Health effects of diazinon on a family.

There is increasing evidence of permanent sequalae from acute organophosphate poisoning. We report on accidental diazinon overexposure with acute organophosphate poisoning through cutaneous absorption and inhalation followed by persistent neurological effects. In addition, we observed skeletal and endocrine effects likely attributable to the diazinon poisoning. A family of seven was exposed to diazinon in June 1999 over a two-day period. The pesticide company mistakenly used diazinon to heavily spray the inside of the home instead of permethrin. The applicator applied the pesticide over the entire surface of the floor, carpeting, furniture, and clothing in closets to eradicate an infestation of fleas. Acute symptoms in the family members included headaches, nausea, skin irritation, runny nose, and vomiting. The family was first evaluated at 3 months and then 3 years after the acute poisoning. There were persisting neurological symptoms of memory loss, decreased concentration, irritability, and personality changes of varying degrees in all family members. Objective neurological findings of impaired balance, reaction time, color vision, slotted pegboards and trials making were present in the three older children who could be tested. Neuropsychological evaluation revealed evidence of organic brain dysfunction in all seven family members. Bone growth difficulties are present in four of five children. One child has delayed menarche.

The effects of inhaled nitric oxide on postoperative pulmonary hypertension in infants and children undergoing surgical repair of congenital heart disease.

UNLABELLED: The role of inhaled nitric oxide in the immediate post-bypass period after surgical repair of congenital heart disease is uncertain. In a controlled, randomized, double-blind study, we tested the hypothesis that inhaled nitric oxide (NO) would reduce pulmonary hypertension immediately after surgical repair of congenital heart disease in 40 patients with preoperative evidence of pulmonary hypertension (mean pulmonary arterial pressure [MPAP] exceeding 50% of mean systemic arterial pressure [MSAP]). Patients were then followed in the intensive care unit (ICU) to document the incidence of severe pulmonary hypertension. Of the patients, 36% (n = 13) emerged from bypass with MPAP > 50% MSAP. In these patients, inhaled NO reduced MPAP by 19% (P = 0.008) versus an increase of 9% in the placebo group. No effect on MPAP was observed in patients emerging from bypass without pulmonary hypertension (n = 23). Inhaled NO was required five times in the ICU, always in the patients who had emerged from cardiopulmonary bypass with pulmonary hypertension (5 of 13 [38%] versus 0 of 23). We conclude that, in infants and children undergoing congenital heart surgery, inhaled NO selectively reduces MPAP in patients who emerge from cardiopulmonary bypass with pulmonary hypertension and has no effect on those who emerge without it. IMPLICATIONS: In a randomized double-blind study, inhaled nitric oxide selectively reduced pulmonary artery pressures in pediatric patients who developed pulmonary hypertension (high blood pressure in the lungs) immediately after cardiopulmonary bypass and surgical repair.

Opioid-induced analgesia in neonatal dogs: pharmacodynamic differences between morphine and fentanyl.

Whether the analgesic effects of opioids change as a neonate matures is not well understood. To address this issue, we determined the pharmacokinetics and pharmacodynamics of analgesic effects of morphine and fentanyl in 35 dogs aged 1 to 34 days. Opioids were infused to produce analgesia, response times to a noxious thermal stimulus were measured and plasma opioid concentrations were determined. An effect compartment pharmacodynamic model was fit to the values for time to response to determine the rate constant for equilibration (Keo) between plasma and effect-site (Ce) concentrations and analgesic effect (increase in time to response to a noxious stimulus) above baseline per microgram/ml of Ce (delta). A time-to-event data analysis (modeled with a Weibull function) was used to account for censored time to response values. For both opioids, values for Keo did not vary with age. Values for delta decreased with age (i.e., decreasing sensitivity with increasing age), and the magnitude of the change during the first month of life was similar for the two opioids. In the context of our previous study concerning ventilatory depressant effects of these opioids (that sensitivity to morphine, but not to fentanyl, decreased markedly during the first month of life), these results in dogs suggest that fentanyl has greater utility than morphine in neonates during spontaneous ventilation.

Inhaled nitric oxide enhances oxygenation but not survival in infants with alveolar capillary dysplasia.

A complex vascular abnormality in the lungs, termed alveolar capillary dysplasia (ACD) and misalignment of the lung vessels, has been recently recognized in some infants with persistent pulmonary hypertension. These infants die despite maximal medical support including extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide has been reported to improve oxygenation in neonates with persistent pulmonary hypertension of the newborn, and may allow some infants to avoid the need for ECMO. We identified five infants who had received inhaled nitric oxide to treat refractory hypoxemia caused by persistent pulmonary hypertension of the newborn, and who subsequently died and had autopsy confirmation of ACD. Each infant received care at a different medical center. In each patient, inhaled NO increased the arterial partial pressure of oxygen dramatically. Despite initial clinical improvement, the response to NO was not sustained in any patient. As responsiveness was lost, each infant with ACD required inhaled NO concentrations of 80 ppm or higher to sustain oxygenation. Each infant died, four after extensive periods of ECMO support. This experience demonstrates that a short-term improvement after inhalation of nitric oxide does not lead to long-term survival in ACD. Further, in three infants the diagnosis of ACD was established by lung biopsy before death. Increasing awareness of this clinical entity may allow for the avoidance of costly, invasive procedures such as ECMO until more specific therapies become available.

Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group.

BACKGROUND: Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension. METHODS: In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise, it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used. RESULTS: Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P=0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase methemoglobin levels. CONCLUSIONS: Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.

Opioid pharmacodynamics in neonatal dogs: differences between morphine and fentanyl.

Clinical experience and laboratory studies suggest that neonates are more sensitive than adults to the ventilatory depressant effects of morphine. Similar sensitivity has been cited, but not demonstrated, for fentanyl. To examine this issue, we determined ventilatory pharmacodynamics of morphine and fentanyl in 28 dogs aged 2-35 days. During isohypercapnia, morphine or fentanyl was infused to depress minute ventilation by > 50% and arterial plasma opioid concentrations were measured. For each drug, an effect compartment pharmacodynamic model was fit to the values for minute ventilation to determine the steady-state opioid plasma concentration depressing ventilation by 50% (C50) and the rate constant for equilibration between plasma concentration and effect (keo). For morphine, there was a marked age-related increase in C50 but no change in keo. For fentanyl, there was a small maturational increase in C50 and no change in keo. We conclude that there are marked maturational changes in the ventilatory depressant effects of morphine resulting from maturational changes in sensitivity rather than in equilibration. Maturational changes in the ventilatory effects of fentanyl are much smaller in magnitude than those for morphine.

Inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn.

Increasing evidence suggests that the pulmonary vascular endothelium is an important mediator of resting pulmonary vascular tone through the synthesis and release of a variety of vasoactive substances including nitric oxide (NO). In addition, pulmonary endothelial dysfunction (such as impairment of NO synthesis) is present in lung injury and may contribute to the pathophysiology of pulmonary hypertensive disorders. Recently, exogenously administered NO gas has been utilized to treat infants with persistent pulmonary hypertension of the newborn (PPHN). These preliminary studies suggest that inhaled NO is a promising new therapy for the treatment of infants with PPHN. Controlled clinical trials must now be performed to determine if the use of inhaled NO improves the long-term outcome of patients with PPHN. Long-term exposure must be monitored closely for potential toxicity which includes methemoglobinemia and lung injury secondary to peroxynitrite and nitrogen dioxide production.

Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios.

OBJECTIVE: We determined whether inhaled nitric oxide (NO) could improve systemic oxygenation in human neonates with hypoplastic lungs. METHODS: A multicenter nonrandomized investigation was performed to study the efficacy of short-term NO inhalation. Inhaled NO was administered at 80 ppm to nine neonates without evidence of structural cardiac disease by echocardiography. Lung hypoplasia was due to congenital diaphragmatic hernia (CDH) in eight patients and to oligohydramnios in one patient. A total of 15 trials of NO inhalation were performed in these nine patients. Eight trials in seven patients were performed before extracorporeal membrane oxygenation ((ECMO); one patient had two trials) and seven trials were performed in five patients after decannulation from ECMO (two patients had two trials each). RESULTS: NO inhalation before ECMO did not change postductal PaO2 (42 +/- 3 mmHg vs 42 +/- 4 mmHg), oxygen saturation (SpO2; 89% vs 88%) or oxygenation index (31 +/- 4 cm H2O/torr vs 31 +/- 4 cm H2O/torr) for the group. All patients required ECMO support, which lasted from 5 to 17 days (mean 9). After decannulation from ECMO, NO inhalation increased postductal PaO2 from a median of 56 mm Hg (range 41 to 94) to a median of 113 mm Hg (range 77 to 326), P < .05. It decreased the oxygenation index from a median of 23 cm H2O/torr (range 11 to 7) to a median of 11 cm H2O/torr (range 4 to 21), P < .05. It increased SpO2 from 91% to 96% (P < .05) and pH from 7.48 +/- .03 to 7.50 +/- .03. CONCLUSION: In our patients with hypoplastic lungs, inhaled NO was effective only after ECMO. This could be due to maturational changes such as activating the endogenous surfactant system. Inhaled NO may be effective in neonates with hypoplastic lungs who have recurrent episodes of pulmonary hypertension after ECMO, even if they were previously unresponsive.

Chronic recurrent esophageal strictures treated with balloon dilation in children with autosomal recessive epidermolysis bullosa dystrophica.

Two children (8- and 17-yr old) with autosomal recessive epidermolysis bullosa dystrophica and chronic esophageal strictures were treated with repeated balloon dilations. General anesthesia was by face mask adapted specifically for this procedure, with careful attention to avoid skin and mucus membrane damage. A balloon dilator positioned fluoroscopically over an angiographic guidewire was gently inflated until narrowings resolved. Dilations have been performed every 1-11 [4.3 +/- 3.2 (mean +/- SD)] months in the younger patient over the last 4.3 yr, and every 8-20 (14.5 +/- 5.9) months in the older patient over the last 4.8 yr, without serious complications. Both patients were able to swallow normal foods following dilations. Repeated balloon dilations of esophageal strictures in patients with epidermolysis bullosa dystrophica can be done safely. Further studies are indicated to determine its effectiveness and appropriateness as an alternative to colonic interposition.

MAC of desflurane in 60% nitrous oxide in infants and children.

Desflurane, an inhaled anesthetic, may be useful for outpatient procedures in pediatric patients because its blood solubility (similar to that of nitrous oxide and less than that of commercially available potent inhaled anesthetics) may facilitate emergence and recovery from anesthesia. Although the MAC of desflurane without nitrous oxide has been determined in pediatric patients, it is likely that clinicians will administer desflurane with nitrous oxide. To determine the potency of desflurane administered with 60% nitrous oxide in pediatric patients, the authors determined the minimum alveolar concentration that prevents movement in 50% of subjects (MAC) in 12 infants aged 17 weeks-12 months and 12 children aged 1-5 yr. Anesthesia was induced with desflurane in oxygen; nitrous oxide was not administered during induction of anesthesia to minimize the likelihood of hypoxia if laryngospasm occurred. Following tracheal intubation, nitrous oxide and desflurane were administered and maintained at target concentrations for a minimum of 10 min before surgical incision. No additional anesthetic, sedative/hypnotic, or analgesic drugs were administered prior to incision. Following surgical incision, anesthesia was maintained with nitrous oxide, desflurane, and fentanyl, 4 +/- 1 micrograms/kg (mean +/- SD). MAC, determined using a modification of Dixon's "up-and-down" technique, was 7.5 +/- 0.1% (mean +/- SE) for infants and 6.4 +/- 0.2% for children; similar values were obtained using logistic regression (7.5 +/- 0.01% and 6.3 +/- 0.03%, respectively). Time from discontinuation of anesthesia to eye-opening and tracheal extubation was 5.4 +/- 3.6 min (mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)

Induction and maintenance characteristics of anesthesia with desflurane and nitrous oxide in infants and children.

To determine the induction and maintenance characteristics of desflurane in pediatric patients, the authors anesthetized 206 infants and children aged 1 month to 12 yr with nitrous oxide plus desflurane and/or halothane in oxygen. Patients were assigned to one of four groups: anesthesia was 1) induced and maintained with desflurane after premedication with an oral combination of meperidine, diazepam, and atropine; 2) induced and maintained with desflurane; 3) induced with halothane and maintained with desflurane; or 4) induced and maintained with halothane. An unblinded observer recorded time to loss of consciousness (lid reflex), time to intubation, and clinical characteristics of the induction and maintenance of anesthesia. Moderate-to-severe laryngospasm (49%) and moderate-to-severe coughing (58%) occurred frequently during induction of anesthesia with desflurane; the incidence of these was not altered by premedication. In contrast, laryngospasm and coughing were rare during induction of anesthesia with halothane. In unpremedicated patients, time to loss of lid reflex (mean +/- SD) was similar for desflurane (2.4 +/- 1.2 min) and halothane (2.1 +/- 0.8 min). During induction of anesthesia, before laryngoscopy and intubation, mean arterial pressure less than 80% of baseline was more common with halothane; heart rate and mean arterial pressure greater than 120% of baseline were more common with desflurane. Intraoperatively, heart rate greater than 120% of baseline was more common with desflurane; blood pressures were similar for the two anesthetics. The authors conclude that the high incidence of airway complications during induction of anesthesia with desflurane limits its utility for inhalation induction in pediatric patients. Anesthesia can be safely maintained with desflurane if induced with a different anesthetic.

The "educated hand". Can anesthesiologists assess changes in neonatal pulmonary compliance manually?

To determine whether anesthesiologists can manually detect significant changes in pulmonary compliance in neonates using an "educated hand," the authors tested whether clinicians could detect clamping of an endotracheal tube connecting a neonatal lung model to one of three anesthesia breathing circuits. The test lungs corresponded to the lung of a full-term neonate (large lung) or a premature neonate (small lung), and the circuits were a disposable Mapleson D and a disposable pediatric circle system with and without a humidifier. Clinicians having four levels of expertise (inexperienced anesthesia residents, experienced anesthesia residents, faculty not specializing in pediatric anesthesia, and specialized pediatric anesthesia faculty) were permitted to choose fresh gas flows, ventilatory pattern, and rate. After an acclimation period, the endotracheal tube connecting the test lung to the circuit was occluded once for 30 s. Clinicians were credited with a successful detection if they reported the occlusion within 15 s and had fewer than one false positive per minute. With the large lung model, only 4 of 24 clinicians detected occlusion with the Mapleson D circuit; similar results were obtained with the other circuits. With the small lung model, the only successful detection occurred with the Mapleson D circuit. Success at detecting occlusion was similarly low for clinicians with different levels of expertise. The authors conclude that the commonly held belief that the "educated hand" permits clinicians to detect subtle changes in pulmonary compliance in neonates during anesthesia (necessitating manual rather than mechanical ventilation) is not true.

Clinical characteristics of desflurane in surgical patients: minimum alveolar concentration.

Desflurane (formerly I-653) is a new inhalaticnal anesthetic with a promising pharmacokinetic profile that includes low solubility in blood and tissue, including fat. Since its lipid solubility is less than that of other volatile agents, it may have lower potency. Low solubility would be expected to increase the rate at which alveolar concentration approaches inspired concentration during induction as well as to increase the rate of elimination of desflurane from blood at emergence. We determined the minimum alveolar concentration (MAC) of desflurane in 44 unpremedicated ASA physical status 1 or 2 patients undergoing elective surgery. We prospectively studied four patient groups distinguished by age and anesthetic regimen: 18-30 versus 31-65 yr and desflurane in 60% N2O/40% O2 versus desflurane in O2. Anesthesia was induced with desflurane or desflurane in 60% N2O/40% O2. MAC was determined by a modification of Dixon's up-and-down method with increments of 0.5% desflurane. The MAC of desflurane in O2 was 7.25 +/- 0.0 (mean +/- SD) in the 18-30-yr age group, and 6.0 +/- 0.29 in the 31-65-yr group; the addition of 60% N2O reduced the MAC to 4.0 +/- 0.29 and 2.83 +/- 0.58, respectively. The median time from discontinuation of desflurane to an appropriate response to commands was 5.25 min. Desflurane appears to be a mild airway irritant but was well tolerated by all patients.