Parthak Prodhan

Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children

OBJECTIVE: After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. PATIENTS AND METHODS: Relevant manuscripts published in the English language were searched in Medline by using search terms “opioid,” “opiate,” “sedation,” “analgesia,” “child,” “infant-newborn,” “tolerance,” “dependency,” “withdrawal,” “analgesic,” “receptor,” and “individual opioid drugs.” Clinical and preclinical studies were reviewed for data synthesis. RESULTS: Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. CONCLUSIONS: Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal.

Bridge to Cardiac Transplant in Children: Berlin Heart versus Extracorporeal Membrane Oxygenation

BACKGROUND For small children requiring mechanical circulatory support as a bridge to transplantation (BTT), extracorporeal membrane oxygenation (ECMO) has been the only option until the recent introduction of the Berlin Heart EXCOR ventricular assist device (Berlin Heart AG, Berlin, Germany). We reviewed our recent experience with these two technologies with particular focus on early outcomes. METHODS Data for 55 consecutive children undergoing BTT between 2001 and 2008 were abstracted from an institutional database. The analysis excluded 13 patients because EXCOR was not used for acute postcardiotomy BTT. Patients were divided into ECMO (n = 21) and EXCOR groups (n = 21). Specific end points included survival to transplant, overall survival, and bridge to recovery. Incidences of adverse events and the duration of support were determined. RESULTS Groups were similar in weight, age, and etiologies of heart failure. Likewise, the incidences of stroke and multisystem organ failure were similar. Survival to transplant, recovery, or continued support was 57% in ECMO and 86% in EXCOR (p = 0.040). EXCOR patients had overall significantly better survival (p = 0.049). Two ECMO patients and 1 EXOR patient were bridged to recovery. The mean duration of support was 15 +/- 12 days in the ECMO group and 42 +/- 43 days in the EXCOR group (p < 0.001). CONCLUSIONS In children requiring BTT, EXCOR provided substantially longer support times than ECMO, without significant increase in the rates of stroke or multisystem organ failure. Survival to transplant and long-term survival was higher with EXCOR.

Outcomes After In-Hospital Cardiac Arrest in Children With Cardiac Disease A Report From Get With the Guidelines–Resuscitation

Background— Small studies suggest that children experiencing a cardiac arrest after undergoing cardiac surgery have better outcomes than other groups of patients, but the survival outcomes and periarrest variables of cardiac and noncardiac pediatric patients have not been compared. Methods and Results— All cardiac arrests in patients <18 years of age were identified from Get With the Guidelines–Resuscitation from 2000 to 2008. Cardiac arrests occurring in the neonatal intensive care unit were excluded. Of 3323 index cardiac arrests, 19% occurred in surgical-cardiac, 17% in medical-cardiac, and 64% in noncardiac (trauma, surgical-noncardiac, and medical-noncardiac) patients. Survival to hospital discharge was significantly higher in the surgical-cardiac group (37%) compared with the medical-cardiac group (28%; adjusted odds ratio, 1.8; 95% confidence interval, 1.3–2.5) and the noncardiac group (23%; adjusted odds ratio, 1.8; 95% confidence interval, 1.4–2.4). Those in the cardiac groups were younger and less likely to have preexisting noncardiac organ dysfunction, but were more likely to have ventricular arrhythmias as their first pulseless rhythm, to be monitored and hospitalized in the intensive care unit at the time of cardiac arrest, and to have extracorporeal cardiopulmonary resuscitation compared with those in the noncardiac group. There was no survival advantage for patients in the medical-cardiac group compared with those in the noncardiac group when adjusted for periarrest variables. Conclusion— Children with surgical-cardiac disease have significantly better survival to hospital discharge after an in-hospital cardiac arrest compared with children with medical-cardiac disease and noncardiac disease. # Clinical Perspective {#article-title-25}Background— Small studies suggest that children experiencing a cardiac arrest after undergoing cardiac surgery have better outcomes than other groups of patients, but the survival outcomes and periarrest variables of cardiac and noncardiac pediatric patients have not been compared. Methods and Results— All cardiac arrests in patients <18 years of age were identified from Get With the Guidelines–Resuscitation from 2000 to 2008. Cardiac arrests occurring in the neonatal intensive care unit were excluded. Of 3323 index cardiac arrests, 19% occurred in surgical-cardiac, 17% in medical-cardiac, and 64% in noncardiac (trauma, surgical-noncardiac, and medical-noncardiac) patients. Survival to hospital discharge was significantly higher in the surgical-cardiac group (37%) compared with the medical-cardiac group (28%; adjusted odds ratio, 1.8; 95% confidence interval, 1.3–2.5) and the noncardiac group (23%; adjusted odds ratio, 1.8; 95% confidence interval, 1.4–2.4). Those in the cardiac groups were younger and less likely to have preexisting noncardiac organ dysfunction, but were more likely to have ventricular arrhythmias as their first pulseless rhythm, to be monitored and hospitalized in the intensive care unit at the time of cardiac arrest, and to have extracorporeal cardiopulmonary resuscitation compared with those in the noncardiac group. There was no survival advantage for patients in the medical-cardiac group compared with those in the noncardiac group when adjusted for periarrest variables. Conclusion— Children with surgical-cardiac disease have significantly better survival to hospital discharge after an in-hospital cardiac arrest compared with children with medical-cardiac disease and noncardiac disease.

Outcomes after extracorporeal cardiopulmonary resuscitation (ECPR) following refractory pediatric cardiac arrest in the intensive care unit

AIM To describe our experience using extracorporeal cardiopulmonary resuscitation (ECPR) in resuscitating children with refractory cardiac arrest in the intensive care unit (ICU) and to describe hospital survival and neurologic outcomes after ECPR. METHODS A retrospective chart review of a consecutive case series of patients requiring ECPR from 2001 to 2006 at Arkansas Childrens Hospital. Data from medical records was abstracted and reviewed. Primary study outcomes were survival to hospital discharge and neurological outcome at hospital discharge. RESULTS During the 6-year study period, ECPR was deployed 34 times in 32 patients. 24 deployments (73%) resulted in survival to hospital discharge. Twenty-eight deployments (82%) were for underlying cardiac disease, 3 for neonatal non-cardiac (NICU) patients and 3 for paediatric non-cardiac (PICU) patients. On multivariate logistic regression analysis, only serum ALT (p-value=0.043; OR, 1.6; 95% confidence interval, 1.014-2.527) was significantly associated with risk of death prior to hospital discharge. Blood lactate at 24h post-ECPR showed a trend towards significance (p-value=0.059; OR, 1.27; 95% confidence interval, 0.991-1.627). The Hosmer-Lemeshow tests (p-value=0.178) suggested a good fit for the model. Neurological evaluation of the survivors revealed that there was no change in PCPC scores from a baseline of 1-2 in 18/24 (75%) survivors. CONCLUSIONS ECPR can be used successfully to resuscitate children following refractory cardiac arrest in the ICU, and grossly intact neurologic outcomes can be achieved in a majority of cases.

Noninvasive Cerebral Oximeter as a Surrogate for Mixed Venous Saturation in Children

We evaluated the relationship between regional cerebral oxygen saturation (rSO2) measured by near-infrared spectroscopy (NIRS) cerebral oximeter with superior vena cava (SVC), inferior vena cava (IVC), right atrium (RA), and pulmonary artery (PA) saturation measured on room air and 100% inspired oxygen administered via a non-rebreather mask (NRB) in children. Twenty nine pediatric post-orthotopic heart transplant patients undergoing an annual myocardial biopsy were studied. We found a statistically significant correlation between rSO2 and SVC saturations at room air and 100% inspired oxygen concentration via NRB (r = 0.67, p = 0.0002 on room air; r = 0.44, p = 0.02 on NRB), RA saturation (r = 0.56, p = 0.002; r = 0.56, p = 0.002), and PA saturation (r = 0.67, p < 0.001; r = 0.4, p = 0.03). A significant correlation also existed between rSO2 and measured cardiac index (r = 0.45, p = 0.01) and hemoglobin levels (r = 0.41, p = 0.02). The concordance correlations were fair to moderate. Bias and precision of rSO2 compared to PA saturations on room air were −0.8 and 13.9%, and they were 2.1 and 15.6% on NRB. A stepwise linear regression analysis showed that rSO2 saturations were the best predictor of PA saturations on both room air (p = 0.0001) and NRB (p = 0.012). In children with biventricular anatomy, rSO2 readings do correlate with mixed venous saturation.

Serious Air Leak Syndrome Complicating High-Flow Nasal Cannula Therapy: A Report of 3 Cases

Despite the absence of clinical safety data, heated, humidified high-flow nasal cannula (HHFNC) therapy is increasingly being used as an alternative to positive-pressure ventilation in pediatrics. This use of HHFNC is “off label” because the US Food and Drug Administration’s approval for these devices was only for air humidification and not as a modality to provide positive distending pressure. For the first time we describe 3 cases who developed serious air leaks related to HHFNC therapy. The first child was a previously healthy 2-month-old male infant with respiratory syncytial virus bronchiolitis who developed a right pneumothorax on day 5 of his illness at 8 liters per minute (lpm). He subsequently required intubation and ventilation for 14 days. The second case involved an otherwise healthy 16-year-old boy with cerebral palsy who developed pneumomediastinum and died of its complications. He was receiving 20 lpm HHFNC therapy when he developed pneumomediastinum. The third case involved a 22-month-old, previously healthy boy who developed subdural hematoma secondary to abuse. He developed a right pneumothorax while receiving HHFNC at a flow of 6 lpm, requiring chest tube placement. These cases emphasize the need for extreme caution while using HHFNC for the off-label indication of providing positive distending pressure in children, especially at flows higher than the patient’s minute ventilation. A more detailed study to specifically look at the serious adverse events related to HHFNC is urgently needed.

Hemolysis during cardiac extracorporeal membrane oxygenation: a case-control comparison of roller pumps and centrifugal pumps in a pediatric population.

Extracorporeal membrane oxygenation (ECMO) is a lifesaving therapy, which has been used for the support of children with a broad range of diseases. Two pumps of differing mechanisms have been used to generate the extracorporeal flow: roller-head pumps and centrifugal pumps. Seven patients supported during ECMO with Levitronix Centrimag (Centrimag group [CG]) were matched to 14 patients supported with Stockert-Shiley SIII (Stockert-Shiley group [SSG]) at a single institution from July 2007 to July 2009. We hypothesized that hemolysis as measured by plasma-free hemoglobin (PFH) is elevated in the SSG versus the CG during cardiac ECMO. Categorical data were analyzed using Fishers exact test. Plasma-free hemoglobin differences between groups were analyzed using both Wilcoxon rank sum and beta regression. Overall, SSG patients had two times the odds of having a higher PFH than CG patients adjusting for repeated measures (odds ratio [OR] = 1.96, 95% confidence interval [CI]: [1.15–3.34], p < 0.014). Differences between circuit failure in the first 168 hours did not reach statistical significance (1/7 CG vs. 7/14 SSG; p = 0.174). In this population of cardiac patients requiring ECMO support, more hemolysis occurred in the SSG, a roller-head pump supported group, when compared with the CG, a centrifugal pump supported group. Differences in circuit life did not reach statistical significance. This pilot study contrasts with past studies, which have demonstrated more hemolysis occurring with centrifugal pumps when compared with roller-head pumps.

Slit and robo: expression patterns in lung development

First described as an axonal guidance cue through its repulsive effect on neurons expressing its receptor Roundabout (Robo), the Slit ligand has effects on cell migration, axon branching and elongation. Indirect evidence implicates Slit and Robo in lung development. We now demonstrate that Slit-2 and Slit-3 are developmentally regulated in embryonic murine lung. Immunohistochemistry demonstrates Slit-2 and Slit-3 expression by the pulmonary mesenchyme and airway epithelium. Robo-1 and Robo-2 are also expressed by the developing mesenchyme and airway epithelium. As lung development progresses, Robo-1 and Robo-2 expression localizes to only the airway epithelium. We conclude Slit/Robo are expressed in temporo-spatially adjacent domains suggesting interactive roles in pulmonary bronchiolar development.

Functional Status Scale: New Pediatric Outcome Measure

OBJECTIVE: The goal was to create a functional status outcome measure for large outcome studies that is well defined, quantitative, rapid, reliable, minimally dependent on subjective assessments, and applicable to hospitalized pediatric patients across a wide range of ages and inpatient environments. METHODS: Functional Status Scale (FSS) domains of functioning included mental status, sensory functioning, communication, motor functioning, feeding, and respiratory status, categorized from normal (score = 1) to very severe dysfunction (score = 5). The Adaptive Behavior Assessment System II (ABAS II) established construct validity and calibration within domains. Seven institutions provided PICU patients within 24 hours before or after PICU discharge, high-risk non-PICU patients within 24 hours after admission, and technology-dependent children. Primary care nurses completed the ABAS II. Statistical analyses were performed. RESULTS: A total of 836 children, with a mean FSS score of 10.3 (SD: 4.4), were studied. Eighteen percent had the minimal possible FSS score of 6, 44% had FSS scores of ≥10, 14% had FSS scores of ≥15, and 6% had FSS scores of ≥20. Each FSS domain was associated with mean ABAS II scores (P < .0001). Cells in each domain were collapsed and reweighted, which improved correlations with ABAS II scores (P < .001 for improvements). Discrimination was very good for moderate and severe dysfunction (ABAS II categories) and improved with FSS weighting. Intraclass correlations of original and weighted total FSS scores were 0.95 and 0.94, respectively. CONCLUSIONS: The FSS met our objectives and is well suited for large outcome studies.

Expression of Netrin-1 and its two receptors DCC and UNC5H2 in the developing mouse lung

The ligand Netrin-1 and its receptors DCC and UNC5H2 are critical for the regulation of neuronal migration in nervous system development. Here we demonstrate expression of these molecules in lung development. The mRNA expression profiles of Netrin-1, DCC and UNC5H2 are developmentally regulated during embryonic mouse lung formation. Netrin-1 shows a bimodal expression pattern with elevated mRNA levels early followed by a second peak in late gestation. Peak expression of DCC occurs early in development whereas expression of UNC5H2 peaks late in development. We also demonstrate localization of Netrin-1, DCC and UNC5H2 during the stages of lung development. We present evidence that these proteins are modulated spatially in the mesenchyme and epithelium during lung organogenesis.