Cardiovascular adaptation to spaceflight.
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Body Fluids↗
Biomedical subjects
C M Lathers
Publications and source records attributed to C M Lathers.
Humans in space: NASA's contributions to medical technology and health care.
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Aerospace Medicine↗
The effect of dilevalol on cardiac autonomic neural discharge, plasma catecholamines, and myocardial beta receptor density associated with coronary occlusion.
Cats anesthetized with alpha chloralose received saline or dilevalol (1 mg/kg, IV) during a 10-minute infusion. Fifteen minutes later, the left anterior descending coronary artery was subjected to coronary occlusion 2 mm below its origin. Regional differences in the beta receptor densities were found for the atria and ventricles and for the areas within the left ventricle in cats with no coronary occlusion and dilevalol or saline. The variation in beta receptor density distribution may be related to functional differences. Coronary occlusion and saline or dilevalol did not modify the myocardial beta receptor density regional distribution. Mean times to arrhythmia and death in five saline cats were 5.8 +/- 3.6 (N = 3) and 5.4 (N = 2) minutes; three cats were killed 6 hours after coronary occlusion. In five dilevalol cats the times to arrhythmia and death were 2.2 +/- 0.8 (N = 5) and 75.9 +/- 70.7 (N = 4); 1 cat was killed. Dilevalol induced a significant decrease in blood pressure and heart rate prior to coronary occlusion. Coronary occlusion decreased blood pressure and heart rate in both groups. Twenty-five minutes after dilevalol but prior to coronary occlusion, postganglionic cardiac sympathetic neural discharge decreased to 81%. In the minutes prior to arrhythmia, postganglionic cardiac sympathetic neural discharge was 95% and was significantly increased to 121% 3 minutes after coronary occlusion. The postganglionic cardiac sympathetic neural discharge values after coronary occlusion were similar to those in the saline cats. Dilevalol depressed postganglionic cardiac sympathetic neural discharge prior to coronary occlusion but did not prevent the nonuniform (i.e., increases, decreases, or no change) discharge in the postganglionic cardiac sympathetic neural discharge associated with coronary occlusion-induced arrhythmia. Norepinephrine and epinephrine values in saline cats increased the first 5 minutes after coronary occlusion; this increase was associated with arrhythmia. Norepinephrine and epinephrine values from minute 15 to minute 360 did not differ from control. Dilevalol prevented the increase in norepinephrine and epinephrine levels associated with arrhythmia and death.
Adrenergic beta-Antagonists↗
Acute and intermediate cardiovascular responses to zero gravity and to fractional gravity levels induced by head-down or head-up tilt.
Determination of early cardiovascular responses to simulated gravity levels between 0 and 1 G will add knowledge of cardiovascular responses to space flight. Cardiovascular responses to 6 hours in a -5 degrees head-down bedrest model of weightlessness (0 G) were compared to those in head-up tilts of +10 degrees, +20 degrees, and +42 degrees (1/6, 1/3, and 2/3 G, respectively). Six healthy young adult males experienced the four angles on separate days. Impedance cardiography was used to measure thoracic fluid index, cardiac output, stroke volume, and peak flow. Although much intersubject variation occurred, the mean thoracic fluid content at -5 degrees decreased during the first hour and remained decreased; 6-hour values were similar to +10 degrees and +20 degrees. Heart rate decreased the first 2 hours for all angles, then increased, converging at 3-4 hours, and reached control by hour 6. Stroke volume decreased for the first 3 hours at -5 degrees, +10 degrees, +20 degrees; values at all four angles converged at hour 3 and increased in unison thereafter. Cardiac output and peak aortic flow reflected the angle at start of tilt; values at all angles converged by the second hour, decreased through the third hour, and increased thereafter. Pulse pressure decreased for the first 3 hours for angles -5 degrees, +10 degrees, and +20 degrees, converged at the fourth hour, and returned to control. Peak flow at +42 degrees was constant for the first 3 hours and increased thereafter. Blood pressure decreased for the first 2 hours, although the greatest decrease occurred at -5 degrees and +42 degrees; thereafter, values at all angles increased in unison and converged at the fourth hour. Total peripheral resistance increased during the first hour at -5 degrees and +20 degrees and decreased from hour 3 to hours 5-6 at the +42 degrees angle. Cardiovascular values were related to tilt angle for the first 2 hours of tilt, but after hour 3 values at all four angles began to converge, suggesting that cardiovascular homeostatic mechanisms seek a common adapted state regardless of effective gravity level (tilt angle) up to 2/3 G.
Bed Rest↗
Instruction in clinical pharmacology: changes in the wind.
We have presented some views on past, present and potential trends for teaching clinical pharmacology in the medical curriculum. Clinical pharmacology as subject matter in the medical curriculum has been operationally defined for our purposes as: (1) the application of fundamental principles of basic pharmacology to rational drug therapy in humans; and (2) the application of appropriate nuances of the human pharmacology of individual drugs to their use in particular disease states. In terms of improving the results of drug therapy, arguments were advanced for the importance of teaching clinical pharmacology at all levels in the medical curriculum and in postgraduate medical education. The introduction of so many new and potent pharmaceuticals over the past 25 years requires well educated and skilled medical practitioners adept and well versed in the fundamental principles of basic and applied pharmacology, so as to achieve the most prudent, effective and economically sound use of these drugs as possible. This creates a challenge to medical educators, particularly those involved in teaching clinical pharmacology, to devise innovative teaching techniques and curricular changes that foster these goals. In an attempt to address these challenges, we have reviewed some innovative teaching approaches and curricular reforms, both published and unpublished, that have already met with success, and we have also discussed some future trends in teaching both undergraduate and graduate physicians the fundamental principles of rational drug therapy. The challenges and issues involved in these future trends have been identified and will be addressed in subsequent articles in this journal. These will be concerned with teaching clinical pharmacology: (1) in basic medical pharmacology courses; (2) to upperclass medical students; and (3) in continuing medical education programs. Subsequent articles will also deal with new and innovative teaching modalities for clinical pharmacology and with the role of the drug industry in these modalities.
Education, Medical↗
An investigation of the pathological and physiological effects of intraosseous sodium bicarbonate in pigs.
Recent interest in the intraosseous (IO) route as an alternative venous access for drug and fluid administration has increased. This study examined the physiological and skeletal pathological effects of IO NaHCO3 in pigs. In the pathological studies, swine (8-10 kg) received NaHCO3 (1 mEq/kg) in one tibia and saline (1 ml/kg) in the other tibia via an 18-gauge spinal needle inserted into the anteromedial surface of the bone. The animals were then observed for one month, sacrificed, and the tibias were isolated, sectioned, and stained for pathological examinations. The physiological effects of IO NaHCO3 infusion were studied and compared with that of intravenous (IV) administration using a cardiac arrest model as previously described. The results demonstrated that NaHCO3 had no effect on the mean arterial blood pressure and plasma catecholamine levels, but increased arterial pH values within two minutes of administration. Similar effects were found with IV NaHCO3. Pathological data indicated signs of minimal local increase in skeletal turnover associated with IO NaHCO3 infusion. It is concluded that the IO route is a safe alternative venous access for NaHCO3 administration in swine.
Animals↗
Teaching clinical pharmacology: coordination with medical pharmacology courses.
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Education, Medical, Undergraduate↗
Acute hemodynamic responses to weightlessness in humans.
As NASA designs space flights requiring prolonged periods of weightlessness for a broader segment of the population, it will be important to know the acute and sustained effects of weightlessness on the cardiovascular system since this information will contribute to understanding of the clinical pharmacology of drugs administered in space. Due to operational constraints on space flights, earliest effects of weightlessness have not been documented. We examined hemodynamic responses of humans to transitions from acceleration to weightlessness during parabolic flight on NASA's KC-135 aircraft. Impedance cardiography data were collected over four sets of 8-10 parabolas, with a brief rest period between sets. Each parabola included a period of 1.8 Gz, then approximately 20 seconds of weightlessness, and finally a period of 1.6 Gz; the cycle repeated almost immediately for the remainder of the set. Subjects were semi-supine (Shuttle launch posture) for the first set, then randomly supine, sitting and standing for each subsequent set. Transition to weightlessness while standing produced decreased heart rate, increased thoracic fluid content, and increased stroke index. Surprisingly, the onset of weightlessness in the semi-supine posture produced little evidence of a headward fluid shift. Heart rate, stroke index, and cardiac index are virtually unchanged after 20 seconds of weightlessness, and thoracic fluid content is slightly decreased. Semi-supine responses run counter to Shuttle crewmember reports of noticeable fluid shift after minutes to hours in orbit. Apparently, the headward fluid shift commences in the semi-supine posture before launch. is augmented by launch acceleration, but briefly interrupted immediately in orbit, then resumes and is completed over the next hours.
Adult↗
The relationship of the lock-step phenomenon and precipitous changes in mean arterial blood pressure.
The lock-step phenomenon (LSP) is the occurrence of postganglionic cardiac sympathetic discharge (PCSD) and cortical epileptiform activity (EA) in a time-locked fashion. The relationship between the LSP and precipitous changes in blood pressure (PCBP: greater than 23 mm Hg in 10 sec) was determined in 9 cats after EA was induced with pentylenetetrazol following pretreatment with phenobarbital (20 mg/kg, i.v.). Electrocorticogram (ECoG), PCSD, lead II EKG, and mean arterial blood pressure (MAP) were monitored. Since an interspike interval of 2.8 sec was frequently found to exist between ECoG spikes when the LSP was present, 4 categories of LSP were defined: LSP absent; stable LSP with 2.8 sec interval; stable LSP without 2.8 sec interval; and unstable LSP with increasing or decreasing rates of discharge. The duration of each LSP pattern and the proportion of time spent in PCBP were determined. A one-way repeated measures ANOVA and the Newman-Keuls post-hoc test showed that a higher mean proportion of time spent in PCBP was associated with the unstable LSP pattern (P less than 0.05). The LSP and associated patterns as related to precipitous changes in MAP are indicators of changes in autonomic function. Autonomic dysfunction with EA, causing cardiac arrhythmias, has been postulated as a cause of sudden unexplained death (SUD) in persons with epilepsy. Thus, an understanding of the autonomic changes, as indicated by PCBP associated with LSP, may contribute to the understanding and prevention of SUD in persons with epilepsy.
Animals↗
Pharmacology in space. Part 1. Influence of adaptive changes on pharmacokinetics.
The topic of pharmacology in space, i.e. the administration of drugs during space flight and the subsequent pharmacokinetic handling of the pharmaceuticals, is a new field about which little is known. In a two-part series, Claire Lathers and colleagues highlight some of the current questions in this field. In this first article the physiological and biochemical changes associated with weightlessness in space are discussed. These changes induce adaptive alterations which may influence the pharmacokinetic properties of drugs. The cardiovascular system is of particular relevance here. Also discussed are the classes of pharmacological agent that are most likely to be used during space flight for medical problems and thus, by necessity, will become drugs to be examined in space to determine whether their pharmacokinetic and pharmacodynamic properties are altered. Therapy of the most common spaceflight ailment-motion sickness-will be considered next month in Part 2.
Humans↗
Pharmacology in space. Part 2. Controlling motion sickness.
In this second article in the two-part series on pharmacology in space, Claire Lathers and colleagues discuss the pharmacology of drugs used to control motion sickness in space and note that the pharmacology of the 'ideal' agent has yet to be worked out. That motion sickness may impair the pharmacological action of a drug by interfering with its absorption and distribution because of alteration of physiology is a problem unique to pharmacology in space. The authors comment on the problem of designing suitable ground-based studies to evaluate the pharmacological effect of drugs to be used in space and discuss the use of salivary samples collected during space flight to allow pharmacokinetic evaluations necessary for non-invasive clinical drug monitoring.
Humans↗
Plasma catecholamines, pH, and blood pressure during cardiac arrest in pigs.
This study examined plasma epinephrine (E) and norepinephrine (NE) concentrations, pH, and mean arterial blood pressure (MAP) in a cardiac arrest model. Twenty-three domestic swine (15-26 kg) were anesthetized with ketamine 20 mg/kg, i.m. and alpha-chloralose 25 mg/kg, i.v. and ventilated with a respirator. Catheters were placed in the right ventricle, left ventricle and femoral arteries for MAP recordings and blood pH sampling every 2 min. Catecholamine samples were taken from the femoral artery every 2 min. Cardiac arrest was induced by endocardial stimulation with a Grass S88 stimulator. Five minute post arrest resuscitation was initiated with a mechanical resuscitator. Ten minute post arrest NaHCO3 1 mEq/kg was administered by the peripheral i.v. (P; n = 6), central (CE; n = 5), or intraosseous, via the tibia, (I; n = 6), route. Controls (C; n = 6) did not receive NaHCO3. MAP (mean +/- S.D.) prior to arrest was: C 144 +/- 16, P 139 +/- 11, CE 137 +/- 13 and I 133 +/- 11 mmHg. Five and 25 min post arrest it was: C 21 +/- 5 and 17 +/- 6, P 34 +/- 8 and 23 +/- 7, CE 17 +/- 7 and 14 +/- 10 and I 26 +/- 6 and 11 +/- 3 mmHg, respectively. A 2-way analysis of variance did not reveal any difference in MAP values in the four groups. In all groups the blood pH from the femoral artery demonstrated a respiratory alkalosis that peaked at approximately 7.48 5 min after initiation of mechanical resuscitation. In the groups receiving NaHCO3, it peaked at 7.77 +/- 0.09 CE and 7.65 +/- 0.06 P 2 min post infusion and at 7.71 +/- 0.06 I 8 min post infusion. An analysis of variance revealed that the CE and I routes were significantly different (P less than 0.05) from the P group and that all three groups were different (P less than 0.05) from the C. Plasma E and NE concentrations at 0, 6, 10, 12, 20 and 30 min post arrest in the C group were, respectively: 3 and 10, 94 and 327, 119 and 329, 92 and 234, 33 and 135, and 127 and 62 ng/ml, respectively. All 3 groups receiving NaHCO3 demonstrated similar patterns and were not significantly different from C when compared with a 2-way analysis of variance.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Intraosseous crystalloid and blood infusion in a swine model.
The technique of intraosseous infusion has attracted increasing interest in recent years, and has proven valuable for drug administration. This study was undertaken to determine whether it was also a potential route for fluid resuscitation. Thirteen- or eighteen-gauge tibial intraosseous needles were placed in eight "large" (mean weight, 14.4 kg) and eight "small" (mean weight, 5.8 kg) swine and the flow rate of blood and saline measured under gravity and 300 mm Hg. Flow was significantly greater using 13-gauge needles in the "large" swine, significantly greater for saline than for blood, and for pressure infusion versus gravity in all animals. A fluid bolus of 20 ml/kg could be given to all animals in less than 10 minutes using pressure infusion. These data suggest that intraosseous infusion is a reasonable initial step in fluid resuscitation of pediatric subjects until more conventional vascular access has been established.
Animals↗
Does chlorpromazine produce cardiac arrhythmia via the central nervous system?
The influence of the central nervous system in the production of phenothiazine-induced arrhythmia and death was examined in this study. In a series of cats, spinal cords were transected at the atlanto-occipital junction prior to the 1 mg/kg/min, i.v. infusion of chlorpromazine or thioridazine. No protection against drug-induced arrhythmia or death was afforded by this procedure. In other cats, 6OH-dopamine was administered prior to intravenous injection of atropine and infusion of chlorpromazine, 1 mg/kg/min. In these in situ denervated heart preparations, there was no protection against chlorpromazine-induced arrhythmia or death. In alpha-chloralose anesthetized cats, 0.5 mg chlorpromazine administered intracerebroventricularly did not induce arrhythmia or death, although blood pressure decreased initially. Thus, chlorpromazine or thioridazine do not appear to produce arrhythmia or death via a central locus and may instead be acting directly on myocardial conduction to produce arrhythmia and death.
Animals↗
The effect of timolol given five minutes after coronary occlusion on plasma catecholamines.
The reported study determined whether timolol would afford a protective effect by preventing the coronary occlusion-induced arrhythmias associated with the increase in plasma norepinephrine (NE) and epinephrine (E). Ten anesthetized cats received saline or timolol (5 mg/kg, IV) five minutes after coronary occlusion of the left anterior descending coronary artery 10 to 14 mm below its origin. Coronary occlusion produced arrhythmia in three of the cats that received saline and in four of the cats that received timolol. Three of the saline-treated cats died in cardiogenic shock; two were sacrificed six hours postocclusion. Four of the timolol-treated cats died in congestive heart failure postcoronary occlusion. There was a gradual increase in NE (P greater than .05) and E (P less than .05) in both groups after coronary occlusion. Death produced a significant increase in NE and E levels. Timolol did not modify the occurrence of arrhythmias and the associated increase in plasma NE and E that developed after coronary occlusion and at death.
Animals↗
Cocaine-induced seizures, arrhythmias and sudden death.
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Arrhythmias, Cardiac↗
The effect of chronic timolol in an animal model for myocardial infarction.
The effect of no drug or timolol (5 mg/kg, PO, for 1, 2, or 8 weeks on postganglionic cardiac sympathetic neural discharge, blood pressure, heart rate and beta-receptor density after acute coronary occlusion of the left anterior descending artery was compared. Beta-receptor density, determined by binding of 3H-dihydroalprenolol, was examined in the myocardium (LA = left atrium, RA = right atrium, LV1 = proximal and LV2 = distal left anterior descending artery distribution, LV3 = posterior left ventricle, S = septum, and RV = right ventricle). In control cats (no coronary occlusion or timolol) beta-receptor density of LV2 and LV3 was greater (P less than .05) than LA, RA, LV1, and RV. LV3 was greater (P less than .05) than S and RA, and LA was less than S. Longer treatment with timolol increased beta-receptor density. When compared with no timolol, beta-receptor density was greater in RA after 8 weeks and in LV1 after 2 weeks and not different in LV2 and S. Beta-receptor density and LV3 and RV were greater after 8 weeks than after 1 week or no timolol. Spearman rank correlation coefficients between dose and beta-receptor density revealed an increase (P less than .05) for all heart areas. Heart rate did not vary before timolol and was decreased after all doses of timolol. Timolol increased the mean times to coronary occlusion-induced death although the increase was not statistically significant. Timolol did not prevent postganglionic cardiac sympathetic neural discharge associated with arrhythmia. Timolol may increase beta-receptor density and decrease synaptic norepinephrine, causing a decreased release per cardiac sympathetic nerve impulse. Alternatively, molecules of timolol may accumulate in nerve endings and be released in greater concentrations at the receptors. This could explain the protection against coronary occlusion-induced arrhythmia and death.
Anesthesia↗
Suppression of pentylenetetrazol-elicited seizure activity by intraosseous propranolol in pigs.
The intraosseous (IO) route provides a rapid and effective alternative venous access in the pediatric population when the conventional intravenous (IV) route cannot be easily obtained. DL-propranolol, a beta-adrenoceptor antagonist, exhibits antiepileptic activity in various animal seizure models. This study assessed the efficacy of IO propranolol in suppressing pentylenetetrazol (PTZ)-induced seizure activity in pigs. Domestic swine (13-20 kg) were prepared for recordings of arterial blood pressure, ECG and electrocortical activity. Seizure activity was induced by pentylenetetrazol (PTZ; 100 mg/kg; IV). Sixty seconds after the onset of seizure activity, the animals either received no drug (control) or propranolol (IV or IO via an 18-gauge spinal needle placed in the right proximal tibia). A transient increase (16.3-50.0%) in the mean arterial blood pressure (MAP) was observed following PTZ administration. Both IO and IV propranolol significantly suppressed the seizure duration (SD) (sec/min interval) at 1 min following drug administration; SD control, 36.3 +/- 4.8; IV propranolol, 12.3 +/- 5.1; IO propranolol, 18.3 +/- 6.0. In addition, both IV and IO propranolol produced a maximal decrease of 32-38% in the basal heart rate; and reduced the transient increase in MAP elicited by PTZ, with no significant effect on the basal MAP. The data demonstrate that 1) propranolol possesses anticonvulsant activity against PTZ-induced seizure in the pig, and 2) the intraosseous route is a rapid and effective alternative venous access for propranolol administration in swine.
Animals↗