Comparison of gravimetric and a double-indicator dilution technique for assessment of extra-vascular lung water in endotoxaemia.

OBJECTIVE: To compare a molecular double-indicator dilution technique with the gravimetrical reference method for measurement of extra-vascular lung water in porcine endotoxin shock. DESIGN: Open comparative experimental study. SETTING: Animal research laboratory. MEASUREMENTS AND RESULTS: In fourteen anaesthetised, mechanically ventilated landrace pigs, central and pulmonary haemodynamics as well as pulmonary gas exchange were measured. Extra-vascular lung water was quantitated gravimetrically as well as with a molecular double indicator dilution technique. Eight of these animals were subjected to endotoxaemia, the rest serving as sham controls. No difference in extra-vascular lung water was observed between the two methods in sham animals. Furthermore, extra-vascular lung water assessed with the molecular double-indicator dilution technique at the initiation of endotoxin infusion did not differ significantly from the corresponding values for sham animals. Endotoxaemia induced a hypodynamic shock with concurrent pulmonary hypertension and a pronounced deterioration in gas exchange. No increase in extra-vascular lung water was detected with the molecular double-indicator dilution technique in response to endotoxin, whereas this parameter was significantly higher when assessed with the gravimetric method. CONCLUSION: The molecular double-indicator dilution technique showed similar results as the gravimetrical method for assessment of extra-vascular lung water in non-endotoxaemic conditions. However, during endotoxin-induced lung injury the molecular double indicator dilution technique failed to detect the significant increase in extra-vascular lung water as measured by the gravimetric method. These data suggest that the molecular double indicator dilution technique may be of limited value during sepsis-induced lung injury.

Effects of rapid colloid volume expansion on pulmonary microvascular pressure and lung water in the conscious sheep.

Increased pulmonary microvascular pressure (Pmv), in combination with other factors, may cause pulmonary interstitial oedema. Whether increased Pmv alone induces alveolar oedema is questionable. In the present study we used the heavy water-indocyanine green dilution method to measure lung water during a rapid intravascular volume expansion in the sheep. Eight conscious sheep were given two 10-min intravenous infusions of either 50 ml/kg (N = 2) or 35 ml/kg (N = 6) of dextran 60 with an interval of 10 min between them. At a Pmv of 40 mmHg, respiratory distress was observed in sheep no. 2 which had been given a total amount of 100 ml/kg of dextran; this was immediately followed by a lethal pulmonary haemorrhage. Mean Pmv in the remaining seven sheep increased to 31 (7) mmHg in response to the volume expansion without causing any respiratory distress or increase in lung water. These results show that in conscious sheep the lungs have strong protective mechanisms against hydrostatic oedema. They do not support the hypothesis that increased Pmv alone induces alveolar oedema, but suggest that an increase in Pmv to 40 mmHg may cause stress failure of the pulmonary vasculature.

Quantitative estimation of errors in the indicator dilution measurement of extravascular lung water.

OBJECTIVE: To assess the accuracy of the diffusible indicators heavy water and thermal indicator in the measurement of extravascular lung water (EVLW). DESIGN: Cardiac output (CO), mean transit time and EVLW for the two diffusible indicators were measured. CO for indocyanine green, gravimetric EVLW and the calculated mean transit time for a diffusible indicator were used as independent reference variables. CO, mean transit time and EVLW for the two diffusible indicators were compared to the reference variables and the percentage error for each measured variable was calculated for each bolus injection. SETTING: 6 sheep with healthy lungs and 6 with pulmonary oedema in a research laboratory. INTERVENTIONS: CO was altered with positive end-expiratory pressure and dobutamine. MEASUREMENTS: All indicators were given together in a bolus through a central venous line. Indicators were detected simultaneously in the aorta, and CO, mean transit time and EVLW were measured. EVLW was measured gravimetrically (EVLWgrav) postmortem. RESULTS: In the combination of a low CO and a large distribution volume, heavy water and thermal indicator produced a large number of slow wash-out curves. These curves were abolished from further analysis. The mean errors in CO and mean transit time for heavy water were close to zero and independent of the distribution volume; the product EVLW was close to EVLWgrav. The mean error in thermodilution CO measured in the aorta was close to zero but dependent on the distribution volume. The mean error in mean transit time for the thermal indicator was 36% and dependent on the distribution volume. Their product EVLW overestimated EVLWgrav by 70%. CONCLUSIONS: The results obtained for heavy water confirmed the theoretical basis of the indicator dilution method. The mean transit time for the thermal indicator was not proportionate to its distribution volume. The magnitude of this error prevents the calculation of an anatomically defined EVLW using a catheter-mounted thermistor in the aorta.

Subclinical pulmonary oedema and intermittent haemodialysis.

It has been postulated that patients with chronic renal failure, even in the absence of cardiopulmonary symptoms, accumulate interstitial pulmonary fluid, which is removed by haemodialysis. To test this hypothesis we used the indocyanine green (ICG)-heavy water double indicator dilution method to measure lung water, cardiac output, and central blood volume in relation to haemodialysis. Ten uraemic patients, without cardiopulmonary symptoms, were investigated at the beginning and end, and 2 h after, a regular dialysis session. A group of 18 surgical patients about to undergo elective abdominal surgery served as controls. Despite normal gas exchange, central blood volume, and cardiac output at the start of dialysis the mean (SD) lung water was significantly higher than in the control group [4.8 (0.9) compared with 3.6 (0.7) ml/kg, P < 0.001]. There was no correlation between weight gain between sessions of dialysis and the magnitude of lung water at the start of dialysis. Lung water decreased (P < 0.001) to the level of the control group in response to dialysis. There was no correlation between weight loss and reduction in lung water induced by dialysis. In conclusion, we have verified the presence of subclinical pulmonary oedema which was removed by dialysis in a group of patients with established renal failure. The variations in lung water cannot be explained by hydrostatic mechanisms alone.

Estimation of extravascular lung water in humans with use of 2H2O: effect of blood flow and central blood volume.

In the present human study we evaluated a newly developed double-indicator-dilution densitometric system for the estimation of cardiac output (Q), central blood volume (CBV), and extravascular lung water (EVLW) by using indocyanine green and heavy water (2H2O) as indicators. Eighteen cardiopulmonary healthy patients scheduled for abdominal surgery were studied. A routine anesthesia procedure was used [thiopental (3-5 mg/kg), N2O (inspired fraction of O2 = 0.4), and isoflurane (end tidal 0.5-1.5%)]. Q, CBV, and EVLW were measured at seven defined data collection points: awake, anesthetized spontaneously breathing, apneic, mechanically ventilated with and without positive end-expiratory pressure, post-operatively anesthetized, and postoperatively awake. During the whole study EVLW (3.8 +/- 0.9 ml/kg) was stable in the presence of large fluctuations in Q (2.5-10.1 l/min) and CBV (0.8-2.4 l). We concluded that the method is versatile and of low invasiveness, allowing reliable on-line Q and EVLW data for repeated measurements in the clinical setting.

Microemboli reduce phase III slopes of CO2 and invert phase III slopes of infused SF6.

We investigated the effect of increasing doses of intravenously infused glass microspheres (mean diameter 125 microns) on gas exchange in anesthetized, heparinized, mechanically ventilated goats (VT = 16-18 ml/kg). Breath-by-breath CO2 expirograms were collected using a computerized system (Study A) during the infusion of a total of 15 g of microspheres. We found a 50% decrease in extravascular lung water by indicator dilution with a corresponding doubling of alveolar dead space (VDalv). Airways deadspace (VDaw) decreased by 13 ml (10%) and mean normalized phase III slope for CO2 decreased from 0.23 to -0.08 L-1 becoming negative in 3 of 5 animals. In a second study (Study B), simultaneous breath-by-breath CO2 and infused SF6 expirograms were collected using an infrared CO2 analyzer and a mass spectrometer. Under baseline conditions VDaw for CO2 was smaller than for SF6 and the ratio of the phase III slope for SF6 to the phase III slope for CO2 was 1.39. Following embolization there were no differences in VDaw between the two gases, however, the phase III slope for CO2 became either slightly negative or extremely flat, while the phase III slope for SF6 became negative in 73% of the breaths (-0.17 L-1, P < 0.05). Negative phase III slopes have been predicted by a single path model when blood flow is confined to the most mouthward generations of the acinus (Schwardt et al., Ann. Biomed. Engin, 19: 679-697, 1991). The agreement between the numerical model and the experimental data is consistent with a serial distribution of blood flow within the acinus.

Hemodynamic effects of vasopressin antagonism and angiotensin I converting enzyme inhibition during halothane anesthesia in sheep.

The hemodynamic effects of separate and combined intravenous administration of the vasopressin (AVP) V1-receptor antagonist SK&F 100273 (10 micrograms/kg) and the angiotensin I converting enzyme inhibitor captopril (20 mg + 1 mg/h) were studied in 12 sheep during stable halothane anesthesia (1.5% end-tidal conc.). The separate blockade of either V1-receptors or angiotensin II (ANG II) synthesis induced a small (7-10%), but significant, fall in mean systemic arterial pressure (MSAP), whereas the combined treatment caused a 30% reduction in blood pressure. The changes in systemic vascular resistance paralleled those of the MSAP. Consequently, the cardiac output was largely unaffected by the interference with AVP effects and/or ANG II synthesis. The halothane anesthesia effectively increased the plasma levels of AVP and ANG II, and plasma renin activity without any relation to changes in MSAP. When either the AVP effects or ANG II synthesis were blocked separately, there was a slight tendency for a compensatory increase of the unimpeded hormonal system. It is concluded that halothane anesthesia increases the plasma levels of AVP and ANG II in sheep, and that the maintenance of the arterial pressure is dependent on the concurrent vasopressor effects of the two hormones in this situation.

Measurement of extravascular lung water--methods and clinical implications.

The estimation of changes in extravascular lung water during different experimental and clinical conditions forms an intriguing field of research. Present methods for the measurement of lung water are difficult to apply in day-to-day clinical practice. Most methods are not only low in accuracy and sensitivity but are also invasive. A new indicator-dilution technique using heavy water and indocyanine green as diffusible and nondiffusible indicators, respectively, may provide us with a new investigative method for longterm bedside estimation of lung water.

Commercial double-indicator-dilution densitometer using heavy water: evaluation in oleic-acid pulmonary edema.

We evaluated a commercially available, double-indicator-dilution densitometric system for the estimation of pulmonary extravascular water volume in oleic acid-induced pulmonary edema. Indocyanine green and heavy water were used as the nondiffusible and diffusible tracers, respectively. Pulmonary extravascular water volume, measured with this system, was 67% of the gravimetric value (r = 0.91), which was consistent with values obtained from the radioisotope methods. The measured volume was not influenced by changes in cardiac index over a range of 1 to 4 L.min.m2. This system is less invasive than the thermal-dye technique and has potential for repeated clinical measurements of pulmonary extravascular lung water and cardiac output.

Evaluation of heavy water for indicator dilution cardiac output measurement.

We evaluated deuterium oxide (D2O) as a tracer for cardiac output measurements. Cardiac output measurements made by thermodilution were compared with those made by indicator dilution with D2O and indocyanine green as tracers. Five triplicate measurements for each method were made at intervals of 30 minutes in each of 9 anesthetized, mechanically ventilated goats. Cardiac output ranged between 0.68 and 3.79 L/min. The 45 data points yielded a correlation coefficient of 0.948 for the comparison of D2O indicator dilution cardiac output measurements with thermodilution measurements and a linear regression slope of 1.046. D2O indicator dilution measurements were biased by -0.11 +/- 0.22 L/min compared with thermodilution measurements and had a standard deviation of +/- 0.12 L/min for triplicate measurements. Hematocrits ranging between 20 and 50 vol% had no effect on optical density for D2O. D2O is more stable than indocyanine green and approximately one-tenth the price (40 cents per injection compared with $4). The basic instrumentation cost of approximately $9,000 is an additional initial expense, but provides the ability to perform pulmonary extravascular water measurements with a double-indicator dilution technique. D2O has potential as a tracer for the clinical determination of indicator dilution cardiac output measurements and pulmonary extravascular water measurements.

A new fixation device for the Leksell stereotaxic system. Technical note.

A device is presented that permits several applications for the Leksell stereotaxic system. The patient is fixed in this new system by means of a rectangular instrument that connects to the standard Leksell stereotaxic coordinate frame and maintains spatial orientation after the frame itself is removed. Specific uses for this device include stereotaxic radiosurgery and stereotaxic guidance during microsurgery. Other attractive features of this device are its capability of being precisely reapplied, its compatibility with both computerized tomography and magnetic resonance imaging, and the availability of an accessory device to adapt it for animal stereotaxis.

Stereotaxis and nuclear magnetic resonance.

The application of nuclear magnetic resonance (NMR) imaging to a stereotactic method is described. The physical properties of NMR offer some important advantages such as good contrast between grey and white matter and the possibility to scan the brain in three planes and at any desired angle. Stereotactic localisation by NMR gives very satisfactory and precise visualisation of the target structures based on transaxial, coronal and sagittal scans. With the technique described stereotactic localisation is performed by the surgeon directly in the operating room.

Visualisation of stereotactic radiolesions by nuclear magnetic resonance.

The ability to visualise stereotactic brain lesions produced by irradiation from the stereotactic Gamma Unit at the Karolinska Hospital was investigated. A patient who had undergone bilateral stereotactic gamma capsulotomy in two stages was examined by the nuclear magnetic resonance imaging technique, which demonstrated that the stereotactic lesions in the internal capsule could be visualised in the immediate postoperative period. This gives stereotactic radiosurgery a reliable anatomical basis and facilitates the planning and follow-up studies in this type of cerebral surgery.

Water diuretic effect of intravenously administered 9-deoxo-16, 16-dimethyl-9-methylene-PGE2 in conscious man.

The stable prostaglandin analogue 9-deoxo-16, 16-dimethyl-9-methylene-PGE2 (9-methylene-PGE2) was infused intravenously (0.5 ml/min) in the dosage of 20 micrograms/min for 2 h in conscious euhydrated man. The administration of 9-methylene-PGE2 rapidly induced an increase in urine flow (from 1.2 +/- 0.07 to 5.35 +/- 1.07 ml/min) concomitantly with a decrease in urine osmolality (from 827 +/- 40 to 193 +/- 44 mOsm/kg). Parallel to this tubular reabsorption of sodium (Na+), calcium (Ca2+) and magnesium (Mg3+) increased and that of potassium (K+) decreased as shown by a reduction in the clearance for respective ion divided by the clearance of inulin. Apparently the water diuresis was mediated by an inhibition of arginine vasopressin's (AVP) antidiuretic effect. The mechanism behind the increase in renal tubular reabsorbtion of Na+ could possibly be a 9-methylene-PGE2 mediated modulation of the renal aldosterone effect. However the protocol followed did not provide any evidence for this, or any other explanation of the observed renal retention of Na+, Ca2+ and Mg2+. The results reported here indicate that 9-methylene-PGE2 may have a future use as a water diuretic agent in patients suffering from water retention and dilutional hyponatraemia such as seen in the syndrome of inappropriate antidiuretic hormone (AVP) release commonly known as SIADH or Schwartz-Bartter's Syndrome.

The prostaglandin-analogue-9-deoxo-16,16-dimethyl-9-methylene-PGE2 inhibits the antidiuretic effect of vasopressin (AVP) in the conscious sheep.

The effects of intravenous infusions of the stable prostaglandin analogue 9-deoxo-16,16-dimethyl-9-methylene-PGE2 (9-methylene-PGE2) in a dosage of 10 or 24 micrograms/min were studied in the consicious euhydrated, dehydrated, and hyperhydrated with the simultaneous administration of exogenous arginine vasopressin (AVP), sheep. The infusions decreased urine osmolality and increased urine flow and renal free water clearance. The results indicate that 9-methylene-PGE2 exhibits its diuretic effect by antagonizing the antidiuretic action of AVP. In the hyperhydrated sheep receiving AVP the syndrome of inappropriate antidiuretic hormone release (SIADH) was simulated. As the prostaglandin analogue effectively blocked the antidiuretic effect of the AVP-administration it appears that 9-methylene-PGE2 may play a future role as a diuretic agent, especially in conditions characterized by water retention and dilutional hyponatremia such as SIADH.

Vasopressin release in response to acute hypotension induced at different time intervals in the conscious sheep.

The renal arginine vasopressin (AVP) excretion in response to acute systemic hypotension induced by intravenous infusion of sodium nitroprusside (SNP) (30-40 micrograms/kg min-1) at different experiment intervals (0, 2, 4, 7 and greater than or equal to 12 days) was studied in the conscious hyperhydrated sheep. During the first post-infusion hour, 2.5 times more AVP was excreted in response to hypotension induced at greater than or equal to 12 day intervals than that observed at intervals of 0-7 days. No interexperimental time dependence of the AVP response to SNP infusion was seen with intervals of 0-7 days. The attenuated AVP release obtained with reduced experiment intervals (0-7 days) was accompanied by shorter antidiuresis and a less accentuated natriuresis during the post-hypotensive period in comparison to what was observed with greater than or equal to 12 day experiment intervals. There were no interval-dependent differences in maximal fall of mean arterial pressure, or onset and recovery of the hypotension induced by SNP administration. It is suggested that acute systemic hypotension causes such a massive AVP release that more than one week is needed for complete restoration of a releasable neurohypophyseal pool of the hormone.

Stereotactic radiosurgery.

The development and scope of stereotactic radiosurgery is described. The technique, which combines well with the latest diagnostic methods, has already proved a safe and effective way of treating inaccessible cerebral lesions and in particular small arteriovenous malformations, acoustic neuroma and the solid component of craniopharyngioma, as well as playing an increasingly useful role in the therapy of pituitary adenoma.