RESPIRATORY SINUS ARRHYTHMIA AND THE VAGUS

1268 A 1985

study of

womeni with

a previous stillbirth in the index pregnancy, even without specific treatment. Patients with a previous stillbirth did not have a higher incidence of IUGR or perinatal deaths than did the general population. The incidence of perinatal loss, birthweight less than 2500 g, and toxaemia of pregnancy was not significantly different in a group of women with previous spontaneous abortion from that in a group of normal primigravida in another study.2 Perhaps Beaufils’ untreated patients, despite randomisation, had an intrinsically worse pregnancy prognosis related to variable(s) not specified in the report. The proportion of patients with pre-existing hypertension was higher in this group (38% vs 29%) and perhaps contained a greater number of women with occlusive vascular disease. The findings of this study are intriguing. However, the study groups were heterogeneous and the information given is insufficient to allow the reader to discern which of the many varieties of "at risk pregnancy" benefited from the treatment prescribed. In corroborative studies attention should be given to describing the patients studied in the hope of achieving greater homogeneity. It is certainly too early to recommend prophylactic antiplatelet agents in this group of already troubled women.

demonstrated

a

337 favourable

outcome

Suite 6, 400 Barker Road, Subiaco, Western Australia 6008

B. N. J. WALTERS T. WALTERS

RD, Dorchester W, Anderson G, Garite TJ. The significance of a previous stillbirth. Am J Obster Gynecol 1985; 151: 7-13. 2. Schoenbaum SC, Monson RR, Stubblefield PG, Darney PD, Ryan KJ. Outcome of the delivery following an induced or spontaneous abortion. Am J Obstet Gynecol 1980; 136: 19-24. 1. Freeman

SIR,-Pre-eclampsia is a major cause of maternal and fetal morbidity and mortality but there are risks associated with aspirin use during pregnancy,l and before aspirin and dipyridamole are studied in larger trials or used in clinical practice a more detailed assessment of Dr Beaufils and colleagues’ study is warranted. As pointed out; "the empirical selection of patients did not lead to a very homogenous population". This is especially true for the most important risk factor for pre-eclampsia: hypertension at entry was present in 29% of the treated group and in 38% of the controls. The other risk factors for pre-eclampsia, such as diabetes lueilitus, are not given and these are important to establish the comparability of the two groups. Of the 7 excluded patients (4 treated, 3 controls), how many were hypertensive? What were the means and SD of blood pressure at entry in each group and in the subsets of hypertensive patients, the duration of known hypertension, and concentrations of plasma creatinine in each group? Since the diagnosis of pre-eclampsia in the 6 controls was based on proteinuria levels (>1’ 5 g/day) in the third trimester, what were the proteinuria levels in the first trimester or at the 4th month for these six patients? In the absence of before and after measurements of proteinuria the diagnosis of pre-eclampsia may not be reliable. Department of Medicine, Escola Paulista of Medicine,

ALVARO N. ATALLAH

São Paulo, Brazil Clinical Epidemiology Unit, School of Medicine,

University of Pennsylvania, Philadelphia, Pennsylvania 19104

USA

RITA SCHINNAR

1 Davies AM.

Epidemiology of hypertensive disorders of pregnancy. Bull WHO 1979; 57: 373-86 2. Zuspan FP Hypertension and renal disease in pregnancy. Clin Obstet Gynecol 1984; 27: 797-98. 3. Stuart MJ, Gross SJ, Elrod H, Groeber JE. Effects of acetylsalicyclic acid ingestion on maternal and neonatal hemostasis. N Engl J Med 1982; 307: 909-12.

SIR,-An investigation of our obstetric patients has revealed that 70% of

women had taken aspirin at some time during their placental and its action on the pregnancy. Aspirin crosses newborn has been studied. Aspirin causes acetylation of cyclo-. oxygenase and irreversible inhibition of thromboxane synthesis throughout the platelet’s life3 and it inhibits the platelet release reaction induced by adenosine diphosphate and the aggregation by arachidonic acid in vitro.

the

Dr Beaufils and colleagues found that aspirin plus dipyridamole prevent pre-eclampsia. However, haemorrhagic effects in the newborn have been reported.4We took the opportunity of prenatal diagnosis of congenital toxoplasmosis5to study the action of aspirin on the fetal platelet function between 20 and 24 weeks of gestation. With their informed consent, five pregnant women ingested 600, 400, 200, 100, or 50 mg aspirin in a single oral 3 h before fetal blood sampling by direct puncture under ultrasound guidance.Blood samples from the mother’s antecubital vein were taken just before ingestion and at the same time as fetal blood sampling. Samples were anticoagulated with 0 -13 molll sodium citrate solution in a 9:1 ratio. Platelet aggregation was measured on a Payton aggregometer with arachidonic acid (1mmol/1 final concentration). With 600, 400, and 200 mg doses of ASA, inhibition of maternal and fetal platelet aggregation was complete. With 100 and 50 mg doses, inhibition was, respectively, 85 and 70% in the mothers and no aggregation was observed in fetuses, whose platelets normally respond in presence of arachidonic acid at that stage of gestation. The data demonstrate that aspirin crosses the placental barrier during the second trimester and suggest that fetuses may be more susceptible to the effects of aspirin than their mothers. More studies are needed for a better understanding of the exact - effect of aspirin on fetal and maternal coagulation but for the moment we think that aspirin should be used with great care during pregnancy even in small doses. We agree with Stuart et al, who strongly advise against its use during the last weeks of pregnancy. can

Department of Prenatal Diagnosis and Fetology, Hôpital Notre Dame de Bon Secours, 75014

Paris, France

F. FORESTIER F. DAFFOS M. RAINAUT

1. Stuart MJ, Gross SJ, Elrad H, Graeber JE. Effects of acetylsalicyclic acid ingestion on maternal and neonatal hemostasis. N Engl J Med 1982; 307: 909-12. 2. Hoack JC. Mechanisms of action: Aspirin. Thromb Res 1983 (suppl 4); 47-51. 3. Palmisano PA, Cassady G. Salicylate exposure in the perinate. JAMA 1969; 209: 556-58. 4. Rumack CM, Guggenheim MA, Rumack BH, Peterson RG, Johnson ML, Braithwaite WR Neonatal intracranial hemorrhage and maternal use of aspirin. Obstet Gynecol 1981; 58 (suppl): 52S-6S. 5. Desmonts G, Daffos F, Forestier F, Capella-Pavlovsky M, Thuilliez PH, Chartier M. Prenatal diagnosis of congenital toxoplasmosis. Lancet 1985; i: 500-04. 6. Daffos F, Capella-Pavlovsky M, Forestier F. Fetal blood sampling via the umbilical cord using a needle guided by ultrasound. Report of 66 cases. Prenat Diagn 1983, 3: 271-77.

RESPIRATORY SINUS ARRHYTHMIA AND THE VAGUS

SIR,-Mediation of respiratory sinus arrhythmia (RSA) is

wholly to the vagus nerve, and the absence of RSA is taken to indicate autonomic nerve damage, especially in the diabetic patient. This was reaffirmed in your Feb 16 editorial. I suggest that the vagus has very little to do with RSA, which is probably mediated entirely by intrathoracic reflexes triggered by pressure changes within the heart secondary to intrathoracic pressure changes during respiration. If this is so, loss of RSA in diabetes does not necessarily confirm autonomic neuropathy but might indicate inelasticity of the heart or loss of intracardiac receptors. Much evidence for a vagal role in RSA has come from studies on anaesthetised dogs or humans under suboptimal conditions for evaluating RSA.1,2 In many studies results were derived by "correlation". If RSA is a result of biological ageing it will correlate positively with conditions associated with that (eg, diabetes) but via a mechanism other than vagal damage. Some work on anaesthetised dogs, diabetics, and heart transplant patients2,3 suggests that whatever the afferent mediator of RSA is (chest wall, stretch receptors, baroreceptors,4 atrial receptors, brainstem interactions’) the efferent one is the vagus nerve.2 However, there are several reported examples where, were the vagus the only mediator, RSA would be difficult to explain. Fader et al have described a patient with autonomic neuropathy associated with longstanding diabetes and a 44-year-old man with the transplanted heart of a 35-year-old male road accident victim, both with RSA. In 25 healthy volunteers aged 20-82 Fader et al demonstrated RSA in all, but amplitude declined with age. Both the attributed

very

1269 above patients showed RSA amplitude as expected for age. The view that RSA is only present in young persons is not valid.7,8 Melcher9studied RSA in unanaesthetised healthy human volunteers aged 19-39 and looked at the effect of intermittent positive (IPPV) and negative (INPV) pressure ventilation. INPV produced RSA with increased heart rate during inspiration and decreased during expiration. However, during IPPV, which reversed "normal" intrathoracic pressure swings, right ventricular end-diastolic pressure, stroke volume, and systemic arterial pressure changes, the heart rate response was completely reversed, decreasing during inspiration and increasing during expiration. A more likely explanation is that RSA is mediated by intrinsic cardiac reflexes, possibly modified by the vagus,1O and that the absence of RSA and age-related decline in amplitude represents a loss of intrinsic suppleness, elasticity, or tissue compliance and is a useful indication of biological age or intrinsic damage rather than autonomic neuropathy, although the two may coexist. The presence of RSA in a patient with other evidence of autonomic neuropathy should not exclude that diagnosis, and the absence of RSA should never be used as the sole bedside test for autonomic neuropathy.

readings above the 40 mm Hg threshold) but during acute tubular necrosis 21% (10/47) appeared falsely positive. The data of Salaman and Griffin suggest that sensitivity and specificity in their series are similar to ours, although they did not see the effect of acute tubular necrosis which Wagner et al and we have noted. Measurement of IRP may be a helpful adjunct to conventional diagnostic methods for the differentiation of cyclosporin toxicity and rejection, but in a significant proportion of the more difficult cases lacking local physical signs of graft rejection and during acute tubular necrosis the result may be less reliable and caution should be exercised in its interpretation. Renal

Transplant Unit,

Royal

Hallamshire

Sheffield S10 2JF

Department

JOANNA M. WARDLAW

1. Wheeler

T, Watkins 2. Katina PJ, Jih F 3. 4. 5. 6. 7

PJ. Cardiac denervation in diabetes Br Med J1973; iv. 584-86. Respiratory sinus arrhythmia: a non-invasion measure of parasympathetic cardiac control. J Appl Physiol 1975; 39: 801-05. Ewing DJ, Nelson JMM, Travis P. New method for assessing cardiac parasympathetic activity using 24 hour ECG. Br Heart J 1984; 52: 396-402. O’Toole MF, Durster RD, Phillips JG, Randall WC. Parallel baroreceptor control of sinoatrial rate and atrioventricular conduction. Am J Physiol 1984; 246: 149-53. Levy MH, DeGeest H, Zieske H. Effects of respiratory centre activity on the heart. Circulation Res 1966; 18: 67-78. Fader D, Schmitt O, Gilbertsen V Respiratory sinus arrhythmia: a measure of cardiac age. Science 1984; 224: 1001-04 Cort J, Edholm OG, Lobstein T, Webb R Some observations in sinus arrhythmia. J Physiol 1977, 268: 21-22. JB, Stacy RW. Variations of respiratory sinus arrhythmia with age. J Appl Physiol 1976, 41: 734-38. Melcher A. Respiratory sinus arrhythmia in man: a study in heart rate regulating mechanisms. Acta Physiol Scand 1976 (suppl 435): 1-31. Bambridge FA. JPhysiol (Lond) 1920; 54: 192.

8. Hellman

9. 10.

PLACE OF INTRARENAL PRESSURE MEASUREMENT IN TRANSPLANT MANAGEMENT

SlR,—The intrarenal (IRP) or subcapsular hydrostatic pressure is raised in renal allografts undergoing rejection but not in patients with cyclosporin toxicity, so these tests may be useful in distinguishing between the two conditions.I,2 However, the enthusiasm for this test shown by Mr Lear and his colleagues (April 20, p 922) should be tempered with caution. We have assessed the value of serial IRP measurements in 38 transplant recipients during 1984. 207 postoperative measurements were made by a fine needle technique in conjunction with an electrical recording system. We confirmed that IRP was significantly raised (p<0-001) during acute rejection (44’3±2-33 mm Hg in 77 readings) in comparison with kidneys which were not rejecting (23 -6--t1 - 0 mm Hg in 130 readings), but not in cyclosporin toxicity (17-8±4-22 mm Hg in 7 cases). However, we were disappointed to find that those patients with a rejecting kidney and raised IRP tended to be those with graft tenderness and swelling (52’ 5--t3 -0mm Hg in 38 readings) rather than those without local signs (36 -3:t3 .1mm Hg in 39 cases, p<0 01). Moreover we found a significant increase in pressure in kidneys with acute tubular necrosis (29 -4±1 - 9 mm Hg) in comparison with immediately functioning grafts (20-4±0-99 mm Hg, p<0-01). A logistic regression model3 revealed that rejection was the more probable diagnosis when the IRP was above 38 - 7 mm Hg, a value similar to the 40 mm Hg suggested by Salaman and Griffin* and Wagner et awl. Using the 40 mm Hg cut-off point, we found that 90% (19/21) of rejection episodes in grafts with local signs had at least one positive IRP reading but only 56% (10/18) of those without local signs were positive, giving an overall sensitivity of 74%. In functioning grafts specificity was excellent (only 1 out of 83

of Probability and

University of 1 Salaman 2.

3.

Metabolic Unit, Western General Hospital, Edinburgh EH4 2XU

C. P. GIBBONS C. B. BROWN A. T. RAFTERY

Hospital, Statistics,

R. KAY

Sheffield

JR, Griffin PJA.

Fine needle mtrarenal manometry:

a new test

for rejection

in

cyclosporin-treated recipients of kidney transplants. Lancet 1983, ii: 709-11. Wagner E, Pichlmayr R, Wonigeit K, et al. Differentiation between rejection and cyclosporin A nephrotoxicity by monitoring interstitial pressure in human renal allografts. Transplant Proc 1983; 15: 489-96. Cox DR. The analysis of binary data. London: Methuen, 1970. CEREBRAL DYSFUNCTION IN INTENSIVE CARE

SIR,-Cerebral dysfunction in patients in intensive care units is likely to be multifactorial, but the study by Dr Ball and colleagues

(April 6, p 784) helps clarify the clinical picture, familiar to nephrologists, characterised by difficulty in weaning off ventilation and prolonged non-specific neurological dysfunction in a "floppy" and non-communicative patient without localising features. These signs develop despite intensive parenteral nutrition. Over a five year period, in this unit, 41 patients with combined respiratory and renal failure required positive pressure ventilation and dialysis. There were 13 survivors, 2 of whom had’neurological complications with complete recovery; 28 patients died, 11 of whom had cerebral complications during their illness. 4 patients died after recovery of renal and respiratory function, though they remained neurologically abnormal. Necropsy in some cases revealed appearances compatible with watershed ischaemia affecting the brainstem. Besides the narcotic, analgesic sedative effects reported in renal failure, three other factors may be relevant to the neurological dysfunction. In our patients 39% of all narcotic analgesic doses resulted in a blood pressure drop of up to 40 mm Hg, sustained for up to 2 h (excluding the resolution of hypertension related to "fighting" the ventilator). Cardiac arrhythmias occurred in 38% of all patients during dialysis on ventilation; and positive-pressure ventilation, especially with positive end-expiratory pressure, will reduce right-heart filling and so further compromise cerebral circulation. Medical Renal

Unit, Royal Infirmaly,

Sunderland SR2 7JE

A. M. MARTIN M. I. MCHUGH S. J. SCOTT

CHORIONIC VILLUS SAMPLING

SiR,—Dr Modell (March 30, p 737) and your accompanying editorial do an admirable yet incomplete job in discussing chorionic villus sampling (CVS). The four major risks associated with CVS are (1) miscarriage, (2) developmental and other effects on surviving infants, (3) diagnostic error, and (4) impact on the quality of life. Other risks are maternal infection and risks to the fetus due to ultrasound exposure. The debate, as reflected in Modell’s paper, has focused on the risks of miscarriage and paid little attention to postnatal development and the quality of life. The quality of karyotypes obtained from CVS samples appears to be inferior to that obtained from amniotic fluid cultures, and there have been anecdotal reports of chromosomal mosaicism.There have also been reports of maternal cell contamination.2For the moment it seems reasonable to suspect that CVS may be less sensitive and less specific than amniocentesis. The wisdom of