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Biomedical subjects

J Ludbrook

Publications and source records attributed to J Ludbrook.

At least 19 recordsLinked to original sources
PubMed1998

Correction of hypovolemic hypotension by centrally administered naloxone in conscious rabbits.

Our goal was to test directly whether the vasoconstrictor action of naloxone during hypovolemic hypotension is centrally mediated. In eight chronically instrumented rabbits, progressive central hypovolemia and fall in cardiac output (CO) were produced by gradually inflating a cuff on the thoracic vena cava. Central hypovolemia was then sustained for 8 min by holding CO constant. In the main experiment (n = 4), each rabbit was studied eight times over 4 experimental days. Saline or naloxone treatment commenced 10 min before progressive hypovolemia (early treatment) or 2 min after the onset of sustained hypovolemia (late treatment), given by intravenous infusion or into the fourth ventricle (V4). With saline treatment, there was spontaneous recovery of systemic vasoconstriction and arterial pressure during sustained hypovolemia. Late treatment with naloxone (4 mg/kg i.v.; 4-37 micrograms/kg V4) accelerated and exaggerated these changes. Thus, under conditions of constant CO and central blood volume, the vasodilatation of the decompensatory phase of acute hypovolemia is not sustained, and intravenous nalox one's vasoconstrictor action is via a brain stem mechanism.

Animals↗
PubMed1997

Comparing methods of measurements.

1. The purpose of comparing two methods of measurement of a continuous biological variable is to uncover systematic differences not to point to similarities. 2. There are two potential sources of systematic disagreement between methods of measurement: fixed and proportional bias. 3. Fixed bias means that one method gives values that are higher (or lower) than those from the other by a constant amount. Proportional bias means that one method gives values that are higher (or lower) than those from the other by an amount that is proportional to the level of the measured variable. 4. It must be assumed that measurements made by either method are attended by random error: in making measurements and from biological variation. 5. Investigators often use the Pearson product-moment correlation coefficient (r) to compare methods of measurement. This cannot detect systematic biases, only random error. 6. Investigators sometimes use least squares (Model I) regression analysis to calibrate one method of measurement against another. In this technique, the sum of the squares of the vertical deviations of y values from the line is minimized. This approach is invalid, because both y and x values are attended by random error. 7. Model II regression analysis caters for cases in which random error is attached to both dependent and independent variables. Comparing methods of measurement is just such a case. 8. Least products regression is the reviewer's preferred technique for analysing the Model II case. In this, the sum of the products of the vertical and horizontal deviations of the x,y values from the line is minimized. 9. Least products regression analysis is suitable for calibrating one method against another. It is also a sensitive technique for detecting and distinguishing fixed and proportional bias between methods. 10. An alternative approach is to examine the differences between methods in order to detect bias. This has been recommended to clinical scientists and has been adopted by many. 11. It is the reviewer's opinion that the least products regression technique is to be preferred to that of examining differences, because the former distinguishes between fixed and proportional bias, whereas the latter does not.

Animals↗
PubMed1996

Roles of carotid baroreceptor and cardiac afferents in hemodynamic responses to acute central hypovolemia.

When central blood volume is progressively reduced, there is a biphasic hemodynamic response. In phase I, sympathetic vasoconstrictor drive and systemic vasoconstriction steadily increase so arterial pressure is well maintained. In phase II, these compensatory mechanisms fail abruptly. The origin of the signal that triggers the onset of phase II is unclear. In this study of conscious rabbits, we have compared the responses of arterial pressure, systemic vascular conductance, the heart rate with acute central hypovolemia produced by gradual constriction of the inferior vena cava with those resulting from graded reduction in carotid sinus pressure, with the input from carotid baroreceptors and cardiac afferents present or absent. We confirm that the compensatory changes in phase I are due to input from arterial baroreceptors with no contribution from cardiac afferents. Input from cardiac afferents played an important role in triggering phase II during acute central hypovolemia, but there was no suggestion of a central switch from sympathoexcitation to sympathoinhibition when input from carotid baroreceptors reached a critically low level during carotid constriction.

Animals↗
PubMed1995

L-Arginine reverses the abolition of hypovolaemic decompensation by N-nitro-L-arginine methyl ester and naloxone in conscious rabbits.

Graded caval occlusion in conscious rabbits caused a biphasic haemodynamic response. Phase I was characterized by a fall in systemic vascular conductance so that arterial pressure was maintained. When cardiac output had fallen to 65 +/- 2% of its baseline level, phase II supervened. During phase II, conductance rose abruptly and arterial pressure fell to a life-threatening level (< or = 40 mm Hg). Fourth ventricular administration of either N-nitro-L-arginine methyl ester or naloxone prevented the occurrence of phase II. Fourth ventricular administration of L-arginine had no effect on the response to graded caval occlusion but was able to reverse the phase II blocking action of N-nitro-L-arginine methyl ester and naloxone. It is concluded that central nitrergic and opioid mechanisms interact to cause the vasodilatation characteristic of the decompensatory phase II of the cardiovascular response to acute hypovolaemia.

Animals↗
PubMed1995

N-nitro-L-arginine methyl ester blocks the decompensatory phase of acute hypovolaemia in conscious rabbits by a brainstem mechanism.

Graded caval occlusion in conscious rabbits caused a biphasic response. Phase I was characterized by a fall in conductance so that arterial pressure was maintained. When cardiac output had fallen to 71 +/- 4% of its baseline level, phase II supervened. During phase II, conductance rose abruptly and arterial pressure fell to a life threatening level (< 40 mm Hg). When administered into the fourth ventricle, the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester prevented the onset of phase II. The mean threshold dose for this effect was 4 mumol (range: 0.4-11). When administered intravenously, a dose of 275 mumol N-nitro-L-arginine methyl ester prevented the onset of phase II in only one out of six rabbits. It is concluded that a central brainstem nitrergic mechanism is involved in the onset of the decompensatory phase II of the haemodynamic response to hypovolaemia.

Analysis of Variance↗
PubMed1995

ACTH-(1-24) blocks the decompensatory phase of the haemodynamic response to acute hypovolaemia in conscious rabbits.

Graded caval occlusion in conscious rabbits caused a biphasic cardiovascular response. Phase I was characterized by a fall in systemic vascular conductance so that arterial pressure was maintained. When cardiac output had fallen to 64 +/- 3% of its baseline level, phase II supervened. During phase II, conductance rose abruptly and arterial pressure fell to a life-threatening level (< 40 mm Hg). Intravenous (i.v.) or central (fourth ventricular) administration of the adrenocorticotrophin (ACTH) fragment ACTH-(1-24) prevented the occurrence of phase II. The central dose of ACTH-(1-24) needed to block the occurrence of phase II was approximately 39 times less than the i.v. dose. Central administration of the delta 1-opioid receptor agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) reversed this effect of both central and i.v. ACTH-(1-24). I.v. ACTH-(1-24) also lowered arterial pressure while raising cardiac output and vascular conductance. These effects were insensitive to propranolol and hyoscine methyl bromide, and were not mimicked by cortisol or adrenaline. It is concluded that ACTH-(1-24) has an acute, adrenal-independent, peripheral vasodilator effect as well as a central, anti-shock, effect.

Animals↗
PubMed1995

Haemodynamic response to simulated haemorrhage in the rabbit: interaction of i.v. anaesthesia and hypoxia.

We have studied in eight rabbits the cardiovascular effects of midazolam, propofol and alfentanil with graded hypoxia. Central blood volume was reduced progressively by gradual inflation of a thoracic vena cava cuff so that cardiac index (CI) decreased at a constant rate. Under control conditions the haemodynamic response was biphasic. During phase I, mean arterial pressure (MAP) was maintained by a progressive decrease in systemic vascular conductance (SVCI). When CI had declined to a critical level, phase II occurred with an abrupt increase in SVCI and decrease in MAP. Phase I was prolonged by hypoxia, alfentanil and midazolam, but the effects were not additive. Phase I was shortened by propofol and this effect increased with hypoxia. The gradient of the SVCI response in phase I was also reduced by propofol > midazolam, but not by alfentanil. The occurrence of phase II was less frequent during alfentanil infusion than midazolam and propofol with all of the inspired gas mixtures. Thus the opioid was protective against circulatory collapse with hypoxia and simulated hypovalaemia.

Alfentanil↗
PubMed1995

Microcomputer statistics packages for biomedical scientists.

1. There are hundreds of commercially available microcomputer statistics packages, ranging from the very cheap and elementary to the very expensive and complex, and from the very general to the very specialized. This review covers only those that appear to be popular with biomedical investigators who deal with fairly small sets of data but may wish to use relatively complex analytical techniques. 2. It is highly desirable, if not essential, that biomedical investigators who use microcomputer statistics packages have access to a spreadsheet program. These provide sample statistics and simple statistical analyses but, more importantly, they are often the best way of entering data into the files of the statistics packages proper. 3. A vital component of any statistics package is its manual. This should be easy to follow, but at the same time it must provide full documentation of, and references to, precisely how the various statistical tests are performed. 4. Some packages are elementary and offer only a narrow range of test procedures (mini-packages). Some are designed to be used as statistical libraries and programming tools for professional statisticians. Between these extremes are the general purpose packages (mid-range, maxi- and supermaxi-packages) that constitute the main body of this review. 5. All the packages reviewed have some shortcomings or flaws. It is argued that the ideal package for biomedical investigators should have the following features: (i) it should provide a wide range of test procedures for analysing continuous, rank-ordered, and categorical data; (ii) the way in which these tests are carried out should be clearly stated in the manual; and (iii) lastly, although not unimportantly, the package should be easy to use. 6. It is recommended that biomedical investigators purchase a package that provides many more statistical routines than they use in their everyday practice. Provided the manual is a good one and the package itself has no serious flaws, this is an excellent stimulus to continuing education in statistical techniques.

Humans↗
PubMed1995

Issues in biomedical statistics: comparing means by computer-intensive tests.

In this review there are described two alternatives to classical tests for distinguishing means. These are called computer-intensive because they can only be performed on fast computers. Permutation procedures have the virtue in that they are easy to understand, they can be employed to analyse small sets of experimental data, and under the randomization model of inference (though not the population model) they require no assumptions except that the experimental groups have been constructed by randomization. Bootstrap procedures are designed for use under the population model of inference (though not the randomization model) and are best suited to larger sets of experimental data. Non-parametric bootstrapping requires populations to be sampled randomly, but it depends on no prior assumptions about the distributions of those populations. It is argued that if randomization rather than random sampling has been done, permutation tests are superior to the classical t and F tests for detecting differences between means and therefore should replace them. If random sampling has been done, non-parametric bootstrap techniques may prove to be superior to classical tests for constructing population confidence intervals or testing hypotheses. However, their accuracy, especially for hypothesis-testing and when samples are small, has yet to be firmly established and there is a dearth of commercial software with which they can be executed on personal computers.

Computer Simulation↗
PubMed1995

Issues in biomedical statistics: comparing means under normal distribution theory.

The test used most commonly in biomedical research to compare means when measurements have been made on a continuous scale is Student's t-test, followed closely by various forms of analysis of variance. These tests require that defined populations have been randomly sampled, but there are other assumptions about populations and samples that must be satisfied. These include: (i) normality of the population distributions; (ii) equal variance in those normal populations; and (iii) statistical independence of the samples. This review offers advice to investigators on how to recognize breaches of the assumptions of normality and equality of variance, and how to deal with them by modifying the usual t-test or by transforming the experimental data. The sample-size also has an important bearing on statistical inferences: (i) if it is too small, the risk of Type II error is inflated; and (ii) inequality of sample size exaggerates the effects of inequality of variance. The assumption of independence is breached if repeated measurements are made serially rather than in random order, but adjustments to analysis of variance can be made to correct for the inflated risk of Type I error. The review also considers the problem of making multiple comparisons of means, and recommends solutions.

Analysis of Variance↗
PubMed1994

The decompensatory phase of acute hypovolaemia in rabbits involves a central delta 1-opioid receptor.

Graded caval occlusion in conscious rabbits caused a biphasic response. Phase I was characterized by a fall in conductance so that arterial pressure was maintained. When cardiac output had fallen to 69 +/- 2% of its baseline level, phase II supervened. During phase II, conductance rose abruptly and arterial pressure fell to a life-threatening level (< 40 mmHg). Centrally administered delta-opioid receptor antagonists prevented the occurrence of phase II. The relative order of potency was 7-benzylidene-naltrexone (BNTX, delta 1-selective) > N,N-diallyl-Tyr-Aib-Phe-Leu-OH (ICI 174,864) > naltrindole (delta 2-selective). It is concluded that a central delta 1-opioid receptor is involved in the onset of the second decompensatory phase of the haemodynamic response to haemorrhage.

Animals↗
PubMed1994

Role of vagal afferents in the haemodynamic response to acute central hypovolaemia in unanaesthetized rabbits.

In unanaesthetized mammals, including rabbits, the response to acute central hypovolaemia is biphasic. An initial phase of baroreflex-mediated systemic vasoconstriction is succeeded by an abrupt failure of sympathetic vasoconstrictor drive and haemodynamic decompensation. We have tested whether a signal travelling in the cervical vagus nerves is responsible for the second phase. An inflatable vena caval cuff, an ascending aortic flow probe, and diaphragmatic electrodes were chronically implanted into 7 rabbits. Haemorrhage was simulated by gradual caval constriction so cardiac index (CI) fell linearly at 9% per minute. In Study 1, caval constriction was performed under control conditions, after muscarinic cholinoceptor blockade (MCB), and was repeated twice under MCB after a sham operation. In Study 2, the steps were identical but bilateral cervical vagotomy plus tracheostomy was substituted for sham operation. With or without MCB, caval constriction caused a progressive fall of systemic vascular conductance index (SVCI), and a small decline in mean arterial pressure (MAP) (Phase I). When CI had fallen by approximately 40%, there was an abrupt rise of SVCI and fall of MAP (Phase II). Sham operation had no effect on either phase. Vagotomy had no effect on Phase I, but the onset of Phase II was delayed until CI had fallen by approximately 53% in 6 rabbits. In 1 rabbit, Phase II did not occur, even though CI had fallen by 67%. We conclude that an afferent vagal signal does not contribute to the compensatory Phase I, and is not essential for the occurrence of the decompensatory Phase II, of acute central hypovolaemia in unanaesthetized rabbits.

Acute Disease↗
PubMed1994

Repeated measurements and multiple comparisons in cardiovascular research.

In cardiovascular research, experiments are commonly performed in which repeated measurements are made in the same individual at predetermined intervals of time or at ascending levels of stimulus or dose of drug. The goal is usually to test the effects of treatments or disease state on the time course of the response, or on the stimulus-response relationship. Since the passage of time or the order of stimuli or doses is fixed, statistical analysis of the results of such experiments is associated with an excessive risk of false positive interferences (type I error) unless special precautions are taken. The nature of the statistical problems associated with repeated measures experimental designs, and several solutions to them, have been discussed. An approach much favoured by cardiovascular investigators is to make multiple pairwise contrasts between treatments at each time or dose, or between times or doses within each treatment. This greatly inflates the risk of type I error unless special precautions are taken, and the information provided by making multiple contrasts is of limited value. I believe that repeated measures analysis of variance, with a correction for multisample asphericity, usually provides the most informative and least biased test of the biological hypotheses proposed by cardiovascular investigators. Other analytical techniques, such as comparing areas under curves and regression analysis, have also been discussed. Summary recommendations are given in the table.

Cardiology↗
PubMed1994

Interactions between the circulatory effects of central hypovolaemia and arterial hypoxia in conscious rabbits.

1. Eight conscious rabbits were repeatedly subjected to progressive reduction in central blood volume by gradually inflating a thoracic inferior vena caval-cuff so cardiac index (CI) fell at a constant 8.5% of baseline/min. 2. Caval-cuff inflations were performed after 10 min exposure to 100, 21, 12-14 and 8-10% O2, with and without the addition of 3-4% CO2, in randomized order. 3. The haemodynamic response to progressive reduction in central blood volume was biphasic. In Phase I, systemic vascular conductance index (SVCI) fell linearly, supporting mean arterial pressure (MAP). When CI had fallen to a critical level, Phase II occurred in which SVCI rose abruptly, MAP plummeted and respiratory drive progressively increased. 4. During Phase I, there were independent linear relationships between PaCO2 (but not PaO2) and the rates at which SVCI and MAP changed during the progressive fall of CI. The higher the level of PaCO2, the greater was the rate of fall of SVCI and the less the rate of fall of MAP. 5. There was an inverted U-shaped effect of PaO2 on the level of CI at which Phase II occurred: (a) during hyperoxia (100% O2), Phase II occurred later than during normoxia (21% O2); and (b) across the normoxic and hypoxic gas mixtures (21-8% O2, with and without added CO2), there was an independent linear relationship between PaO2 (but not PaCO2 or PaO2 x PaCO2) and the level of CI at which Phase II occurred. That is, the lower the level of PaO2, the later was the onset of Phase II. This interaction is best explained by an increased level of central sympathetic vasoconstrictor drive during hypoxia.

Analysis of Variance↗