Claire Lathers

Cardiovascular adaptation to spaceflight

Data are presented on the rate of adaptation of the human cardiovascular system to conditions of spaceflight, with particular attention given to data obtained during spaceflight in the U.S. Space Shuttle Program. It is pointed out that many of the cardiovascular changes that occurred during spaceflights that lasted from 2 to 11 days can be traced directly to changes in the body fluid volume. The beneficial effects of a fluid loading countermeasure (oral rehydration) and of the supine body position on the heart rate during the spaceflight are demonstrated. It is noted that, after hours or a few days of spaceflight, a state of adaptation is reached, in which the subject is well adapted and appropriately hydrated for the weightless environment. However, the return to the normal gravity of the earth leaves the individual especially sensitive to orthostatic stress.

Stress and sudden death

Cardiac patients, psychiatric patients, and certain ethnic groups experiencing acute stressful circumstances are at risk for unexpected sudden death. Although stress is associated with changes in autonomic neural function, its role as a potential risk factor for sudden unexpected death in epilepsy (SUDEP) is not known. The association of epilepsy with cardiac abnormalities, such as neurogenic arrhythmias and microscopic perivascular and interstitial fibrosis, and with depression and anxiety indicates that emotional stress should be evaluated as a potential risk factor for SUDEP. The impact of adverse emotional states on the autonomic control of cardiac rhythm is a known important factor leading to cardiac dysrhythmias in humans and other species. The interaction between emotional factors and the arrythmogenic potential of epileptiform discharges and the possibility of benefit from stress management intervention need to be investigated.

The mystery of sudden death: Mechanisms for risks

This review addresses the possible overlapping mechanisms that may apply to the risk of sudden unexpected death occurring in epilepsy and in cardiac disease. It explores the interaction between the central and peripheral autonomic nervous systems and the cardiopulmonary systems. Included is a discussion of the potential interactive role of genetically determined subtle cardiac risk factors for arrhythmias with a predisposition for seizure-related cardiac arrhythmias. We address the possible mechanisms that are operant in producing both epileptogenic and cardiogenic arrhythmias. Finally, we speculate about potential preventive measures to minimize the risk of both sudden unexpected death in epilepsy and sudden cardiac death.

Role of Veterinary Medicine in Public Health: Antibiotic Use in Food Animals and Humans and the Effect on Evolution of Antibacterial Resistance

Veterinary public health is another frontier in the fight against human disease. The veterinary public health scope includes the control and eradication of zoonoses, diseases that are naturally transmitted between vertebrate animals and man. These diseases pose a continuous hazard to the health and welfare of the public. More than 100 diseases are categorized as zoonoses, including salmonellosis. It is important to understand how antibiotics are used in humans and in food animals and how these uses affect the evolution of antibacterial resistance. Appropriate use of antibiotics for food animals will preserve the long‐term efficacy of existing antibiotics, support animal health and welfare, and limit the risk of transfer of antibiotic resistance to humans. An understanding of the epidemiology of antimicrobial resistance allows development of preventive strategies to limit existing resistance and to avoid emergence of new strains of resistant bacteria. Risk assessments are being used by the Center for Veterinary Medicine at the U.S. Food and Drug Administration as regulatory tools to assess potential risk to humans resulting from antibiotic use in food‐producing animals and to then develop microbial safety policies to protect the public health. The veterinary public health scope, in addition to the control and eradication of zoonoses, also includes the development and supervision of food hygiene practices, laboratory and research activities, and education of the public. Thus, it may be seen that there are many ways in which veterinary medicine plays a very important role in public health.

Clinical Pharmacology of Antimicrobial Use in Humans and Animals

Veterinary public health is a frontier in the fight against human disease, charged to control and eradicate zoonotic diseases that are naturally transmitted between vertebrate animals and man. Currently there is a need for clinical pharmacologists and all health care givers to limit the development of bacterial resistance in humans to contain the increased health care expenditures related to morbidity and mortality associated with the use of antimicrobials. The development of resistance predates the use of antibiotics and will always be a problem to the successful treatment of patients. Ongoing discussion debates the extent to which antibiotic use in animals contributes to the development of antibiotic resistance in humans. The veterinary use of antibiotics as antimicrobial growth promoters is thought to influence the prevalence of resistance in animal bacteria and to be a risk factor for the emergence of antibiotic resistance in human pathogens. Transfer of antibiotic resistant bacteria from animals to humans may occur via contact, including occupational exposure and via the food chain. Resistance genes may transfer from bacteria of animals to human pathogens in the intestinal flora of humans. Prevention of the development of resistance in humans necessitates good animal husbandry and hygienic measures to prevent cross contamination and a decrease in the use of antibiotics. Appropriate use of antibiotics for food animals will preserve the long‐term efficacy of existing antibiotics, support animal health and welfare, and limit the risk of transfer of antibiotic resistance to humans. Investigators must also develop new antimicrobial agents. Poole (J Pharmacy Pharmacol 2001;53:283) recommends targeting the three predominate mechanisms of development of resistance by antimicrobials (i.e., antibiotic inactivation, target site modification, and altered uptake via restricted entry and/or enhanced efflux) to specifically complement the development of novel agents with novel bacterial targets. Bacterial resistance and its selection may be evaluated by comparing the relationship to antibiotic pharmacokinetic (PK) values obtained from serum concentrations and organism MICs (minimum inhibitory concentrations; concentration‐dependent killing) to reveal culture and sensitivity tests in patients. Pharmacodynamic (PD) models maybe developed to identify factors associated with the probability that bacterial resistance will develop. Thomas et al (Antimicrobial Agents Chemotherapy 1998;42:521) used this combined approach of PK/PD and MICs to examine data retrospectively. The role of clinical pharmacology is to work with PK/PD models such as these to determine the best use of antibiotics in humans to minimize the development of resistance. The role of any regulatory body responsible for the protection of the public health and food safety for consumers is to assess risk and to then communicate and manage the risk. Scientific uncertainty must be interpreted to propose sound policy options. The conversion of sound science into an appropriate regulatory policy to protect the public health is most important.

Acute Hemodynamic Responses to Weightlessness During Parabolic Flight

Pilots and astronauts experience fluid shifts in variable gravity. Acute effects of fluid shifts on the cardiovascular system were monitored on NASAs KC‐135 aircraft during parabolic flight The variability of R‐R intervals in the electrocardiogram was measured as an indication of vagal cardiac neural activity. R‐R intervals were measured during the gravity transition from 2‐G to 0‐G produced by parabolic flight to assess the involvement of the autonomic nervous system in regulating the acute effects of fluid shifts. In seven subjects, a BoMed noninvasive continuous cardiac output monitor (NCCOM 3) monitored thoracic fluid index (TFI, ohms), heart rate (bpm), and cardiac output (1/min). Data were stored on a lap‐top computer with the subject in one of four postures: sitting, standing, supine, and semi‐supine, during one of four sets of eight to ten parabolas. Five seconds of data were averaged: before parabola onset (1.3‐G); parabola entry (1.9‐G); 0‐G; and parabola exit (1.7‐G). Three to eight parabolas were averaged for subjects in each posture; the mean for each posture was calculated. In each of five additional subjects, the coefficient of variation was calculated by dividing mean value by the standard deviation of 3 to 15 R‐R intervals. Eight to ten parabolas were averaged for each postural set. Compared with values collected before 0‐G, standing values during 0‐G showed that the thoracic fluid index decreased 2.5 ohms, heart rate decreased 22 bpm, and cardiac output increased 1 L/min. During sitting, thoracic fluid index decreased 1.25 ohms, heart rate decreased 10 bpm, whereas cardiac output increased 0.5 L/min. In the supine position, thoracic fluid index and heart rate were constant whereas cardiac output decreased 0.55 L/min. In the semi‐supine position, thoracic fluid index and heart rate were constant. Compared with values collected from 2‐G and 0‐G the coefficient of variation increased 66.4% in the standing position, 53.4% in the sitting position, and 43.3% in the semi‐supine position and decreased 11.6% in the supine position. The data indicated that cardiovascular changes are dependent on posture and gravity. During the four sets of parabolas in the four different postures, the greatest and smallest changes were observed in the standing and supine positions, respectively, during 0‐G. Fluid shifts from the legs to the thorax occurred during 0‐G in the supine and standing positions. The high values of the coefficient of variation at the onset of 0‐G suggest that vagal cardiac neural activity increases, but not significantly, in all positions except supine.

Effect of Phenobarbital Pretreatment on Cardiac Neural Discharge and Pentylenetetrazol-Induced Epileptogenic Activity in the Cat

The effect of phenobarbital on autonomic function associated with ictal discharges and interictal spikes (IS) was examined. Phenobarbital (20 mg/kg, i.v.) was infused over 10 min; 1 h later, pentylenetetrazol (PTZ) 10, 20, 50, 100, 200, and 2,000 mg/kg was given intravenously at 10-min intervals. 10 mg/kg PTZ produced IS in only 3 of 9 phenobarbital-pretreated cats; when used alone, 10 mg/kg of PTZ produced IS in 8 of 9 cats. Ictal discharges first appeared at 20 mg/kg PTZ in 6 of 9 phenobarbital-pretreated cats; all 9 cats receiving only PTZ exhibited ictal discharges after 20 mg/kg. Phenobarbital pretreatment depressed heart rate, blood pressure and postganglionic cardiac sympathetic neural discharge. Maximal ictal discharges in the cats pretreated with phenobarbital occurred with 100 mg/kg PTZ. This discharge was associated with a 10 mm Hg increase in blood pressure and a slight decrease in heart rate, followed by a subsequent return to baseline. The concurrent sympathetic neural discharge increased. When maximal ictal discharges occurred in the cats receiving PTZ alone, blood pressure, heart rate, and sympathetic neural discharge increased significantly. Cardiac vagal neural discharge was not altered after PTZ even in phenobarbital-pretreated cats. Although phenobarbital suppressed PTZ-induced epileptogenic activity and the associated changes in blood pressure and heart rate, a X2 test indicated no significant difference in the incidence of arrhythmias between the two groups. Since phenobarbital did not prevent the changes in cardiac neural discharge and the arrhythmias associated with epileptogenic activity, its effectiveness in decreasing autonomic dysfunction is questionable.

Verbal autopsies and SUDEP

There is a problem in defining the occurrence of sudden unexplained death in persons with epilepsy (SUDEP). The diagnosis of SUDEP in the United States is under-used as many do not use the term on the death certificate. SUDEP is found to be more prevalent worldwide than assumed. However, data for developing countries, which are even more limited than those for Europe and North America, and do not depend on the use of autopsies, indicate that SUDEP is an underreported cause of death in persons with epilepsy. To glean information about the circumstances of the sudden death event in epilepsy, the verbal autopsy may be used, that is, talking with family members and/or close friends of the patient who has died unexpectedly. In contrast to developing countries, where verbal autopsy may be the only means of establishing a possible or probable cause of death, the technique of verbal autopsy may have a different use in more affluent countries. It is a defined technique to help clarify questions not answered by the standard methods of coroner and postmortem reports and not available in medical records. The purpose of verbal autopsy can be multifaceted. When used in conjunction with postmortem autopsy data on persons who die from SUDEP, it can focus on retrospective data that provide additional help in identifying more accurately the cause of death and in conducting retrospective analysis of these postmortem examinations. The value of these cumulative data from all sources is that they provide information for future preventative policy. In circumstances where postmortem information is not or cannot be collected, verbal autopsies offer a method to find information regarding the cause of death, whether conducted in developing countries or in developed countries. In either case, the worldwide database on persons with epilepsy who die suddenly and unexpectedly will gain information that will help in determining the prevalence of SUDEP and contribute to the quest for identification of preventive interventions.

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.

Summary of lower body negative pressure experiments during space flight

This paper summarizes the lower body negative pressure experiments performed in space, beginning with the experiments conducted on Skylab, because this program provided the most cardiovascular physiology data for United States space flight. Data obtained during studies of lower body negative pressure for use as a countermeasure after months of Russian space flight are also presented. Lower body negative pressure experiments conducted aboard Space Shuttle flights provide data about the deadaptation response of the cardiovascular system to orthostatic stress occurring during periods of zero gravity, and about protection against postflight orthostatic intolerance. Data obtained using Russian and American lower body negative pressure devices indicate that, when a crew member stands, as opposed to being supported by a seat or saddle as in the American device, there may be a slight detrimental effect in terms of the cardiovascular response to this orthostatic stress. Comparison of heart rate and blood pressure response to entry and landing of the Shuttle indicate that, although lower body negative pressure is a different stress and is applied in a different manner, the maximum heart rates during lower body negative pressure are reached at approximately the same point that the maximum heart rates are reached during entry and landing. Thus, the use of a lower body negative pressure stress in flight is a fairly good predictor of the cardiovascular response to the actual entry and landing of the Shuttle.