useful adjunct to guide therapeutic interventions.

Retrospective evaluation of a paediatric intensivist-led flexible bronchoscopy service.

OBJECTIVE: To demonstrate the diagnostic yield, therapeutic role and safety of flexible bronchoscopy via an intensivist-led service in critically ill children. DESIGN: Retrospective chart review. SETTING: Regional paediatric intensive care unit. MEASUREMENTS AND RESULTS: One hundred forty-eight flexible bronchoscopies were performed by two intensivists on 134 patients (median age 16.5 months) over a 2.5-year period. Eighty-eight percent of patients required mechanical ventilation, and 22% were receiving inotropes. Case mix included general (n = 77), cardiac surgery (n = 18), cardiology (n = 13), ear-nose-and-throat surgery (n = 17), oncology (n = 8) and renal (n = 1). The indication for bronchoscopy was defined a priori according to one of four categories: suspected upper airway disease (n = 32); lower airway disease (n = 70); investigation of pulmonary disease (n = 25); and extubation failure (n = 21). Bronchoscopy was generally performed soon after PICU admission, at a median time of 1.5 days for the former three categories, and 4 days for extubation failure group. A positive yield from bronchoscopy (diagnosis that explained the clinical condition or influenced patient management) was present in 113 of 148 (76%) procedures, varying within groups from 44% (pulmonary disease) to 90% (extubation failure). Ten percent of patients developed a fall in oxygen saturations > 20% during the procedure and 17% required a bolus of at least 10 ml/kg of 0.9% saline for hypotension. CONCLUSIONS: Critically ill patients with respiratory problems may benefit from a PICU-led bronchoscopy service as the yield for positive bronchoscopic finding is high, particularly for upper airway problems or extubation failure.

Validation of a method to partition the base deficit in meningococcal sepsis: a retrospective study.

INTRODUCTION: The base deficit is a useful tool for quantifying total acid-base derangement, but cannot differentiate between various aetiologies. The Stewart-Fencl equations for strong ions and albumin have recently been abbreviated; we hypothesised that the abbreviated equations could be applied to the base deficit, thus partitioning this parameter into three components (the residual being the contribution from unmeasured anions). METHODS: The two abbreviated equations were applied retrospectively to blood gas and chemistry results in 374 samples from a cohort of 60 children with meningococcal septic shock (mean pH 7.31, mean base deficit -7.4 meq/L). Partitioning required the simultaneous measurement of plasma sodium, chloride, albumin and blood gas analysis. RESULTS: After partitioning for the effect of chloride and albumin, the residual base deficit was closely associated with unmeasured anions derived from the full Stewart-Fencl equations (r2 = 0.83, y = 1.99 - 0.87x, standard error of the estimate = 2.29 meq/L). Hypoalbuminaemia was a common finding; partitioning revealed that this produced a relatively consistent alkalinising effect on the base deficit (effect +2.9 +/- 2.2 meq/L (mean +/- SD)). The chloride effect was variable, producing both acidification and alkalinisation in approximately equal proportions (50% and 43%, respectively); furthermore the magnitude of this effect was substantial in some patients (SD +/- 5.0 meq/L). CONCLUSION: It is now possible to partition the base deficit at the bedside with enough accuracy to permit clinical use. This provides valuable information on the aetiology of acid-base disturbance when applied to a cohort of children with meningococcal sepsis.

The strong ion gap predicts mortality in children following cardiopulmonary bypass surgery.

OBJECTIVE: Stewart's strong ion theory quantifies unmeasured tissue acids produced following hypoxia or hypoperfusion, by calculation of the strong ion gap. Our study objectives were as follows: a) to determine the 24-hr profile of the strong ion gap following cardiopulmonary bypass surgery; and b) to compare the prognostic value in terms of intensive care unit mortality of this variable with blood lactate. DESIGN: Prospective, observational study. SETTING: Tertiary pediatric intensive care unit. PATIENTS: Eighty-five children following surgery for congenital heart disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial blood samples for lactate and strong ion gap calculation were obtained at intensive care unit admission and at 24 hrs. A raised strong ion gap (>3 mEq/L) was present in 41.1% and 51.7% of admission and 24-hr samples, respectively, being elevated at both time points in 30.5%. Both the strong ion gap and lactate increased with surgical complexity, but neither was correlated with length of bypass (r = .13 and -.02) or aortic cross-clamp (r = .13 and .10). The crude mortality was 5.8% (5/85). Four of the five deaths were associated with a persistently elevated strong ion gap, in contrast to two with ongoing hyperlactatemia (>2 mmol/L). The admission strong ion gap (cutoff, >3.2 mEq/L) was superior to lactate (cutoff, >3.0 mmol/L) as a mortality predictor (area under receiver operating characteristic curve of 0.85 [95% confidence interval, 0.74-0.95] vs. 0.71 [95% confidence interval, 0.44-0.98], respectively). CONCLUSIONS: An elevated strong ion gap occurs commonly following bypass surgery and appears to be superior to lactate as a mortality predictor.

Early application of generic mortality risk scores in presumed meningococcal disease.

OBJECTIVE: Mortality from meningococcal disease typically occurs within 24 hrs of intensive care unit (ICU) admission. An early, accurate mortality-risk tool may aid in trial design for novel therapies. We assessed the performance of two generic scores that assign mortality risk within 1 hr of ICU admission: the Preintensive Care Pediatric Risk of Mortality (Pre-ICU PRISM) and Pediatric Index of Mortality (PIM). DESIGN: Prospective, observational study over 21 months. SETTING: Two tertiary pediatric ICUs accepting referrals from southeast England. PATIENTS: Patients were 165 consecutive children with meningococcal disease. Ages ranged from 0.1 to 17 yrs (median 2.3 yrs). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PIM demonstrated greater sensibility, with complete data collected in 93% of cases, compared with 35% for the pre-ICU PRISM. Both scores discriminated well. The area under the receiver operating characteristic curve was 0.90 (95% confidence interval, 0.81-1.00) for PIM and 0.94 (95% confidence interval, 0.88-0.98) for Pre-ICU PRISM; this did not change when applied to the subgroup of patients with complete data. Both scores calibrated poorly, overestimating mortality in the medium-risk strata (and also in the high-risk stratum in the case of Pre-ICU PRISM). When used as a stratification tool for a hypothetical trial (60% reduction in mortality, 80% power), the scores allowed for a reduction in study size by 50% (PIM) and 43% (pre-ICU PRISM). CONCLUSIONS: Pre-ICU PRISM and PIM both discriminate well but calibrate poorly when applied to a cohort of children with meningococcal sepsis. Both scores provide an effective means of stratification for clinical trial purposes. The main advantage for PIM appears to be ease of data collection.

Unplanned extubation in a paediatric intensive care unit: prospective cohort study.

PURPOSE: Unplanned extubation (UE) is an important paediatric intensive care unit (PICU) quality indicator. Studies on UE have been modest in size, with accurate UE rate calculation potentially hampered by ventilation episodes recorded in calendar days. We wished to document UE rates, outcomes, associated factors and quantify error when calendar days rather than exact timings are used. METHODS: We recorded prospectively all UE episodes and potential associated factors in our 20-bed PICU for 12,533 admissions (2000-2013). Ventilation episodes were recorded to the minute, with non-invasive and tracheostomy ventilation excluded. Analysis utilised multilevel mixed-effects Poisson regression, adjusting for multiple ventilation episodes in the same patient. RESULTS: Overall, 243 UEs occurred within 14,141 ventilation episodes (31,564 intubated days), giving a UE rate of 0.77 (95% CI 0.67-0.87) episodes per 100 intubated days. If calendar ventilation days were used, the yearly UE rate was underestimated by 27-35%. UE rates decreased with time, by approximately 0.05/100 intubated days each year. Associations with UE incidence rate included patient age, source of admission, disease severity and diagnostic category, with nasal tubes decreasing the risk. Although UE versus planned extubation was associated with a higher re-intubation rate (43 versus 8%) and longer median PICU stay (4.6 versus 2.6 days, p < 0.001), mortality between the two groups did not differ (3.0 versus 5.1%, p = 0.18). CONCLUSIONS: This study provides contemporaneous UE rates for benchmarking. Recording ventilation in calendar days underestimates UE rate. Several factors associated with UE may serve as a focus of quality improvement.

Predicting fluid responsiveness in 100 critically ill children: the effect of baseline contractility.

PURPOSE: Fluid overload is a risk factor for poor outcome in intensive care; thus volume loading should be tailored towards patients who are likely to increase stroke volume. We aimed to evaluate the paediatric predictive ability (stroke volume increase of at least 15 % after fluid bolus) of novel and established volumetric and dynamic haemodynamic variables, and assess the influence of baseline contractility on response. METHODS: We assessed 142 volume loading episodes (10 ml/kg crystalloid) in 100 critically ill ventilated children, median (interquartile) weight 10 (5.6-15) kg. Eight advanced haemodynamic variables were assessed using two commercially available devices. Systemic ventricular contractility was measured as the maximum rate of systolic arterial pressure rise. RESULTS: Overall, predictive ability was poor, with volumetric variables performing better than dynamic (area under receiver operating characteristic curves ranged from 0.53 to 0.67). The best predictor was total end-diastolic volume index; however, this did not increase in a consistent way with volume loading, with change post volume being weakly related to baseline values (r = -0.19, p = 0.02). A multivariable model quantified the importance of contractility in stroke volume response. Children with high baseline contractility (≥75th centile) typically achieved a positive stroke volume response when end-diastolic volume values changed by 10-15 ml/m(2.6), whereas patients with low contractility (≤25th centile) typically required end-diastolic volume increases of 35-40 ml/m(2.6). CONCLUSIONS: Current paediatric predictors of volume response perform poorly; prediction may be improved if baseline contractility is taken into account.

Adverse events in a paediatric intensive care unit: relationship to workload, skill mix and staff supervision.

OBJECTIVES: A systems approach proposes that hospital adverse events (AE) represent a failure of the organization rather than the individual, and are more likely when sub-optimal working conditions occur. We analysed AE using a systems approach to (a) investigate the association between AE occurrence and "latent" risk factors, which included temporal, workload, skill mix and supervision issues, and (b) document interactions between clinically related risk factors. DESIGN: Prospective observational study. SETTING: Regional paediatric intensive care unit. MEASUREMENTS AND RESULTS: Data from 730 consecutive nursing shifts over 12 months (816 patient episodes, crude mortality 7.2%) were analysed using logistic regression modelling. Two hundred eighty-four AE occurred during 220 of 730 (30%) shifts. There were 103 unit- and 181 patient-related AE; the latter occurred at a rate of 6.0 per 100 patient days. Factors associated with increased AE included day shift, average patient dependency, number of occupied beds and the presence of multiple, simultaneous management-related issues that compromised the supervisory ability of the nurse in charge. Factors associated with decreased AE included the presence of a senior nurse in charge, a high proportion of the shift filled by rostered permanent staff, and/or senior nurses, the number of admissions and discharges and, surprisingly, the presence of new junior doctors. Interaction effects were demonstrated between patient workload factors (bed occupancy and patient acuity) and also between nursing supervision factors (seniority of the nurse in charge and factors compromising the nurse's supervisory ability). CONCLUSIONS: These findings may provide a framework for strategies to reduce AE occurrence.

Amylin is associated with delayed gastric emptying in critically ill children.

OBJECTIVES: Amylin is a novel 37 amino acid that is secreted together with insulin from the pancreas in response to enteral nutrient intake. As a potent inhibitor of gastric motility it plays an important role in the control of carbohydrate absorption. In this study we aimed to determine the relationship between amylin levels and gastric emptying in critically ill children. DESIGN: Prospective interventional study. SETTING: Tertiary paediatric intensive care unit. PATIENTS: Twenty-three patients were studied following admission to a paediatric intensive care unit. The median age (25th-75th centiles) was 5.8 years (1.5-11.6) and weight 20 kg (12.8-47.5). INTERVENTIONS: Patients were defined as feed-intolerant on the basis of gastric residual volume greater than 125% 4 h after a feed challenge. Three objective measures of gastric emptying were then calculated from a 6 h paracetamol absorption test. Blood glucose, serum insulin and amylin levels were averaged across the paracetamol absorption test period. MEASUREMENTS AND RESULTS: Eight patients were classified as feed-intolerant (nTOL) and 15 as feed-tolerant (TOL) [median gastric residual volumes 321% (261-495) and 4% (0-6), respectively]. Gastric emptying was delayed in the feed-intolerant group as assessed by all paracetamol absorption test parameters ( p< or =0.01). The median serum amylin concentration was significantly higher in the feed-intolerant group [nTOL 47.0 (37.7-54.8) versus TOL 22.7 (13.6-26.7) pmol/l, p<0.0001]. A positive correlation between serum amylin and insulin was observed ( r=0.46, p=0.02) but not between amylin and glucose ( r=0.25, p=0.23). CONCLUSIONS: The use of gastric residual volumes to define feed intolerance is justified in critically ill children. High serum amylin levels are associated with delayed gastric emptying in these patients. The correlation between serum amylin and insulin levels indicates a degree of preservation of pancreatic hormonal co-release.

Use of oral clonidine for sedation in ventilated paediatric intensive care patients.

OBJECTIVES: We aimed to document our experience with oral clonidine when used as a sedative in combination with intravenous morphine and lorazepam in a group of mechanically ventilated children with single-organ, respiratory failure. In particular, our objectives were to establish the relationship between oral dose, plasma concentration, and sedative effect, and second, to document the side-effect profile. DESIGN: Prospective, cohort study over a 72-h period. SETTING: Regional paediatric intensive care unit. PATIENTS AND PARTICIPANTS: Twenty-four children were enrolled (median age 3 months) of whom ten were excluded (six due to extubation before 72 h, three sedation failures, one protocol violation). MEASUREMENTS AND RESULTS: Plasma clonidine was measured using gas chromatography mass spectrometry, and sedation assessed using the COMFORT score. Using a dose of 3-5 microg/kg every 8 h, plasma concentrations appeared to plateau at approximately 41 h giving a mean value of 1.38 ng/ml (95% confidence interval 1.0-1.8). Adequate sedation was achieved during 82% (837/1022 h) of the study period; however, this decreased to 70.3% when analysed on an intention-to-treat basis. There was a concomitant overall decrease in the average hourly requirements for both morphine ( P = 0.02) and lorazepam ( P = 0.003). There were no documented episodes of bradycardia, hypotension or hyperglycaemia. CONCLUSIONS: Oral clonidine may be a safe and effective sedative in combination with morphine and lorazepam for young children with single-organ, respiratory failure. This agent may also exhibit opioid and benzodiazepine sparing effects in this patient group. A full pharmacokinetic study is warranted.

Neonatal decompensation before surgery in hypoplastic left heart syndrome: a case control study.

OBJECTIVE: Prior to Norwood 1 surgery, neonates with hypoplastic left heart syndrome (HLHS) are at risk of decompensation from systemic underperfusion secondary to pulmonary overcirculation. We examined whether preoperative temporal profiles of physiological and laboratory variables differed between neonates who did and did not decompensate preoperatively. DESIGN: Case control study. SETTING: Paediatric Intensive Care Unit, 2002-2013. PATIENTS: Eighty-five neonates with HLHS, matched by birth weight and admission date. MEASUREMENTS: Decompensation was defined as the need for emergency intubation and ventilation due to clinically diagnosed impaired systemic oxygen delivery. The end point was time of decompensation (cases, n=33) or discharge for surgery (controls, n=52). Variable trajectories were modelled non-linearly using generalised estimating equations. RESULTS: Decompensation occurred on median (IQR) day 3 (2-4) of life in cases, with surgery occurring on day 4 (3-7) in controls. Oxygen saturation and blood pressure trajectories were identical between groups (p>0.2). Heart and respiratory rates increased with time overall, but significantly faster in cases than controls; by an average of 4.0 bpm/day versus 1.4 bpm/day (p=0.002) and 5.3 respirations/minute/day versus 1.5 respirations/minute/day, respectively, (p=0.003). Although metabolic blood gas components began to decline subtly 24 h before clinical decompensation, they remained in the normal range for much of this period. CONCLUSIONS: Heart and respiratory rates, and metabolic acid base trajectories show subtle differences prior to decompensation in neonates with HLHS. These findings highlight the importance of evaluating rates of change rather than absolute values of physiological and laboratory variables.

The temporal relationship between glucose-corrected serum sodium and neurological status in severe diabetic ketoacidosis.

OBJECTIVE: Cerebral oedema is a potentially devastating complication of diabetic ketoacidosis (DKA). The relationship between osmolar changes, acid-base changes and development of cerebral oedema during therapy is unclear. DESIGN: Retrospective cohort study on 53 children with severe DKA (mean pH at presentation 6.92±0.08). Cerebral oedema was diagnosed using neurological status, response to osmotherapy, and neuroimaging, and classified as: early (occurring ≤1 h after presentation, n=15), late (1-48 h, n=17) or absent (controls, n=21). The temporal profiles for various osmolar and acid-base profiles were examined using a random coefficients fractional polynomial mixed model, adjusted for known risk factors. RESULTS: The three groups could not be differentiated by demographic, osmolar or acid-base variables at presentation. All osmolar and acid-base variables showed non-linear temporal trajectories. Children who developed late onset oedema showed dramatically different temporal profiles for effective osmolality and glucose-corrected serum sodium (both p<0.001). Glucose-corrected sodium provided better qualitative discrimination, in that it typically fell in children who developed late oedema and rose in controls. The maximum between-group difference for both variables approximated the median time of clinical cerebral oedema onset. Blood glucose and acid-base temporal profiles did not differ between the groups. Late onset oedema patients received more fluid in the first 4 h, but this did not influence the osmolar or glucose-corrected sodium trajectories in a predictable fashion. CONCLUSIONS: Glucose-corrected serum sodium may prove a useful early warning for the development of cerebral oedema in DKA.

Hyperchloremia is the dominant cause of metabolic acidosis in the postresuscitation phase of pediatric meningococcal sepsis.

OBJECTIVE: Metabolic acidosis is common in septic shock, yet few data exist on its etiological temporal profile during resuscitation; this is partly due to limitations in bedside monitoring tools (base excess, anion gap). Accurate identification of the type of acidosis is vital, as many therapies used in resuscitation can themselves produce metabolic acidosis. DESIGN: Retrospective, cohort study. SETTING: Multidisciplinary pediatric intensive care unit with 20 beds. PATIENTS: A total of 81 children with meningococcal septic shock. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Acid-base data were collected retrospectively on 81 children with meningococcal septic shock (mortality, 7.4%) for the 48 hrs after presentation to the hospital. Base excess was partitioned using abridged Stewart equations, thereby quantifying the three predominant influences on acid-base balance: sodium chloride, albumin, and unmeasured anions (including lactate). Metabolic acidosis was common at presentation (mean base excess, -9.7 mmol/L) and persisted for 48 hrs. However, the pathophysiology changed dramatically from one of unmeasured anions at admission (mean unmeasured anion base excess, -9.2 mmol/L) to predominant hyperchloremia by 8-12 hrs (mean sodium-chloride base excess, -10.0 mmol/L). Development of hyperchloremic acidosis was associated with the amount of chloride received during intravenous fluid resuscitation (r = .44), with the base excess changing, on average, by -0.4 mmol/L for each millimole per kilogram of chloride administered. Hyperchloremic acidosis resolved faster in patients who 1) manifested larger (more negative) sodium chloride-partitioned base excess, 2) maintained a greater urine output, and 3) received furosemide; and slower in those with high blood concentrations of unmeasured anions (all, p < .05). CONCLUSIONS: Hyperchloremic acidosis is common and substantial after resuscitation for meningococcal septic shock. Recognition of this entity may prevent unnecessary and potentially harmful prolonged resuscitation.

"Early" delayed sternal closure following pediatric cardiac surgery.

BACKGROUND: Delayed sternal closure is commonly used following pediatric cardiopulmonary bypass surgery for many reasons including support of the failing myocardium. We hypothesized that, as a result of improvements in perioperative care, sternal closure could be achieved at an earlier postoperative time than the 3 to 5 days typically reported in the literature. METHODS: Retrospective chart review of all bypass surgery (n = 585) performed in a single center over a 3-year period (2000-2002). RESULTS: We identified 66 children (11.3%), median age 5 days old, who underwent delayed sternal closure. In 60 of these patients, sternal closure was achieved at a median (interquartile) postoperative time of 21 hours (18 to 40 hours). The most common indication was inadequate hemostasis, although early sternal closure was also achieved in the subgroup with poor myocardial function as the primary indication at a median of 36 hours (21 to 44 hours). There was no noticeable hemodynamic, respiratory or metabolic compromise following sternal closure, although patients with poor myocardial function tended to have a lower mean blood pressure than those with inadequate hemostasis (ANOVA, p = 0.02). The overall mortality was 19.7% (13 of 66), with a median duration of ventilation and intensive care stay among survivors of 3.8 days (2.4 to 6.3 days) and 4.8 days (3.7 to 7.9 days), respectively. CONCLUSIONS: Delayed sternal closure is possible at an earlier stage than previously reported.

Measurement of cardiac output and tissue perfusion.

Recent technologic innovations have allowed a greater scope for cardiac output measurement in critically ill children. There is a move toward both less invasive and continuous methods, several of which also offer novel measures of preload. Many of the new methods are still undergoing preliminary evaluation in the pediatric population and will be summarized in this article.

Effects of feeding on gastric tonometric measurements in critically ill children.

OBJECTIVE: To determine the effect of gastric feeding on the measurement of gastric intramucosal PCO2 (PiCO2) and its derived gastric intramucosal PCO2-arterial PCO2 difference (PiCO2-PaCO2 difference) and gastric intramucosal pH (pHi) in a group of critically ill children using recirculating gas tonometry. DESIGN: Prospective clinical pilot study. SETTING: Sixteen bed pediatric intensive care unit. PATIENTS: Ten mechanically ventilated and hemodynamically stable children (median age, 20.1 months [interquartile range (IQR), 9.7-47.6 months] and median weight, 10.2 kg [IQR, 10-16.5 kg]). INTERVENTIONS: A 7-French recirculating gas tonometer was placed in the stomach via the orogastric route. MEASUREMENTS: In each patient, baseline fasted/unfed PiCO2, PiCO2-PaCO2 difference, and pHi were determined hourly over a 5-hr period. Gastric feeding was then reestablished (3 mL/kg/hr) within a median time of 3 hrs and a further 5 hourly measurements were determined. Concurrent arterial blood gas and lactate measurements were taken. Blood pressure and heart rate was monitored throughout. MAIN RESULTS: Hemodynamic parameters remained stable throughout the study period. When compared with the unfed/fasting state, PiCO2 measurements and PiCO2-PaCO2 difference were consistently lower and pHi values higher than when the patients were fed (two-way analysis of variance for repeated measures: all p <.001 between groups). Measurements did not vary over time. CONCLUSIONS: In our patient group, gastric feeding decreased the PiCO2 and PiCO2-PaCO2 difference and increased pHi compared with the unfed state. These findings are in contrast to those found in adult studies.