Fetal cardiovascular, endocrine, and fluid responses to atrial natriuretic factor infusion.

The purpose of this study was to determine the effects of atrial natriuretic factor (ANF) in the fetus and to explore the interactions among the fetal cardiovascular, endocrine, and fluid responses to ANF. In 12 chronically catheterized fetal sheep at 130 +/- 1 (SE) days gestation, ANF was infused intravenously for 30 min at 14-300 ng.min-1.kg-1. Fetal arterial plasma ANF concentration increased by 174 to 5,410 pg/ml from a preinfusion value of 163 +/- 13 pg/ml. The clearance of ANF from the circulation was 122 +/- 28 ml.min-1.kg-1 and the half-life was 0.46 +/- 0.07 min. When plasma ANF was greater than 2,000 pg/ml, fetal arterial pressure decreased, venous pressure increased transiently, and heart rate was unchanged. Plasma arginine vasopressin (AVP) concentration and plasma renin activity (PRA) increased with high ANF concentrations, while norepinephrine concentrations were unaffected. Fetal blood volume decreased in all fetuses, and urine flow increased significantly but not in every fetus. Blood and urine osmolalities did not change. On terminating the infusion, venous pressure and urine flow decreased below control, while blood volume and arterial pressure remained reduced. Plasma AVP concentration increased further, and this was accompanied by an increase in urine osmolality. Thus the most consistent effect of ANF in the fetus was a reduction in blood volume, which was independent of urine flow changes. Other cardiovascular, endocrine, and fluid responses to ANF as well as interactions among them appeared to occur largely at supraphysiological concentrations and may be secondary to the changes in blood volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic modulation of ovine fetal responses to atrial natriuretic factor infusion.

The aim of this study was to determine whether the autonomic nervous system modulates the cardiovascular, endocrine, and/or urinary responses to atrial natriuretic factor (ANF) infusion in the fetus. We infused ANF intravenously for 30 min into chronically catheterized, late-gestation sheep fetuses with autonomic blockade and compared the responses to those in autonomically intact fetuses. During the infusions, plasma ANF concentration increased similarly in the blocked and intact fetuses. Arterial pressure decreased by 2 mmHg in both groups, but the decrease occurred earlier in the blocked fetuses. Heart rate was significantly decreased by an average of 15 beats/min in the blocked compared with the intact fetuses. Plasma protein concentration decreased in the blocked fetuses compared with a rise in the intact fetuses. In the blocked fetuses, the restoration of blood volume to normal during the postinfusion period occurred earlier. In the blocked animals, low doses of ANF produced a diuresis, whereas high doses did not increase urine flow; the opposite responses occurred in the intact group. Plasma arginine vasopressin (AVP) concentration increased during the infusion only in the blocked animals. The fetal venous pressure, plasma renin activity, and norepinephrine responses were similar in both groups. These data suggest that the autonomic nervous system may play a role in modulating the fetal arterial pressure, heart rate, blood volume, plasma protein concentration, AVP, and urine flow responses to ANF. Thus the autonomic nervous system appears to significantly modulate multiple responses to ANF in the late-gestation ovine fetus.

Hearing loss in children with brain tumors treated with cisplatin and carboplatin-based high-dose chemotherapy with autologous bone marrow rescue.

Carboplatin is less ototoxic than cisplatin, but ototoxicity may occur with carboplatin at higher doses. We evaluated hearing in children with brain tumors treated with conventional dose cisplatin followed by high-dose carboplatin. Children under 6 years of age, newly diagnosed with brain tumors, were treated after surgery with cisplatin, Etoposide, cyclophosphamide, and vincristine, followed by consolidation with carboplatin, ThioTEPA, Etoposide, and autologous bone marrow rescue. Hearing was assessed before and after consolidation, utilizing standard audiometric techniques. Seven of the 11 evaluable patients developed high-frequency sensorineural hearing loss after induction therapy. Hearing deteriorated after consolidation in five patients, with pure tone threshold shifts of up to 65 dB between 2,000 and 8,000 Hz. Of these five patients, audiological abnormalities were documented in four prior to consolidation, one received cranial irradiation after consolidation, and all five received aminoglycoside antibiotics for at least 2 weeks, with toxic drug levels in four. Three patients have subsequently required hearing aids. Significant ototoxicity is common in these patients. Ototoxicity related to consolidation therapy is likely due to the high dose of carboplatin used, prior cisplatin therapy, aminoglycosides, and, in one patient, cranial irradiation. Audiological assessment is essential in children treated with dose-intensive chemotherapy regimens containing cisplatin and carboplatin for identification and rehabilitation of ototoxicity.

Acute neurologic dysfunction associated with high-dose chemotherapy and autologous bone marrow rescue for primary malignant brain tumors.

UNLABELLED: Acute neurologic complications occurred 103 times in 50 (54%) of 92 patients (primarily children) treated with high-dose chemotherapy and autologous bone marrow rescue for primary central nervous tumors. Different types of neurologic compromise occurred during the chemotherapy infusion as compared to the first 100 days after the chemotherapy and the greater-than-100-day time period. The causes of the neurologic compromise were also time sensitive. BACKGROUND: Results of treatment for children with primary brain tumors using high-dose chemotherapy with autologous marrow rescue (ABMR) have been encouraging. However, the neurotoxicity associated with this technique remains a major concern. We reviewed the records of 92 patients who underwent ABMR for malignant brain tumors between 1986 and 1992 for the occurrence and timing of acute neurologic dysfunction (AND). METHODS: Individual investigators at the participating institutions retrospectively completed standardized forms on each patient. The manner in which the distribution of AND versus time of treatment emerged led to the establishment of distinct time periods for data analysis and discussion. The pre-ABMR period included those events that occurred during the chemotherapy infusion, the early posttreatment period included the first 100 days following bone marrow rescue, and the late posttreatment period was greater than 100 days following bone marrow rescue. RESULTS: Fifty patients (54%) had 103 episodes of AND. AND included encephalopathies with or without hallucinations or coma (32), seizures (23), headaches (9), ataxia-tremor-dysarthria syndrome (7), anorexia and nausea syndrome (7) and others (25). During the chemotherapy infusion, encephalopathies and seizures were most common. Hallucinations occurred primarily related to drug infusion, while encephalopathies without hallucinations were usually due to demonstrable dysmetabolic states. In the 100 days following ABMR, dysmetabolic states and iatrogenic factors caused 45% and progressive disease caused 33% of AND. Greater than 100 days from ABMR, progressive disease caused 55% of AND; 7 patients were noted to develop chronic anorexia and nausea of unclear etiology. The occurrence of neurologic compromise was not related to the chemotherapy regimens, tumor histology, tumor location, patient age, prior treatment, or the amount of tumor at time of treatment. Dexamethasone use was the only clinical factor associated with AND (p < 0.004). CONCLUSIONS: The cause of AND was definable for 95% of instances that occurred within 100 days of ABMR. Early AND was often iatrogenic and reversible. The greater the time from ABMR the more likely AND was due to progressive disease. Clinical factors could not predict the occurrence of AND as only the concurrent use of dexamethasone at the time of treatment proved significant. Although frequent, AND should not be considered a limiting toxicity of this approach or preclude the use of this technique.