British Journal Anaesthesia 1990; 65: 796-800


Effective renal plasma flow (ERPF) and linear cardiac output (aortic blood velocity) were measured in 15 patients who received halothane, enflurane or isoflurane in oxygen. All three agents caused a significant reduction in ERPF (P < 0.05) and the effect was greater at 1.25 MAC than at 0.75 MAC. No significant difference was demonstrated between the agents. Linear cardiac output did not change significantly during the study, suggesting that the observed reduction in ERPF was not caused by cardiovascular depression. KEY WORDS Anaesthetics, volatile, enflurane, halothane, isoflurane. Heart: aortic blood velocity. Kidney: renal plasma flow.

Although the effects of halothane, enflurane and isoflurane on renal function, and particularly on renal blood flow, have been studied elsewhere [1-3], agents were examined individually, during separate experiments, by separate researchers. Hence, it is difficult to compare data. Furthermore, there were drawbacks in methodology in previous trials, but these may now be circumvented by recent advances. For example, an assessment of fractional distribution of cardiac output to the kidney could not be made, as cardiac output had not been measured, probably because no reliable non-invasive method of measuring cardiac output was available. Lastly, standard renal clearance techniques used to measure renal blood flow become inaccurate during low or changing urine output, conditions often encountered during anaesthesia [4, 5]. To overcome this problem, fluid loads and ethyl alcohol were administered to promote diuresis, but these manoeuvres would have altered measured flows.

Newer developments now permit some of these difficulties to be overcome [6-11]. PATIENTS AND METHODS

Approval for the study was obtained from the Joint Ethics Committee of the University of Wales College of Medicine and South Glamorgan Health Authority. Fifteen adult patients undergoing general or ear, nose and throat surgery, gave informed written consent to the trial. They were aged 25-50 yr, and ASA grade I or II. Patients with evidence of cardiovascular or renal disease or receiving intercurrent drug therapy were excluded. Preanaesthetic medication consisted of lorazepam 2 mg orally 2 h before transfer to the operating theatre. Under local anaesthesia, a 17gauge i.v. cannula was inserted in one forearm for fluid infusion and administration of radioisotopes, and a 14-gauge cannula in the antecubital fossa of the opposite arm for blood sampling and the administration of anaesthetic drugs. Before measurements were made, patients were rehydrated with 4 % dextrose and 0.18 % saline at 10 ml/kg body weight over a period of 40 min (as all were investigated before afternoon surgery after only a light breakfast at 06:00). Electrocardiogram and indirect arterial pressure monitoring was commenced and recorded at 5-min intervals. Then, effective renal plasma flow

N. D. GROVES, M.B., CH.B., M.R.C.P., F.F.A.R.C.S., M. ROSEN, C.B.E., M.B., B.CH., F.F.A.R.C.S. (Department of Anaesthetics);

K. G. LEACH*, B.SC., PH.D. (Department of Medical Physics); University Hospital of Wales, Heath Park, Cardiff CF4 4XW. Accepted for Publication: April 5, 1990. •Present address: Department of Medical Physics, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia.

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Halothane, enflurane and isoflurane groups were compared using unpaired t tests with Bonferroni correction. Comparisons between different levels of anaesthesia using the same vapour were made using paired t tests with Bonferroni correction. Values of P < 0.05 were considered significant. RESULTS

Table I summarizes patient data. The actual renal plasma flow decreased significantly from awake values at both 0.75 MAC and 1.25 MAC for all agents tested, but there was no significant difference between the agents (table II). For this comparison the t test used would have a power of 0.87 in demonstrating a difference of 30%. The results found by previous workers are recorded for comparison (table II). Changes in cardiac output are presented in table III. TABLE I. Age

and weight of patients {mean (SD) for each

group) Group

Age (yr)

Weight (kg)

Halothane Enflurane Isoflurane

37.8 (7.5) 36.2 (5.6) 37.2 (7.7)

75.1 (15.4) 67.5 (8.6) 70.9 (17.7)

TABLE II. Mean (SEM) ERPF compared with depth of anaesthesia (MAC units) for halothane, enflurane and isoflurane groups, as percentage of awake value, in the present and previous studies MAC value

Halothane Enflurane Isoflurane



80(6.6) 77 (5.6) 77 (3.3)

74(3.1) 70 (3.6) 70 (4.6)

Previous studies 62 (at 2 MAC) [1] 77 (at 0.8 MAQ [3] 51 (at 1 MAC) [2]

TABLE III. Mean (SEM) changes in cardiac output (measured as mean aortic blood velocity) as percentage of awake value compared with depth of anaesthesia (MAC units) for halothane, enflurane and isoflurane groups MAC value

Halothane Enflurane Isoflurane



105 (9.8) 95 (5.6) 105 (8.3)

98(9.1) 86 (7.7) 100 (9.8)

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(ERPF) was measured using a non-invasive radioisotope method with three isotopes: iodine-123, -125 and-131 [11]. As a measure of cardiac output, mean blood velocity in the ascending aorta was measured using an ultrasonic pulsed Doppler transcutaneous aortovelograph, with the probe placed in the suprasternal notch [6-9]. Anaesthesia was induced with etomidate 0.20.3 mg kg"1, followed by suxamethonium 1 mg kg"1 i.v. The larynx was sprayed with 4 % lignocaine and the trachea intubated. Anaesthesia was maintained with halothane, enflurane or isoflurane in oxygen to achieve an end-tidal vapour concentration of 0.75 MAC. The choice of anaesthetic vapour was made according to a randomized programme to produce three groups each of five patients. The gas mixture was delivered via a non-rebreathing system (Manley Pulmovent ventilator) set for a minute volume at approximately 150 ml/kg body weight. End-tidal concentration of carbon dioxide was monitored (Datex Normocap) and maintained at 5 % by adjusting tidal volume or adding carbon dioxide to the inspired mixture as necessary. End-tidal anaesthetic vapour concentration was monitored using a Datex Normac. MAC was adjusted for age in patients given halothane or isoflurane [12, 13]; proportionate adjustments were made for those anaesthetized with enflurane. When an end-tidal vapour concentration of 0.75 MAC had been maintained for 15 min, aortovelography and measurement of ERPF were repeated. Inspired vapour concentration was increased until end-tidal vapour concentration was 1.25 MAC, and when this had been maintained for 15 min, aortovelography and ERPF measurements were repeated. At the conclusion of this third pair of measurements, the patient was taken into the operating room for surgery. The output of the aortovelograph was analysed and stored using a BBC microcomputer. Mean linear cardiac output (aortic blood velocity representing cardiac output) was expressed as a percentage of the awake value. ERPF results were expressed in this way also, so that means for each group of five patients could be calculated. For each individual subject, the aortovelograph data were used to adjust the actual ERPF results to give "corrected" ERPF, an estimate of what ERPF would have been if cardiac output had not changed, so that any changes in fractional distribution of blood to the kidneys could be observed.



798 TABLE IV. ERPF "corrected" for cardiac output changes: means (SEM) for each group as percentage of awake value, compared with depth of anaesthesia (MAC units) MAC value

Halothane Enflurane Isoflurane



81 (13.9) 82 (5.9) 75(4.1)

78 (10.3) 84 (7.28) 71 (3.4)


Many factors, independently or in concert, may cause a reduction in renal blood flow. In the investigation of anaesthetic agents the effect of other factors must be excluded as far as possible. Some previous studies did not exclude the effects of stress, anxiety, dehydration, premedication, surgical stimulation and artificially-induced diuresis. The present trial was designed to avoid or reduce the effects of these complicating factors as far as is compatible with clinical research. The method used to measure ERPF is based on the plasma clearance of radiolabelled para-aminohippuric acid (PAH) [11], and assumes (as do all methods based on PAH clearance) that anaesthesia does not greatly alter the renal PAH extraction ratio. The possibility of such a change has not been explored widely, but Deutsch and colleagues showed in two volunteers that halothane did not alter PAH extraction ratio [1]. During times of low urine production, PAH may be stored in the kidney [5], but this would not affect calculation of PAH clearance based on plasma samples. The study has shown significant depression of ERPF during anaesthesia with each of the three agents. The effect appears to be dose related, although the only further significant depression of ERPF after 0.75 MAC occurred with isoflurane.

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Correcting the actual ERPF values for changes in cardiac output reduced the significance of the changes, although the group means are similar to the actual ERPF values (table IV). Isoflurane at 0.75 and 1.25 MAC and enflurane at 0.75 MAC caused significant depression in corrected ERPF. Mean arterial pressure decreased in all subjects after anaesthesia, and the maximum depression from the awake value, expressed as a mean for all 15 patients, was 9%. The maximum depression occurred usually during 1.25 MAC anaesthesia.

Previous studies also have shown that the renal effects of anaesthetic agents are dose related [14, 15]. Since conditions of positive pressure ventilation were the same at 0.75 and 1.25 MAC, the use of IPPV did not seem greatly to affect the results. The depression of ERPF noted with halothane and enflurane was similar quantitatively to that observed in previous studies (table II), but that for isoflurane was not. Our data suggest little difference between the agents, whereas previous work indicated a more profound depression with isoflurane, although valid comparisons between agents should not be drawn too finely from previous studies for the reasons outlined above. However, it is interesting to note that in various previous studies, only subjects in an isoflurane trial [2] and not those in halothane and enflurane trials, were treated with extra i.v. fluid, reduction of depth of anaesthesia, or both, if they became hypotensive. This study used mean aortic blood velocity as an indicator of cardiac output, based on two assumptions. The first is that the velocity profile of blood in the ascending aorta remains relatively constant whilst the velocity varies; spectral analysis suggests that this is so [16]. The second is that there is no significant change in the mean crosssectional area of the aorta during the period of measurement. This is likely to be the case, as studies which make this assumption when comparing Doppler methods with, for instance, thermodilution, show good relationships [8]. In contrast, one study reported the relationship between intra-aortic pressure and aortic diameter [17], and showed that diameter decreased as mean pressure decreased, although to a variable degree in different patients. If this were the case, then velocity measurements would decrease proportionately less than corresponding decreases in flow (as aortic area would be reduced at the same time); in other words, Doppler measurements would underestimate any change in cardiac output. This might have contributed to the fact that we measured only small changes in linear cardiac output. However, in other circumstances, we and many other workers have measured large changes in linear cardiac output using this technique. Furthermore, whilst a reduction in cardiac output often follows induction of anaesthesia, some studies have reported no change or even an increase in cardiac output [18]. The Doppler instrument we used was built by


Some researchers propose that renal vascular resistance increases during anaesthesia, and some

that it decreases. Various extrinsic systems have been implicated, including renin-angiotensin system activation, sympathetic nervous system activation, catecholamine release, and antidiuretic hormone release [1, 17, 23]. Activation of volume receptors caused by relative decrease in plasma volume may cause renin activation [24], although there is said to be complete tachyphylaxis to angiotensin in the renal vascular bed within 20 min [22]. Nevertheless, inhibition of the reninangiotensin system in dogs prevents the decrease in renal blood flow and the increase in renal vascular resistance associated with barbiturate anaesthesia [25]; this might implicate the reninangiotensin system as at least a partial cause of the observed effects.

ACKNOWLEDGEMENTS The authors thank Mr J. Mecklenburgh for the BBC microcomputer program and Professor J. P. Woodcock and Mr C. Goodfield for supplying the aortovelograph. Mr M. I. Robinson prepared the radiopharmaceuticals.

REFERENCES 1. Deutsch S, Goldberg M, Stephen GW, Wu WH. Effects of halothane anesthesia on renal function in normal man. Anesthesiology 1966; 27: 793-804. 2. Mazze RI, Cousins MJ, Barr GA. Renal effects and metabolism of isoflurane in man. Anesthesiology 1974; 40: 536-542. 3. Cousins MJ, Greenstein LR, Hitt BA, Mazze RI. Metabolism and renal effects of enflurane in man. Anesthesiology 1976; 44: 44-53. 4. Selkurt EE. The renal circulation. In: Handbook of Physiology. Washington D C : American Physiological Society, 1963; 1457-1516. 5. Balint P. The reliability of PAH clearance as a measure of renal plasma flow. In: Proceedings of the 2nd International Congress of Nephrology, Vol. 84, Part 2. Amsterdam: Excerpta Medica Foundation 1964; 84-85. 6. Chandraratna PA, Nanna M, McKay C, Nimalasuriya A, Swinney R, Elkayam U, Rahimtoola SH. Determination of cardiac output by continuous wave ultrasonic doppler computer. American Journal of Cardiology 1984; 53: 234-237. 7. Schuster AH, Nanda NC. Doppler echocardiographic measurement of cardiac output: comparison with a non golden standard. American Journal of Cardiology 1984; 53:257-259. 8. Huntsman LL, Stewart DK, Barnes SR, Franklin SB, Colocousis JS, Hessel EA. Non invasive Doppler determination of cardiac output in man. Clinical validation. Circulation 1983; 67: 593-601. 9. Gisvold SE, Brubakk AD. Measurement of instantaneous bloodflow velocity in the human aorta using pulsed Doppler ultrasound. Cardiovascular Research 1982; 16: 26-33.

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the biomedical engineering department of the University Hospital of Wales, using the same principles as commercially available models. It was tested for accuracy in vitro on aflowrig before being used in clinical trials. Aortic velocity figures were used to adjust ERPF data in each case, to simulate ERPF changes irrespective of change in cardiac output (table IV). The "corrected" ERPF changes look similar to the original ERPF changes, the main difference being that only three of the six group means differed significantly from control: those for isoflurane at 0.75 MAC and 1.25 MAC, and for enflurane at 0.75 MAC. The absence of statistical significance for the other three corrected means is a result of the larger SEM in these cases, induced by variance in the individual aortic blood flow measurements. Presumably analysis of larger groups in a study would rectify this. Taken as a whole, the data show that the three anaesthetic vapours tested caused a significant decrease in ERPF, and that there was no difference between the agents in degree of depression caused. The depression seemed to be independent of any change in cardiac output, and in the absence of significant hypotension. Renal blood flow is known to decrease during many types of anaesthesia, and the mechanism responsible is not understood. The fact that renal blood flow decreases during anaesthesia in spite of maintained perfusion pressures has led some to believe that autoregulation of renal blood flow is impaired. However, studies claim that halothane does not affect autoregulation [19]; and autoregulation has been shown to persist in isolated perfused kidney exposed to halothane [20]. Moreover, studies on the isolated dog kidney revealed that halothane acts as a direct renal vasodilator [21]. This evidence suggests that anaesthesia alters ERPF by an indirect effect on the kidney; evidence from experiments measuring tubular function concurs with this. Hollenberg summarized the situation thus: "It is equally important to recognise that the concept of autoregulation does not preclude quantitatively important changes in renal perfusion; rather, when such changes occur they are rarely due to changes in perfusion pressure unless striking hypotension is present. Thus, local and systemic vasoactive factors play a much more important role in determining renal perfusion and function" [22].




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diameter in the ascending aorta of man. Circulation Research 1962; 10: 778-781. Virtue RW, Vogel JHK, Press P, Grover RF. Respiratory and hemodynamic measurements during anesthesia. Journal of the American Medical Association 1962; 179:

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224-225. Leighton KM, Bruce C. Distribution of kidney blood flow; a comparison of methoxyflurane and halothane effects as measured by heated thermocouple. Canadian Anaesthetists Society Journal 1975; 22: 125-137. Bastron RD, Perkins FM, Pyne JL. Autoregulation of renal blood flow during halothane anesthesia. Anesthesiology 1977; 46: 142-144. Bastron RD, Pyne JL, Inagaki M. Halothane-induced renal vasodilation. Anesthesiology 1979; 50: 126-131. Hollenberg NK. The renal circulation. In: Zelis R, ed. The Peripheral Circulations. New York: Grune & Stratton, 1975: 131. Utting JE. Anaesthesia and the kidney. In: Gray TC, Nunn JF, Utting JE, eds. General Anaesthesia, 4th Edn. London: Butterworths, 1980; 763. Ganong WF. Review of Medical Physiology, 12th Edn. Los Altos: Lange, 1985; 575. Burger BM, Hopkins T, Tulloch A, Hollenburg NK. The role of angiotensin in the canine renal vascular response to barbiturate anesthesia. Circulation Research 1976; 38: 196-202.

Effects of halothane, enflurane and isoflurane anaesthesia on renal plasma flow.

Effective renal plasma flow (ERPF) and linear cardiac output (aortic blood velocity) were measured in 15 patients who received halothane, enflurane or...
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