Andrew Durward

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 r2 = 0.71). Clot strength decreased rapidly when (a) fibrinogen concentration was <1 g/L, (b) platelets were <120 × 109/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.

Massive diltiazem overdose treated with extracorporeal membrane oxygenation.

Objective To describe a case of massive diltiazem overdose with a good outcome achieved after early and aggressive supportive therapy. Design Case report. Setting Pediatric Critical Care Unit. Patient Sixteen-year-old adolescent girl. Measurements and Main Results A 16-yr-old adolescent girl presented to the emergency department 6 hrs after the intentional ingestion of 40 300-mg sustained-release diltiazem tablets (12 g of Cardura CD). She was hypotensive and required a glucagon and epinephrine infusion despite initial fluid resuscitation with saline and intravenous calcium (1 g). Multiple asystolic cardiac arrests ensued which became increasingly refractory to high-dose epinephrine. Hemodynamic support was achieved with a 48-hr period of extracorporeal membrane oxygenation for atrial standstill. Severe multiorgan dysfunction ensued (cardiac, neurologic, renal, hepatic, gastrointestinal, hematologic, and metabolic). Plasma diltiazem and its metabolites were measured and its half-life was reported between 28 and 48 hrs. A sustained decline in plasma diltiazem levels and its metabolites was not observed after two periods of charcoal hemoperfusion. Recovery of organ function occurred with sinus rhythm noted on the ninth day. The patient made a full recovery and was discharged from the critical care unit after 15 days. Conclusions Although massive calcium channel blocker overdose can produce profound and prolonged cardiac or multiorgan dysfunction, its toxic effects may be reversible. Supportive therapy, particularly of the cardiovascular system, is the most important goal.

Relationship Between Arterial Partial Oxygen Pressure After Resuscitation From Cardiac Arrest and Mortality in Children

Background— Observational studies in adults have shown a worse outcome associated with hyperoxia after resuscitation from cardiac arrest. Extrapolating from adult data, current pediatric resuscitation guidelines recommend avoiding hyperoxia. We investigated the relationship between arterial partial oxygen pressure and survival in patients admitted to the pediatric intensive care unit (PICU) after cardiac arrest. Methods and Results— We conducted a retrospective cohort study using the Pediatric Intensive Care Audit Network (PICANet) database between 2003 and 2010 (n=122 521). Patients aged <16 years with documented cardiac arrest preceding PICU admission and arterial blood gas analysis taken within 1 hour of PICU admission were included. The primary outcome measure was death within the PICU. The relationship between postarrest oxygen status and outcome was modeled with logistic regression, with nonlinearities explored via multivariable fractional polynomials. Covariates included age, sex, ethnicity, congenital heart disease, out-of-hospital arrest, year, Pediatric Index of Mortality-2 (PIM2) mortality risk, and organ supportive therapies. Of 1875 patients, 735 (39%) died in PICU. Based on the first arterial gas, 207 patients (11%) had hyperoxia (PaO2 ≥300 mm Hg) and 448 (24%) had hypoxia (PaO2 <60 mm Hg). We found a significant nonlinear relationship between PaO2 and PICU mortality. After covariate adjustment, risk of death increased sharply with increasing hypoxia (odds ratio, 1.92; 95% confidence interval, 1.80–2.21 at PaO2 of 23 mm Hg). There was also an association with increasing hyperoxia, although not as dramatic as that for hypoxia (odds ratio, 1.25; 95% confidence interval, 1.17–1.37 at 600 mm Hg). We observed an increasing mortality risk with advancing age, which was more pronounced in the presence of congenital heart disease. Conclusions— Both severe hypoxia and, to a lesser extent, hyperoxia are associated with an increased risk of death after PICU admission after cardiac arrest.

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.

Relationship between Arterial Partial Oxygen Pressure Following Resuscitation from Cardiac Arrest and Mortality in Children

Background— Observational studies in adults have shown a worse outcome associated with hyperoxia after resuscitation from cardiac arrest. Extrapolating from adult data, current pediatric resuscitation guidelines recommend avoiding hyperoxia. We investigated the relationship between arterial partial oxygen pressure and survival in patients admitted to the pediatric intensive care unit (PICU) after cardiac arrest. Methods and Results— We conducted a retrospective cohort study using the Pediatric Intensive Care Audit Network (PICANet) database between 2003 and 2010 (n=122 521). Patients aged <16 years with documented cardiac arrest preceding PICU admission and arterial blood gas analysis taken within 1 hour of PICU admission were included. The primary outcome measure was death within the PICU. The relationship between postarrest oxygen status and outcome was modeled with logistic regression, with nonlinearities explored via multivariable fractional polynomials. Covariates included age, sex, ethnicity, congenital heart disease, out-of-hospital arrest, year, Pediatric Index of Mortality-2 (PIM2) mortality risk, and organ supportive therapies. Of 1875 patients, 735 (39%) died in PICU. Based on the first arterial gas, 207 patients (11%) had hyperoxia (PaO2 ≥300 mm Hg) and 448 (24%) had hypoxia (PaO2 <60 mm Hg). We found a significant nonlinear relationship between PaO2 and PICU mortality. After covariate adjustment, risk of death increased sharply with increasing hypoxia (odds ratio, 1.92; 95% confidence interval, 1.80–2.21 at PaO2 of 23 mm Hg). There was also an association with increasing hyperoxia, although not as dramatic as that for hypoxia (odds ratio, 1.25; 95% confidence interval, 1.17–1.37 at 600 mm Hg). We observed an increasing mortality risk with advancing age, which was more pronounced in the presence of congenital heart disease. Conclusions— Both severe hypoxia and, to a lesser extent, hyperoxia are associated with an increased risk of death after PICU admission after cardiac arrest.

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 (r2 = .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.

Infantile onset myofibrillar myopathy due to recessive CRYAB mutations

Mutations in the αB-crystallin (CRYAB) gene, encoding a small heat shock protein with chaperone function, are a rare cause of myofibrillar myopathy with autosomal-dominant inheritance, late-onset and moderate severity. We report a female infant presenting from 4 months with profound muscle stiffness, persistent creatine kinase elevation and electromyography characterized by spontaneous electrical activity and pseudomyotonic discharges. Muscle biopsy suggested a myofibrillar myopathy and genetic testing revealed homozygosity for the CRYAB mutation c.343delT (p.Ser115ProfsX14). These findings suggest a severe, recessively inherited form of CRYAB-related myofibrillar myopathy. Profound muscle stiffness as the main presenting feature indicates αB-crystallin as a potent modifier of muscle contractility.

Novel method to quantify loss of heart rate variability in pediatric multiple organ failure.

ObjectiveTo develop a power-law model for measurement of heart rate variability (HRV) and to compare this model with established methods for measuring HRV in a group of children with organ failure (OF). DesignProspective, observational study. SettingPediatric intensive care unit of a tertiary children’s hospital. PatientsA total of 104 measurements were made on 50 patients (median age, 8 months; range, 2 days to 16 yrs) and categorized into three groups according to the number of simultaneous organs failing: 0–1 OF, 2 OF, and ≥3 OF. InterventionsHeart rate was recorded over a 5-min period when patients were hemodynamically stable. The power-law model represents a power function relating frequency distribution to magnitude of effect (in this case, squared deviation from the mean heart rate). Plotting the data on a bi-logarithmic scale produces a regression line for each measurement, described in terms of r2, slope, and x-intercept. Comparison with other HRV measures included two time-domain measures (sd of the normal R-R intervals and the square root of the mean squared differences of successive normal R-R intervals), one frequency-domain method (power spectral analysis), and one nonlinear method (detrended fluctuation analysis). Measurements and ResultsFor the power-law model, patients exhibited a similar r2 of .87 (.09) (mean [sd]) and slope of −1.80 (0.29), regardless of the degree of OF. HRV could thus be described purely in terms of x-intercept, which demonstrated a left shift with increasing OF (p < .001). This was independent of age and heart rate. Loss of HRV with increasing OF was demonstrated by all methods; however, only the power-law model was able to discriminate between each OF group. Using the model, change in HRV in individual patients over successive days often concurred qualitatively with the change in OF status. ConclusionThe power-law model is an appropriate measure of HRV in pediatric patients, being neither age nor heart rate sensitive. Loss of HRV occurs with increasing OF; this effect was better demonstrated by the model compared with other measures of HRV.

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.

Extended-interval gentamicin: population pharmacokinetics in pediatric critical illness.

Objectives: Once-daily gentamicin therapy is becoming increasingly common in pediatric practice; however, little is known about pharmacokinetics in critical illness. Gentamicin exhibits concentration dependant killing; thus, peak serum concentrations at least eight times higher than minimum inhibition concentration of the target organism have been recommended. We wanted to derive pharmacokinetic parameters for gentamicin in critical illness and to evaluate whether a dose of 8 mg/kg provides an adequate peak serum concentration (>16 mg/L). Patients and Interventions: Population-based pharmacokinetic analyses were undertaken using therapeutic drug monitoring data collected prospectively in an intensive care unit over 6 months (n = 50 children). Monte Carlo simulations were used to estimate the probability of achieving 1) peak concentrations >16 mg/L; and 2) trough concentrations <2 mg/L at 24 and 36 hrs. Measurements and Main Results: The optimal pharmacokinetic model was of two-compartment disposition with zero order input and additive residual error. Weight was associated nonlinearly with clearance and linearly with volume, and age was a significant covariate for clearance. An 8-mg/kg dose provided near 100% probability of achieving adequate peak concentrations at all ages. However this probability decreased rapidly at doses <7 mg/kg with neonates being the most susceptible. Approximately 50% of nonpremature neonates within the first week of life, 25% of infants, and 10% of children are likely to need a dose interval >24 hrs. Conclusions: A gentamicin dose of 8 mg/kg is highly likely to achieve peak concentrations >16 mg/L in critically ill children. A considerable proportion will require dose intervals >24 hrs; thus, therapeutic drug monitoring is essential.