George M. Vaughan

Update on current therapeutic approaches in burns.

Burn injury results in a rapid loss of intravascular volume as wound edema forms, which reduces the circulating blood volume and generates the need for fluid therapy to combat hypovolemia. Fluid resuscitation of a burn patient is usually carried out with isotonic, sodium- and chloride-containing fluids, such as lactated Ringers solution. The initial 24 h resuscitation volume is based on the burn size and body weight of the patient. Following a successful resuscitation, the burn patient develops stereotypic neurohormonal and metabolic responses that, depending on the extent of injury, last for several weeks or months. Breathing of incomplete products of combustion by the fire victim produces inhalation injury, the incidence of which rises with increasing burn size and the severity of which is proportional to the duration of exposure. Systemic hypoxia from carbon monoxide toxicity causes early death; chemical airway injury increases mortality and predisposes to subsequent pneumonia that further reduces survival. The diagnosis of inhalation injury is made by bronchoscopy and/or xenon scan and therapy involves support of ventilation. Thermal destruction of the cutaneous mechanical barrier and the presence of nonviable avascular burn eschar as well as impairment of other host defenses render the burn patient susceptible to local as well as systemic infections. Care following resuscitation is focused on topical antimicrobial therapy, burn wound excision, and wound closure by grafting. Nutritional support and the prevention and control of infection are constant themes in burn patient management. A progressive improvement in general care of the acutely injured patient, prevention of shock, effective means of maintaining organ function, prevention and control of burn wound and other infections, and physiologically based metabolic support have significantly increased burn patient survival in recent decades.

The link between the insecticide heptachlor epoxide, estradiol, and breast cancer

SummaryGiven the suspected effects of estrogens on breast cancer, xenoestrogenic insecticides may be a risk factor. Studies of the weak xenoestrogen, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), have failed to demonstrate a causal relationship, though another estrogenic organochlorine insecticide, dieldrin, belonging to the cyclodiene family, has recently been linked to breast cancer. Other cyclodienes such as heptachlor epoxide (HE) and oxychlordane (OC) present in breast tissue have not been evaluated as rigorously, presumably due to their lower concentration and lower recovery using solvent extraction procedures. We used sparging extraction coupled with gas chromatography to determine the levels of HE, OC, and DDE in adipose tissue within breast biopsies in a series of 34 women evaluated for breast abnormality. Of the three insecticides tested, only HE (p=0.007) was positively associated with prevalence of breast cancer in the biopsies. In rapid, non-genomic studies using isolated human leukocytes, flow cytometric methods were used to measure HE-induced oxidants and DNA damage. These studies indicated that HE, at concentrations similar to those in breast biopsies, induced an inverted-U increase in intracellular oxidants and DNA strand breaks [both blocked by specific nitric oxide- (NO-) synthesis blockade withl-NMMA] in human polymorphonuclear leukocytes (PMNs). HE-treated PMNs also induced damage to surrounding lymphocytes in mixed-leukocyte incubations (also inhibited by NO blockade). The HE-induced changes in NO were inhibited by 17β-estradiol-(17β-E2) receptor antagonists and were mimicked by similar concentrations of 17β-E2. The addition of tumor necrosis factor-α (TNF-α) increased intracellular oxidants and DNA damage and shifted the responses to lower HE concentrations. This study, along with others, suggests that HE-induced NO production may contribute to initiation, promotion, and progression of cancer.

The renal effects of low-dose dopamine in thermally injured patients.

The renal effects of low-dose dopamine (LDD) therapy in hyperdynamic thermally injured patients are unknown. We investigated the renal effects of LDD in ten burn patients (mean +/- SEM age and % total body surface burned: 30.2 +/- 3.3 years and 53.4% +/- 7%) and six controls (mean age; 20.2 +/- 0.5 years). Administration of LDD significantly increased glomerular filtration rate, effective renal plasma flow, sodium excretion, and urine flow in the controls and effective renal plasma flow, urine flow, heart rate, and cardiac index in the patients. The chronotropic effect of dopamine appears to be a principal contributor to the patients increased effective renal plasma flow. Sodium excretion was increased by LDD only in the patients in whom the predopamine sodium excretion exceeded 5 mEq/h. Lack of a consistent natriuretic effect and the consistent chronotropic effect suggest that the routine use of low-dose dopamine in burn patients is unwarranted. The side effects that attend the desired response determine clinical use, i.e., the potential for blood flow redistribution and increased cardiac work demands must be balanced against increased renal plasma flow and natriuresis.

Dissociation of Blood Volume and Flow in Regulation of Salt and Water Balance in Burn Patients

The relationship between effective blood volume and related hormones in burn patients following resuscitation is not well understood. Previous reports have suggested that hormone secretion is altered by a resetting of neural control mechanisms. Serum and urine sodium, plasma renin activity, serum ADH, cardiac index, effective renal plasma flow, and total blood volume were measured in seven burn patients (mean age, total burn size, and postburn day: 32 years, 56%, and 9 days, respectively). The same values (with the exception of cardiac index and blood volume) were measured in 10 control patients (mean age, 24 years). The blood volume of patients was measured by 51chromium red blood cell (RBC) labeling and compared to normal predicted values based on body surface area and sex. Mean serum sodium and osmolality were 138 mmol/L (millimolar) and 286 mosm/kg, respectively, in both patients and control subjects. Mean +/- standard error of the mean total blood volume in the patients was low, 81% +/- 4% of predicted values. Cardiac index and renal plasma flow were significantly elevated. Plasma renin activity and antidiuretic hormone (ADH) levels were elevated and altered in the direction expected from blood volume measurements despite the findings of increased blood flow. Dissociation of organ flow and hormonal response suggests that simultaneous direct blood volume measurements are necessary to elucidate factors other than altered neural control settings to explain hormonal changes in the flow phase of injury. Depressed total blood volume appears to promote elevated ADH levels in burn patients following resuscitation. Whether there is an additional role of altered neural control settings remains to be established.

Serum Melatonin after a Single Aqueous Subcutaneous Injection in Syrian Hamsters

A single injection of 25 micrograms melatonin was given subcutaneously in 0.1 ml saline either at 3 h into the light phase (morning) in female Syrian hamsters or at 1 h before the beginning of the dark phase (evening) in males (L/D 14/10 h). In both cases, the maximal mean serum values seen at 20 min after injection (50 ng/ml) were more than 1,000 times the normal nocturnal melatonin concentration. By 1 h after injection, serum melatonin had fallen to 10% (morning) or 4% (evening) of the respective 20-min value. The average half-times for plasma concentration during the second hour after injection were 14 min in the morning and 13 min in the evening. After either morning or evening injection, serum melatonin reached normal daytime concentration between 2 and 4 h after injection.

Melatonin and porphyrin in the harderian glands of the syrian hamster: Orcadian patterns and response to autumnal conditions

1. Adult male Syrian hamsters were killed at nine intervals during a 24 hr period in the autumn, after 2 months either indoors in controlled conditions or in natural outdoor conditions. 2. Harderian glands were taken for determination of N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) activities and melatonin and porphyrin concentrations. 3. Mean 24 hr Harderian NAT and melatonin values were lower outside than inside. 4. Twenty-four hour melatonin rhythms were detected with similar daytime (afternoon) acrophases in both environmental conditions. 5. An NAT rhythm was seen only in animals kept inside, with a circadian maximum in the late dark phase. 6. Mean 24 hr HIOMT activity was slightly higher outdoors than indoors, and 24 hr rhythms were not detected in either condition. 7. Mean porphyrin concentrations were higher outdoors, with 24 hr rhythms detected in both conditions and a significantly earlier nocturnal circadian maximum outdoors.

Pineal and retinal lysosomal enzyme rhythms

Pineal glands and the neurosensory portion of the retinae of adult male rats adapted to a 24-h cycle with lights on from 06.00 to 20.00 h were collected at 9 timepoints during the cycle. Significant rhythms in both pineal and retinal hexosaminidase, beta-glucuronidase, acid phosphatase and beta-glucosidase were observed. For each enzyme, pineals had greater overall activity per unit amount of protein than did retinae. All 4 significantly rhythmic pineal enzymes peaked within 30 min of each other (18.30-19.00 h) whereas the retinal enzymes peaked some 6 h earlier, between 11.30 and 13.45 h. To our knowledge, this is the first report demonstrating 24-h rhythms in lysosomal enzymes in the pineal gland and retina. Since the acrophases (peak times) of these enzymes within each tissue are tightly synchronized yet different between tissues, lysosomes may play unique roles in the physiology of different structures in the photoneuroendocrine system with respect to time in the light-dark cycle.

Twenty-four hour variation of α1-adrenergic receptors in the pineal gland of the male Syrian hamster

Specific binding of [125I]iodo-[beta-(4-hydroxyphenyl)-ethylaminomethyl]tetralone ([ 125I]HEAT) was used to assess alpha 1-adrenergic receptors on pineal gland membranes of male Syrian hamsters (Mesocricetus auratus) housed under a 14:10 h light-dark cycle (lights on at 06.00 h). Saturation experiments with pooled pineal membrane preparations showed the presence of alpha 1-adrenergic receptor sites (dissociation constant Kd approx. 0.1 nM). Analysis of 4 time points indicated no significant change in Kd, but significant (P less than 0.01) changes of receptor density (Bmax) with a minimum recorded at night. Binding of a constant amount of [125I]HEAT (200 pM) to pineal membranes at 8 time points exhibited a circadian variation (P less than 0.001) of receptor density with lowest values around midnight and highest levels during daytime.

Injections of α-melanocyte stimulating hormone affect pineal serotonin, melatonin and N-acetyltransferase activity

To determine if exogenously administered alpha-melanocyte stimulating hormone (alpha-MSH) affects nighttime pineal N-acetyltransferase activity, pineal levels of 5-hydroxytryptophan, serotonin and melatonin, and plasma prolactin levels, adult male hamsters were injected at 1900 hr (lights out 2000-0600 hr) with two doses of the peptide and killed at 0300 hr. The low dose of alpha-MSH (200 ng) produced a significant fall in pineal serotonin, pineal NAT activity and plasma prolactin values. The high dose of the peptide (20 micrograms) increased circulating prolactin titers and pineal serotonin levels and caused a concomitant decrease in pineal melatonin levels.

Reduced serum T4 and T3 and their altered serum binding after burn injury in rats.

Total T4 and T3 concentrations are often suppressed in burned patients. To investigate the significance of such changes, we have characterized serum T4 and T3 after full-thickness scald burns (60% body surface under anesthesia) of 270-gm male Sprague-Dawley rats housed in a light:dark cycle of 14:10 hr. Groups (N = 9-15) of BURN, SHAM (anesthesia, fur clipped, no burn) and CON (controls) were sacrificed on postburn days 8 and 14. T4 and T3 (radioimmunoassay), free indices (FT4I and FT3I = respective total T4 or T3 X in vitro charcoal T3 uptake, T3U), and free concentrations (FT4 and FT3 = total T4 or T3 X respective equilibrium dialyzable fraction, T4DF or T3DF) were not different between CON and SHAM. Compared to SHAM, mean T4 and FT4I (by about 48% of respective SHAM means on both days), TT3 (by 36, 43%), and FT3I (by 38, 45%) (days 8, 14) were suppressed in BURN (all p less than 0.001). T4DF (both days) and T3DF (day 14) were significantly elevated in BURN, demonstrating a deficit in serum binding, but T3U was not. FT4 (by 26, 22%) and FT3 (by 33, 34%) (day 8, 14) were significantly lower in BURN. On either day, covariance analyses (BURN vs. combined CON + SHAM) correlated FT4I or FT3I with respective FT4 or FT3 (all p less than 0.001, slopes not different in BURN vs. CON + SHAM), but the lower FT4I and FT3I in BURN significantly overestimated (all p less than 0.001) the depression of respective FT4 and FT3 in BURN.(ABSTRACT TRUNCATED AT 250 WORDS)