Genomic medicine: too great expectations?

As advances in genomic medicine have captured the interest and enthusiasm of the public, an unintended consequence has been the creation of unrealistic expectations. Because these expectations may have a negative impact on individuals as well as genomics in general, it is important that they be understood and confronted.

Effect of extracorporeal membrane oxygenation on left ventricular function of swine.

BACKGROUND: Previous clinical and experimental investigations have produced inconsistent data describing the effects of veno-arterial extracorporeal membrane oxygenation (VA ECMO) on intrinsic left ventricular (LV) function. We report an animal model that allows investigation of the effects of VA ECMO on the mechanics of the LV using two load-insensitive indices: end-systolic pressure-minor axis dimension relationship (ESPDR) and preload recruitable dimensional stroke work (PRDSW). METHODS: Eight piglets (5 to 11 kg) were anesthetized, instrumented, and placed on VA ECMO. Throughout the experiment, systemic and left atrial partial pressure of oxygen were maintained between 100 to 200 mm Hg. At ECMO flow rate of 50% of baseline cardiac output, data were collected prior to ECMO, at 4 and 6 hours during ECMO, and after weaning from ECMO. Data measured or calculated for each time point included heart rate, LV pressures and minor axis dimensions at different pre-loads, first derivative of LV pressure with respect to time, velocity of circumferential fiber length shortening (VCF), LV shortening fraction (LVSF), ESPDR, and PRDSW. RESULTS: A significant (p < 0.05) decrease in LVSF and VCF was seen at 4 and 6 hours during ECMO when compared to baseline, but the ESPDR and PRDSW did not change during ECMO. CONCLUSIONS: VA ECMO alone changes some of the load-dependent parameters of contractility, but intrinsic function of the heart is not significantly affected as measured by load-insensitive indices of LV performance.

Left ventricular dysfunction during extracorporeal membrane oxygenation in a hypoxemic swine model.

BACKGROUND: Perfusion of the coronary circulation with hypoxemic blood from the left ventricle has been postulated to cause myocardial dysfunction during venoarterial extracorporeal membrane oxygenation for respiratory support. METHODS: We investigated this hypothesis in 10 anesthetized open-chest piglets (7 to 9 kg) undergoing venoarterial extracorporeal membrane oxygenation after placement of minor-axis sonomicrometry crystals and left ventricular micromanometer. The left atrial partial pressure of oxygen was made hypoxemic (25 to 40 mm Hg) after initiation of extracorporeal membrane oxygenation by ventilation with a hypoxic gas mixture. Left ventricular contractile function, including peak LV pressure, shortening fraction, maximum rate of increase of left ventricular pressure, velocity of circumferential fiber shortening, end-systolic pressure-minor axis dimension relationship, and preload recruitable dimensional stroke work, was measured or calculated on extracorporeal membrane oxygenation before (baseline) and at 4 and 6 hours after rendering the left atrial blood hypoxemic. RESULTS: Left ventricular shortening fraction and velocity of circumferential fiber shortening were significantly lower (p < 0.05) at 4 and 6 hours when compared with baseline. The slope of the end-systolic pressure-minor axis dimension relationship decreased but was not significantly different at 4 and 6 hours when compared with baseline owing to poor linear correlation (r = 0.30 to 0.93). The preload recruitable dimensional stroke work was more linear (r = 0.87 to 0.99), and the slope was significantly lower (p < 0.01) at 4 and 6 hours when compared with baseline. CONCLUSIONS: Hypoxemic cardiac output from the left ventricle during venoarterial extracorporeal membrane oxygenation is associated with depression of left ventricular systolic function in this animal model. Current use of venoarterial extracorporeal membrane oxygenation for respiratory support may not provide adequate oxygen supply to the myocardium.

Attitudes toward limitation of support in a pediatric intensive care unit.

OBJECTIVE: To prospectively determine opinions of members of a pediatric intensive care unit (PICU) team regarding the appropriateness of aggressive care. The types of support that caregivers sought to limit and their reasons for wanting these limits were collected over time. DESIGN: Prospective survey of caregiver opinions. SETTING: PICU in an academic tertiary care children's hospital. SUBJECTS: A total of 68 intensive care nurses, 11 physicians attending in the PICU, 10 critical care and anesthesia fellows, and 24 anesthesia and pediatric residents. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During a 6-month period, 503 patients were admitted to the PICU. Within this time period, 52.4% of all deaths were preceded by limitation of support, with 100% of noncardiac surgical deaths preceded by limitation of medical interventions. At least one caregiver wished to limit care for 63 of these patients (12.5%). When caregivers wished to limit support they most frequently wished to limit invasive modes of support such as cardiopulmonary resuscitation (94%) and hemodialysis (83%). The ethical rationales identified most often for wishing to limit support were burden vs. benefit (88%) and qualitative futility (83%). Preadmission quality of life was cited less frequently (50%). Caregivers were less likely to limit care on the basis of quality of life. Nurses and physicians in the PICU were very similar to each other in the types of support they thought should be limited and their ethical rationales. CONCLUSIONS: When making decisions about whether or not to limit care for a patient, caregivers were more likely to rely on the perceived benefit to the patient than preadmission quality of life.

Nonpulmonary organ failure and outcome in children treated with high-frequency oscillatory ventilation.

PURPOSE: The purpose of this study was to quantitate the contribution of nonpulmonary organ failure to mortality of patients treated with high-frequency oscillatory ventilation (HFOV) and to determine which gas-exchange differences are associated with improvement on HFOV. MATERIALS AND METHODS: Charts of all patients treated with HFOV in our pediatric intensive care unit from January 1992 until January 1997 were retrospectively reviewed. RESULTS: Sixty-six patients were treated and 21 patients improved during HFOV (group 1); 45 patients did not improve (group 2). Seventeen patients (26%) had isolated respiratory failure and their mortality was 12%. Percentages of patients with 2, and 3 or more organ failure were 45%, 29%, and their mortality was significantly higher, 67% and 95%, respectively. Patients with primary respiratory failure demonstrated a significantly greater risk of improvement on HFOV (RR ratio of 2.5, 95% CI 1.5 to 4.2). There was a significantly greater proportion of patients with primary cardiac failure who did not improve on HFOV compared with all other patients. Oxygenation index significantly improved over the first 72 hours for both groups, but then significantly worsened over the next 48 hours in group 2 but not in group 1. CONCLUSION: Patients with nonpulmonary organ failure were significantly less likely to improve on HFOV and had a significantly higher mortality than patients with isolated respiratory failure. Children who do not improve on HFOV appear to reach a plateau in oxygenation indices after 3 days of HFOV.

Clinical uses and controversies of neuromuscular blocking agents in infants and children.

OBJECTIVE: To review the pharmacology of neuromuscular blocking drugs (NMBDs), their use in critically ill or injured infants and children, and the relevance of developmental changes in neuromuscular transmission. DATA SOURCES: Computerized search of the medical literature. STUDY SELECTION: Studies specifically examining the following were reviewed: a) the developmental changes in neuromuscular transmission; b) the pharmacokinetics and pharmacodynamics of all clinically available NMBDs in neonates, infants, children, and adults; and c) clinical experience with NMBDs in the critical care setting. Particular attention was directed toward studies in the pediatric population. DATA SYNTHESIS: Neuromuscular transmission undergoes maturational changes during the first 2 months of life. Alterations in body composition and organ function affect the pharmacokinetics and pharmacodynamics of the NMBDs throughout active growth and development. Numerous NMBDs have been developed during the last two decades with unique pharmacologic profiles and potential clinical advantages. The NMBDs are routinely used in critically ill or injured patients of all ages. This widespread use is associated with rare but significant clinical complications, such as prolonged weakness. CONCLUSIONS: Significant gaps in our knowledge of the pharmacokinetics and pharmacodynamics of NMBDs in infants and children continue to exist. Alterations in electrolyte balance and organ-specific drug metabolism may contribute to complications with the use of NMBDs in the critical care arena.

High-frequency oscillatory ventilation with partial liquid ventilation in a model of acute respiratory failure.

OBJECTIVE: To determine whether there is an improvement in oxygenation when partial liquid ventilation and high-frequency oscillatory ventilation are combined in the treatment of acute lung injury, compared with high-frequency oscillatory ventilation alone. DESIGN: Controlled animal trial. SETTING: Research laboratory in a university setting. SUBJECTS: Ten 3-kg piglets. INTERVENTIONS: Anesthetized piglets underwent high-frequency oscillatory ventilation, with mean airway pressure of 20 cm H2O, before induction of acute lung injury with repeated saline lavage. When PaO2 values were < 100 torr (< 13.3 kPa), five animals were randomized to receive escalating doses (3, 15, and 30 mL/kg) of perflubron at 60-min intervals. The other five animals remained on high-frequency oscillatory ventilation only. Sham dosing was performed at 60-min intervals in these animals. Arterial blood gases were obtained in both groups at baseline, after injury, and after perflubron and sham doses. MEASUREMENTS AND MAIN RESULTS: Statistically significant improvements in oxygenation were demonstrated in animals that received 3 mL/kg of perflubron with high-frequency oscillatory ventilation compared with animals receiving high-frequency oscillatory ventilation alone (253 +/- 161 vs. 90 +/- 30 torr [33.65 +/- 21.46 vs. 12.0 +/- 4.0 kPa], p < .05). Improvements in oxygenation with additional administration of perflubron were not greater than the improvements seen in the high-frequency oscillatory ventilation-only group. PaCO2 and pH were similar in both groups at all times. No hemodynamic compromise occurred in either group of animals. CONCLUSIONS: The combination of low-dose perflubron with high-frequency oscillatory ventilation leads to more rapid improvement in arterial oxygenation than high-frequency oscillatory ventilation alone, in a piglet model of acute lung injury. Although the group receiving high-frequency oscillatory ventilation alone eventually achieved PaO2 values that were equivalent to the group receiving high-frequency ventilation and perflubron, the combination of perflubron with high-frequency oscillatory ventilation may permit effective oxygenation and ventilation at lower mean airway pressures by facilitating alveolar expansion and decreasing intrapulmonary shunt.

Morphine pharmacokinetics during continuous infusion of morphine sulfate for infants receiving extracorporeal membrane oxygenation.

OBJECTIVES: To determine a) if serum morphine concentration changes during the first 3 hrs of extracorporeal membrane oxygenation (ECMO); and b) if absorption of morphine onto the membrane oxygenator is responsible for these changes. Also, morphine clearance during the first 5 days of ECMO was studied. DESIGN: Prospective, open-label study with consecutive patient enrollment. SETTING: Neonatal intensive care unit at a university-affiliated, children's hospital. SUBJECTS: Eleven neonates with severe persistent pulmonary hypertension of the newborn receiving continuous intravenous infusions of morphine sulfate and requiring ECMO. INTERVENTIONS: Blood samples were obtained from the subjects and ECMO circuits at predetermined time intervals. MEASUREMENTS AND MAIN RESULTS: Serum morphine concentration was determined using high-performance liquid chromatography. Morphine concentrations were no different from baseline at 5 mins, 1 hr, or 3 hrs after beginning ECMO. There was no significant difference in morphine concentration from samples taken immediately proximal and distal to the membrane oxygenator at 5 mins, 1 hr, and 3 hrs after the start of ECMO. Morphine clearance was calculated on days 1, 3, and 5 of ECMO. The mean value for morphine clearance was 11.7 +/- 9.3 (SD) ml/min/kg (range 2.6 to 34.5). CONCLUSIONS: The initiation of ECMO does not lead to a significant decrease in serum morphine concentration and there is no uptake of morphine onto the membrane oxygenator of the ECMO circuit. Morphine clearance for infants receiving ECMO is variable.

A prospective study of femoral catheter-related thrombosis in children.

OBJECTIVES: To establish the incidence and correlate clinical findings of femoral venous catheter-related thrombus formation in critically ill children. RESEARCH DESIGN: Observational prospective blinded study. SETTING: University-affiliated pediatric hospital intensive care unit. PATIENTS: Twenty children admitted to the pediatric intensive care unit who had percutaneous femoral venous catheters placed while in the pediatric intensive care unit. INTERVENTIONS: None. MEASUREMENTS: Duplex Doppler ultrasonography evaluation of femoral vein catheters at 1 to 2, 3 to 5, and 7 to 10 days after placement was used to detect the presence of thrombus formation and venous occlusion. Demographic patient data, pediatric risk of mortality scores, and clinical findings, including leg swelling and whether catheters would aspirate blood, were also recorded. Continuous data were analyzed using the Mann-Whitney U Test, and categorical data were compared with Fisher's Exact Test. Statistical significance was assigned at a P value of .05 or less. CONCLUSIONS: The overall incidence of catheter-related femoral vein thrombus formation was 35% (7/20). Ipsilateral leg swelling and the inability to aspirate blood from the catheter were significantly associated with thrombus formation. Patients who developed thrombi were younger and smaller than those who did not. In six of seven patients, thrombus formation was clinically occult when first demonstrated by ultrasonography.

Repair of a laryngotracheoesophageal cleft in an infant by means of extracorporeal membrane oxygenation.

Few survivors have been reported following attempted repair of laryngotracheoesophageal clefts (LTECs). The major challenge is maintaining oxygenation, both during the surgical repair and during the postoperative period of healing. We report a neonate with an LTEC extending to the carina whose successful repair was facilitated by extracorporeal membrane oxygenation (ECMO) begun intraoperatively and continued postoperatively for 11 days. The intraoperative surgical exposure of the defect was excellent. Postoperative trauma to the fresh tracheal repair from ventilatory pressures and endotracheal tube motion was eliminated through the use of ECMO. The patient was discharged without a tracheotomy and with a normal voice, cry, and swallow. According to this result, the use of ECMO may represent a significant advance in facilitating the correction of major laryngotracheoesophageal anomalies. The rationale, advantages, disadvantages, and potential pitfalls of this approach are presented, as well as preoperative and postoperative documentation of our results.

Spontaneous pneumomediastinum.

A case of spontaneous pneumomediastinum with cervical emphysema is reported. Spontaneous pneumomediastinum may complicate processes that decrease pulmonary interstitial pressure or increase intraalveolar pressure leading to alveolar rupture. Free air may then tract along blood vessels and decompress into the soft tissues of the neck. Clinical symptoms include neck and chest pain, dysphonia, and shortness of breath. Care is supportive unless the patient has a history of trauma or foreign body aspiration. Symptoms typically resolve within days.

Drowning and immersion injuries in children.

Drowning and immersion injuries are leading causes of mortality and morbidity in children. An increasing amount of epidemiologic information is available. New modalities for managing respiratory failure, such as extracorporeal membrane oxygenation, are being explored. The realization that aggressive neurointensive care does not improve desirable outcome after near-drowning has led to investigations on preventing secondary brain injury that focus on monitoring and restoring cerebral oxygenation and circulation, reversing hypothermia, and maintaining normal blood glucose levels. Efforts at early neurologic prognostication and identification of victims who are likely to die or persist in a vegetative state are increasingly accurate and are highly relevant. Critical care physicians are more likely to withhold or withdraw support from victims who have minimal likelihood of meaningful recovery.

Extracorporeal membrane oxygenation: support for overwhelming pulmonary failure in the pediatric population. Collective experience from the extracorporeal life support organization.

Data from the Extracorporeal Life Support Organization (ELSO) regarding the use of extracorporeal membrane oxygenation (ECMO) in pediatric patients with respiratory failure are reviewed. Two hundred eighty-five children between the ages of 14 days and 18 years were supported with ECMO between January 1982 and September 1991. Although these data represent the experience of 52 ECMO centers, seven centers accounted for over 50% of the total. The patients had a mean age of 33 +/- 48 months with a median age of 13 months: 137 (48%) were male and 148 (52%) were female. There were numerous primary pulmonary diagnoses: the two most common were presumed viral pneumonia (32%) and adult respiratory distress syndrome (28%). Entry criteria for ECMO, although poorly defined and specific to each institution, attempted to identify children with an 85% to 100% predicted mortality. The survival rate with ECMO was 47% (135/285). Pre-ECMO mechanical ventilatory support was extreme with an FIO2 .97 +/- .07 and a mean airway pressure (MAP) 23.6 +/- 8 cm H2O used to achieve PaO2 of 50 +/- 39 and PaCO2 51 +/- 22 mm Hg. The MAP was significantly higher in nonsurvivors versus survivors (25.3 +/- 8.7 v 22.0 +/- 7.1 cm H2O, P < .01). The duration of ECMO was 4 hours to 35.5 days with a mean of 245 +/- 165 hours, which is approximately 10 days. Duration for survivors was 222 +/- 151 hours compared with 266 +/- 176 hours for nonsurvivors. ECMO complications are divided into two categories: mechanical (directly related to the ECMO circuit) and medical (patient related).(ABSTRACT TRUNCATED AT 250 WORDS)

Extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation is still a relatively new technology that has recently achieved recognition after initial clinical disappointment in the late 1970s. At present, it is considered standard therapy for the full-term infant with PPHN who fails CMV and extraordinary, heroic therapy for older children and adults with ARF or cardiac failure, or both. Currently, the emphasis is on developing new technologies for increasing safety and effectiveness. Areas of interest include heparinless circuits, carotid artery reconstruction, improved monitoring, and expanding applications of VV ECMO. As ECMO becomes safer and more effective, it is believed that new and expanding patient populations will emerge to include premature infants, earlier intervention in term infants, and more liberal application to pediatric and adult populations.

Delayed repair and preoperative ECMO does not improve survival in high-risk congenital diaphragmatic hernia.

It has been suggested that delayed repair with preoperative stabilization might improve survival in high-risk (symptomatic within 6 hours of birth) congenital diaphragmatic hernia (CDH). This study compares the results of immediate operation versus delayed repair using extracorporeal membrane oxygenation (ECMO) when necessary. Since we first used ECMO in 1984, 101 high-risk CDH infants have been treated. Prior to 1987, we used immediate repair and postoperative ECMO if necessary. Between 1987 and 1990 we combined delayed operation (24 to 36 hours) with preoperative ECMO as necessary. No infant in this series was excluded from ECMO therapy unless absolute contraindications existed (prematurity, intracranial hemorrhage, or other major anomalies). Fifty-five patients received immediate operation and 46 had delayed repair. The two groups were comparable populations based on gestational age, birth weight, age at onset of symptoms, Apgar scores, best postductal PO2 (BPDPO2), and frequency of antenatal diagnosis. There was no statistically significant difference in overall survival between the two groups. Differences in survival among subpopulations (BPDPO2 greater than 100 or less than 100, antenatal diagnosis, inborn v outborn) also are not significant. The requirement for ECMO was similar in both groups. Survivors in the delayed repair group were ventilated longer and on ECMO longer, but had fewer late deaths (greater than 21 days) and fewer pulmonary sequelae (O2 dependency at discharge) than infants in the immediate repair group (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)