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Biomedical subjects

J R Fletcher

Publications and source records attributed to J R Fletcher.

At least 55 records · Page 3Linked to original sources
PubMed1984

Epinephrine absorption after intratracheal administration.

Tracheal intubation during cardiopulmonary resuscitation often precedes establishment of an intravenous route for the administration of drugs. To determine the efficacy of intratracheal administration of drugs during cardiopulmonary resuscitation we measured plasma catecholamine levels and hemodynamic responses to intratracheal epinephrine (EPI) administration using a double-blind, randomized crossover design in 7 male baboons (Papio anubis), each studied twice, who received 5 ml of 1:10000 EPI on one day and 5 ml of 0.9% NaCl on another day. Arterial blood samples for measurement of plasma EPI and norepinephrine (NE) concentrations were collected, and heart rate (HR) and mean arterial blood pressure (MAP) were measured before and 1, 2, 4, 8, 16, and 30 min after intratracheal drug administration. Intratracheal EPI significantly (P less than 0.05) elevated HR to 120 +/- 6 from 105 +/- 6 beats/min, MAP to 120 +/- 4 from 112 +/- 5 mm Hg, and plasma EPI to 8882 +/- 2143 from 928 +/- 209 pg/ml within 1 min of administration, and these effects persisted for 30 min. Plasma NE levels did not change after intratracheal EPI administration. None of the four variables changed after intratracheal saline was given. We conclude that in subhuman primates, intratracheal EPI is rapidly absorbed and is an effective pressor agent when given by this route; and that these data lend support to the clinical practice of intratracheal EPI administration during cardiac arrest or in the treatment of shock.

Absorption↗
PubMed1983

Local dental anesthesia with epinephrine. Minimal effects on the sympathetic nervous system or on hemodynamic variables.

To define the hemodynamic effects of local dental anesthesia, we measured the mean arterial pressure (MAP), heart rate, and plasma catecholamine responses for 60 minutes following an inferior alveolar nerve block with epinephrine-and nonepinephrine-containing lidocaine hydrochloride anesthesia in 14 men using a randomized double-blind crossover trial. Lidocaine alone caused no significant change in MAP or heart rate and only slight, transient changes in plasma catecholamine concentrations when compared with baseline values. Lidocaine with epinephrine caused significant, sustained (60 minutes) increases in plasma epinephrine concentrations (mean +/- SEM, 27 +/- 4 to 94 +/- 13 pg/mL) and a slight, but transient (two-minute) increase in heart rate from 68 +/- 3 to 70 +/- 3 beats per minute. Lidocaine with epinephrine caused no significant change in MAP. There is no significant hemodynamic response to lidocaine dental anesthesia (with or without epinephrine) in healthy young men.

Anesthesia, Dental↗
PubMed1983

Sympathetic nervous system "switch off" with severe hypothermia.

Hypothermia occurs frequently in the critically ill patient, yet little is known about the endogenous catecholamine response to this stress. To study this problem, we measured heart rate (HR), mean arterial blood pressure (MAP), and plasma levels of norepinephrine (NE) and epinephrine (Epi) in subhuman primates (baboons) during progressive hypothermia from 37 degrees to 29 degrees C and then during rewarming to 37 degrees C. As the core temperature decreased from 37 degrees to 33 degrees C, HR and MAP increased significantly (p less than 0.05), but as core temperature further decreased from 33 degrees to 29 degrees C, the HR and MAP fell to prehypothermic levels. Plasma concentrations of NE and Epi increased significantly (p less than 0.01) as core temperature fell from 37 degrees to 31 degrees C, but as core temperature dropped from 31 degrees to 29 degrees C, plasma NE and Epi levels decreased towards prehypothermic concentrations. These findings indicate that the sympathetic nervous system (SNS) responds quickly to hypothermia but may be "switched off" at a threshold temperature of about 29 degrees C. We speculate that hypotensive patients with temperatures less than or equal to 29 degrees C may benefit from infusions of exogenous catecholamines, especially if there have been only minimal benefits achieved with conventional therapy such as fluids, and an increase in ambient temperature.

Animals↗
PubMed1983

Rat intraperitoneal sepsis--a clinically relevant model.

The pathologic changes in septic shock, a disease state involving several hemodynamic and metabolic parameters, are not completely understood. Because research on animals can provide information vital to treating disease in humans, and because of the increasing constraints on clinical trials with humans, a clinically relevant animal sepsis model has been developed using adult male Sprague-Dawley rats. Sepsis was induced in large numbers of rats by IP injections of discrete quantities of live E coli organisms. The following elements were measured at specific times: MAP, CO, CVP, WBC, platelets, hemoglobin, hematocrit, PT, PTT, fibrinogen, clotting factors, glucose, blood gases, Ca++, Mg++, and TSP. The study shows that the model is easily replicated and relatively inexpensive, and that it can be used for detailed study in rats of several of the pathophysiological states characteristic of sepsis in humans.

Animals↗
PubMed1983

Prostaglandin synthetase inhibitors in endotoxin or septic shock--a review.

Prostaglandins are clearly involved in the pathophysiology of shock in animals and man. Prostaglandin synthetase inhibitors, non-steroidal anti-inflammatory drugs, have been utilized for the past two decades in many animal studies, especially in endotoxin or septic shock, to determine what effects they might have. This review shows that the prostaglandins participate in endotoxin and septic shock and that prostaglandin inhibitors improve circulatory function and survival in a variety of species including the subhuman primate. The exact mechanism by which they exert their beneficial effects remain unknown. The data indicate that prostaglandin inhibitors should be tested in clinical trials in humans in shock-like states.

Animals↗
PubMed1983

Thromboxane synthetase inhibitors in septic shock.

Thromboxane (TX) has been reported to cause mortality in endotoxin or septic shock. Cyclooxygenase inhibition improves survival in gram-negative or gram-positive shock. The exact level in the prostaglandin system of which the protection occurs is unknown. This study was designed to compare the effects of a cyclooxygenase inhibitor (indomethacin, IND) to a thromboxane synthetase inhibitor (IMI) on survival and on the production of Tx and prostacyclin (PGI2) in a clinically relevant rat gram-negative sepsis model. Three groups were studied: 1) control (N = 35) animals received E coli only; 2) IND (N = 35) treated animals received 3 mg/kg IP; 3) IMI (N = 35) treated animals received 30 mg/kg IP. All drugs were given 1 h after an IP injection of E coli (LD70) organisms. In this model only IND significantly improved survival. IND and IMI significantly blocked the production of Tx seen in septic shock. IND blocked PGI2 production whereas IMI increased the production. These results show that Tx may not be important in the irreversible stages of shock. Shunting prostaglandin production to PGI2 with thromboxane synthetase inhibitors needs to be considered when using this group of compounds. The mechanism of protection by IND remains unknown.

Animals↗
PubMed1983

Development of a primate model of exposure hypothermia.

A nonhuman primate model of exposure-induced hypothermia was developed and the hemodynamic effects of hypothermia were evaluated in five animals. With decreasing core temperature from 37 degrees C to 33 degrees C there was a 47% increase in heart rate, a 23% increase in mean arterial pressure, a 48% increase in cardiac output, a 260% increase in oxygen consumption, and a 237% increase in minute ventilation. As the core temperature decreased from 33 degrees C to 29 degrees C there were decreases in the heart rate, blood pressure, and cardiac output such that at 29 degrees C these values were not significantly different from the values obtained at 37 degrees C. However, the oxygen consumption was still 180% increased and the minute ventilation 40% higher at 29 degrees C than at 37 degrees C. This model will allow the evaluation of the physiology of hypothermia and the effectiveness of different rewarming techniques.

Animals↗
PubMed1982

Decreased esophageal peristaltic amplitude in response to prostaglandin E1 and prostacyclin in the baboon.

Prostaglandins have been shown to produce significant decreases in lower esophageal sphincter pressure (LESP), although their effect on esophageal peristalsis is unknown. We studied the effect of infusion of prostaglandin E1 (PGE1) or prostacyclin (PI) on esophageal peristalsis in the proximal and distal esophagus in the awake baboon. Peristalsis was recorded using a polyvinyl catheter and a pneumohydraulic perfusion system and was induced by wet swallows. PGE1 infusion significantly (P less than 0.01) diminished peristaltic amplitude in proximal and distal esophagus by 51% and 77%, respectively. The wave duration was significantly (P less than 0.001) shortened by PGE1 in the distal esophagus, but not in the proximal esophagus. Similarly, prostacyclin significantly (P less than 0.05) decreased peristaltic amplitude in proximal and distal esophagus by 31% and 67%, respectively. As seen with PGE1, PI decreased distal esophageal amplitude significantly (P less than 0.02) more than proximal esophageal amplitude. Equivalent decreases in mean arterial blood pressure seen during prostaglandin infusion were reproduced by bleeding with no changes in measurements of peristaltic activity. Decreased peristaltic wave amplitude and duration suggest that prostaglandins exert a modulating local effect on esophageal muscle. In addition, this effect appears to be more pronounced on distal smooth muscle than on proximal striated muscle in the baboon esophagus.

Administration, Oral↗
PubMed1982

Plasma, urine, and CSF catecholamine concentrations during and after ketamine anesthesia.

Ketamine has been reported to increase plasma catecholamine concentrations. Prior investigations have only studied plasma catecholamine levels for short periods after iv ketamine. Because ketamine is one of the most frequently used anesthetic agents in critical care research, we evaluated ketamine's effect on catecholamines over a longer period of time. Plasma, urine, and CSF epinephrine (E) and norepinephrine (NE) concentrations were serially measured during a 2-h ketamine infusion and a subsequent 2-h "wake-up" period. No changes in heart rate, mean arterial blood pressure or urine, plasma, and CSF NE concentrations were noted during the 4-h study period, whereas there were significant (p less than 0.005) increases in urine, plasma, and CSF E levels during ketamine infusion but not during the wake-up period. An unexpected finding was that the baboons have very high basal plasma E levels versus those in humans. It is concluded that ketamine is a useful anesthetic agent for critical care research involving measurements of sympathetic nervous system activity. The interesting observation of high plasma levels in the baboon warrants further investigation.

Anesthesia↗
PubMed1982

Association of prostacyclin production with resistance of C3H/HeJ mice to endotoxin shock.

Persistence of inflammatory cells in the microcirculation due to altered proportions of arachidonate metabolites could contribute to death from endotoxin (ET) shock. We tested this hypothesis by observing ET-induced cellular accumulations in capillaries of genetically resistant C3H/HeJ and sensitive C3HeB/FeJ mice after challenge with 1,000 micrograms of Salmonella typhi ET, a dose lethal only for the sensitive strain. These data were correlated with prostaglandin production by lung tissue. Six hours after challenge with ET, lung capillaries of sensitive animals were occluded with amorphous material and occasional polymorphonuclear leukocytes (PMNL). This inflammation, along with reduction in alveolar volume, was not observed in resistant mice. At this time only 10 PMNL/high-power field were seen with light microscopy in capillaries of resistant mice compared to 60 PMNL/high-power field in sensitive animals. Lung parenchymal tissue was excised from resistant and sensitive (C3H/HeN) mice six hours postchallenge with 800 micrograms of endotoxin and release in vitro of thromboxane A2 (TXA2) or prostacyclin (PGI2) over a 30-minute period was determined by radioimmunoassay. TXA2 and PGI2 released by lung fragments taken six hours after challenge with ET did not differ from normal levels of these substances in C3H/HeN mice. TXA2 release was normal at six hours in C3H/HeJ mice, but PGI2 was significantly increased (from 2.95 ng/mg to 5.73 ng/mg, P less than 0.005). The ratio of PGI2/TXA2 in resistant mice was 24.3 as compared to 10.3 in sensitive mice. Since PGI2 can reduce leukocyte adhesion, an increase in the ratio of this substance to TXA2 may be associated with resolution of PMNL from the pulmonary microcirculation of ET-resistant mice.

Animals↗
PubMed1982

Vascular reactivity in endotoxin shock: effect of lidocaine or indomethacin pretreatment.

The effects of indomethacin or lidocaine pretreatment on vascular reactivity of endotoxin-shocked rats were examined, using the isolated rat aorta preparation. Contractility was examined in a randomized dose-response manner to both norepinephrine and the prostaglandin endoperoxide analog U-46619. One hour after endotoxin in vivo, there was maximal decrease in contractility to both U-46619 and to norepinephrine. Neither lidocaine nor indomethacin alone significantly altered the log dose-response curve to either agonist. Neither lidocaine nor indomethacin prior to endotoxin altered the log dose-response curve when compared to endotoxin treatment alone. These data indicate that the mechanism of protection afforded by both indomethacin and lidocaine in endotoxin shock models may be independent of the effect of endotoxin on vascular reactivity.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1982

Prevention of endotoxin-induced pulmonary hypertension in primates by the use of a selective thromboxane synthetase inhibitor, OKY 1581.

Endotoxin-induced pulmonary hypertension can be attenuated by nonsteroidal anti-inflammatory drugs and is associated with increased plasma levels of thromboxane (Tx) B2, prostaglandin (PG) F2, PGE and PGI2. Because nonsteroidal anti-inflammatory drugs block prostacyclin production and may also shift arachidonic acid into the lipoxygenase pathway, we have evaluated a selective Tx synthetase inhibitor (OKY 1581) as a means for preventing endotoxin-induced pulmonary hypertension. An LD70 dose of Escherichia coli endotoxin (6 mg/kg) was given i.v. to two groups of unanesthetized baboons. Group I received endotoxin alone and Group II was pretreated with i.v. OKY 1581 (2 mg/kg) 10 min before the endotoxin. OKY 1581 produced a significant decrease in the basal plasma TxB2 from 0.432 +/- 0.82 to 0.147 +/- 0.032 ng/ml (P less than .01), but no significant change in plasma 6-keto PGF1 alpha. After the administration of the endotoxin, Group I developed pulmonary hypertension (from 11 +/- 1 to 19 +/- 2 mm Hg. P less than .005) and an 8-fold increase in plasma TxB2 (P less than .02), whereas Group II did not develop pulmonary hypertension or an increase in plasma TxB2. However, Group II had a 26-fold increase in plasma 6-keto PGF1 alpha (P less than .05). From these studies, we conclude that: 1) OKY 1581 is an effective Tx synthetase inhibitor in vivo; 2) endotoxin-induced pulmonary hypertension is mediated largely by increased Tx; and 3) the inhibition of Tx synthetase results in shunting of endoperoxides into the prostacyclin pathway.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

The role of prostaglandins in sepsis.

The prostaglandins are potent vasoactive fatty acids that are ubiquitously distributed throughout the body. It is now well established that the prostaglandins participate in a variety of pathophysiological processes such as inflammation, burns, renal aspects of hypertension, peptic ulcer disease, diarrhea, skin conditions, vasomotor dysfunctions, platelet abnormalities, dysmenorrhea, fever, and shock. We have previously shown that the prostaglandins appeared to be elevated and were related to the circulatory dysfunction in canine and baboon endotoxin shock. In addition, our studies demonstrated that indomethacin, a prostaglandin synthetase inhibitor, not only inhibited the prostaglandin release and improved the hemodynamic derangements, but also significantly improved the survival. Indomethacin clearly improved the survival in baboon endotoxin shock even when administered after shock had occurred. Since the previous studies were in endotoxin models, the next logical step was to determine the effects of indomethacin in a clinically-relevant rat sepsis model. Two hundred sixty-six male rats (250-500 g) were randomly allocated to saline treated controls or to indomethacin treatment. A pure suspension of live E. Coli organisms (225 X 10(10)/rat) were injected i.p. to each rat. Treatment was introduced at three hours when all blood cultures were positive. Groups were divided into gentamicin (4 mg/kg/rat) alone, gentamicin and indomethacin (3 mg/kg), or indomethacin alone in addition to the saline treated controls. Results showed that indomethacin in combination with gentamicin significantly (p = 0.05) improved the survival at 24 (90%) and 48 hours (90%), when compared with saline treated controls (65%, 45%) and with gentamicin (40%, 40%). Indomethacin alone significantly (p = 0.01) improved the survival. Conclusions are that (i) therapeutic doses of indomethacin or gentamycin clearly improved the survival in a clinically relevant rat sepsis model; (ii) the exact mechanism of protection with indomethacin is unknown; and (iii) indomethacin should be considered for use in human clinical sepsis.

Animals↗
PubMed1982

Improved survival in the suckling rat model of group B streptococcal sepsis after treatment with nonsteroidal anti-inflammatory drugs.

The nonsteroidal anti-inflammatory drugs, indomethacin and ibuprofen, have been shown to increase survival in various animal models of Gram-negative or endotoxin shock. To evaluate the use of these drugs in group B streptococcal sepsis, a clinically similar disease state, a newborn suckling rat model (4 to 5 days old) designed to simulate early-onset group B streptococcal sepsis was used. Sepsis was induced by a subcutaneous injection of group B streptococcal organisms (type III). A mortality ranging from 30% to 90% was used for the study. Indomethacin (3 mg/kg) or ibuprofen (4 mg/kg) treatment was administered by an intraperitoneal injection either at the time of the bacterial injection or after bacteremia (four hours) had occurred. Indomethacin clearly improved survival rates, even when given after bacteremia. Ibuprofen also clearly increased survival when given at the same time as the bacterial injection. Ibuprofen was more effective than indomethacin in the high mortality model (lethal dose for 90% survival of group). These drugs alter mechanisms that may be important in the irreversibility of sepsis and they may become useful adjuvants to our present treatment of early onset group B streptococcal sepsis.

Animals↗
PubMed1981

The role of prostaglandins in endotoxemia and comparisons in response in the nonpregnant, maternal, and fetal models. II. Alterations in prostaglandin physiology in the nonpregnant, pregnant, and fetal experimental animal.

The present study evaluates the response of the nonpregnant ewe, the pregnant ewe, and the fetal lamb with regard to prostaglandin physiology after E. coli endotoxin administration. Baseline levels are reported and response to a stimulator (E. coli endotoxin) and an inhibitor (indomethacin) of prostaglandin synthesis is evaluated. The results reveal that the prostaglandin response to stimulation or inhibition relies upon the baseline levels and that acute alterations of prostaglandin ratios may occur with inhibition of prostaglandin synthesis. The fetus reacts differently than the pregnant and nonpregnant animal and appears to be resistant to the effects of endotoxin, which may be secondary to the elevated baseline fetal prostaglandin levels.

Animals↗