Geoffrey Coates

Standardization of a simplified scintigraphic methodology for the assessment of gastric emptying in a multicenter setting

OBJECTIVE:Scintigraphy remains the gold standard to study gastric emptying. The technique is onerous and normal values vary between centers. Standardized protocols, although desirable, are not presently available. We validated a simplified scintigraphic protocol in a multicenter setting.METHODS:In 69 healthy volunteers from seven Canadian institutions, gastric emptying of a standard meal (99mTc- labeled beef liver) was assessed by scintigraphy every 10 min for 1 h, then every 20 min for the next 2 h. Gastric retention was fitted to a power exponential model, Propt={−(κt)β} with Propt= proportion of retention at time t, either using all 13 time intervals (conventional technique) or using measurements at 0, 1, 2, and 3 h (simplified technique).RESULTS:The power exponential model yielded identical emptying curves and T ½ values with both techniques. Gastric emptying was more rapid in men than in women < 35 yr (p < 0.01) and in younger than in older men (p < 0.005). Gastric emptying was slower in women from Québec than in women from Ontario (p < 0.04). Gastric retention was similar at 1, 2, and 3 h among the seven centers. Gastric emptying of a beef liver meal was slower than that of a low fat egg substitute (p < 0.03).CONCLUSIONS:A simpler scintigraphic approach, using four rather than 13 samples, provides results comparable to those of the conventional technique. This simpler approach provides an economical, yet accurate, alternative to the techniques presently used and is applicable to a multicenter setting.

Effects of exercise on lung lymph flow in sheep and goats during normoxia and hypoxia.

Vigorous exercise causes a marked increase in cardiac output with only a minimal increase in measureable pulmonary vascular pressures. These changes in pulmonary hemodynamics should affect lung water and solute movement. On nine occasions, we measured the effect of normoxic exercise on lung lymph flow in four sheep and two goats with chronic lymph fistulas (wt = 15-25 kg). In addition, lymph flow was also measured on five occasions in sheep during exercise at reduced barometric pressures (430 and 380 mmHg). During normobaria, the animals ran at 3-5 km/h with 0-10% elevation of the treadmill for 15 to 85 min. Exercise on average caused a 100% increase in cardiac output, a 140% increase in lung lymph flow, and a slight but significant reduction in lymph to plasma concentration ratio (l/p) for total protein and albumin (mol wt = 70,000). There was a significant linear correlation between lymph flow and cardiac output (r = 0.87, P less than 0.01). There was no change in l/p for IgG (mol wt = 150,000) or IgM (mol wt = 900,000) and no significant change in mean pulmonary arterial (Ppa) or mean left atrial (Pla) pressures. Transition from normobaria to hypobaria caused an increase in Ppa but no change in Pla, cardiac output, or lymph flow. Exercise during hypobaria caused increases in lymph flow that were qualitatively similar to changes observed during normobaric exercise: there was a 60% increase in cardiac output, a 90% increase in lymph flow, and an 11% reduction in l/p for total protein. There was no change in l/p for albumin, IgG, or IgM, and no further change in Ppa. The increased lymph flow during normoxic and hypobaric exercise is best explained by an increase in pulmonary vascular surface area for fluid and protein exchange. Our results suggest that the normal ovine lung has the potential to nearly triple the amount of perfused microvascular surface area. This speculation is relevant to the interpretation of lymph flow data from other experiments.

Pulmonary clearance of99mTc-DTPA: A noninvasive assessment of epithelial integrity

Nonstratified epithelium lines the respiratory tract from the trachea to distal lung units. An abnormality in the integrity of this critical barrier to the outside environment has been suggested as promoting or exacerbating a wide variety of clinical disorders ranging from asthma to acute lung injury syndromes. Recently the noninvasive measurement of the clearance rate of aerosolized and deposited99mtechnetium diethylenetriaminepentaacetate (99mTc-DTPA) has been used to assess pulmonary epithelial integrity. This paper discusses the merits and limitations of this technique, which is presently under extensive investigation in many research centers investigating pulmonary disease.

Pulmonary Deposition of Salbutamol Aerosol Delivered by Metered Dose Inhaler, Jet Nebulizer, and Ultrasonic Nebulizer in Mechanically Ventilated Rabbits

The deposition efficiency of three methods of aerosol delivery of salbutamol into lungs of ventilated rabbits was compared: 1) metered dose inhaler (MDI) with holding chamber (HC), 2) jet nebulizer (JN), and 3) ultrasonic (US) nebulizer. The latter system was tested using two different sized medication reservoirs, a large (20 mL) cup (US20) and a small (10 mL) cup (US10). After delivery of technetium-99m-labeled sulbutamol aerosol, deposition in the lungs, trachea, and ventilator circuit were estimated by a γ counter. Total pulmonary deposition [mean(SEM)] as a percentage of the prescribed drug was: MDI + HC 0.22(0.05)%; JN 0.48(0.05)%; US20 0.90(0.13)%; US10 3.05(0.49%)%. Only the deposition from the US10 was statistically significantly higher than the other modes (p < 0.05). Dynamic scintigraphy showed that, among the nebulizers, the US10 continued to deliver medication for longer than either the JN or the US20. We conclude that the US10 appears to be more efficient in delivering aerosol to the lung in this rabbit model and merits further evaluation for clinical efficiency.

[18F]fluorodeoxyglucose uptake in neonatal acute lung injury measured by positron emission tomography.

The objective of this study was to evaluate positron emission tomography(PET) of [18F]fluorodexoyglucose (18FDG) uptake as a measure of neonatal acute lung injury. Inasmuch as intrapulmonary sequestration of neutrophils is a hallmark of acute lung injury, quantification of neutrophil activity using 18FDG may offer a novel, in vivo technique to examine the progression and resolution of this disease. Ten newborn piglets were studied; six received bronchoalveolar lavage followed by 4 h of high pressure ventilation to create acute lung injury. Four healthy piglets served as controls. 18FDG (0.8 mCi/kg; 29.6 MBq) was given i.v. and PET (ECAT 953/31, Siemens) was performed for 90 min. During PET, all animals were sedated, paralyzed, and ventilated to maintain normal blood gases. The time course of radioactivity in lung regions and in plasma was used to calculate the rate constant for the metabolic trapping of 18FDG in tissue according to the method of C. S. Patlak. Median 18FDG influx constants were significantly higher in injured piglets (0.0187 min-1) than in control piglets (0.0052 min-1) (p < 0.01). Moreover, consistent with the 18FDG uptake data, injured piglets had moderate to severe injury on lung histology whereas control piglets had only slight and focal histologic changes. We conclude that PET of 18FDG uptake is an accurate, readily repeatable in vivo measure of neonatal acute lung injury.

Thrombin inhibitors reduce intrapulmonary accumulation of fibrinogen and procoagulant activity of bronchoalveolar lavage fluid during acute lung injury induced by pulmonary overdistention in newborn piglets

We determined whether antithrombin (AT III) or hirudin (a specific thrombin inhibitor) reduce both the accumulation of fibrinogen in lung parenchyma and the procoagulant activity of bronchoalveolar lavage (BAL) fluid during acute lung injury induced by pulmonary overdistention. Newborn piglets were randomized to six-hourly infusions of AT III concentrate, a continuous infusion of recombinant hirudin, or no anticoagulant therapy. All animals were subjected to 24 h of identical mechanical ventilation at high peak pressures(3.9 kPa or 40 cm H2O). Tidal volumes were raised to a mean of 69 mL/kg in all three groups. Mean AT III levels in supplemented piglets (n = 22) were increased to 1.46 (SD 0.24) U/mL at 24 h, compared with 0.67 (SD 0.16) U/mL in controls (n = 23). The median activated partial thromboplastin time in animals receiving hirudin (n = 18) was prolonged to 53 s versus 34 s in untreated animals. The intrapulmonary accumulation of i.v. administered 125I-fibrinogen was reduced by AT III concentrate or hirudin, compared with untreated littermates(p = 0.003). The procoagulant activity of BAL fluid was also decreased by both thrombin inhibitors (p = 0.001). Intrapulmonary accumulation of fibrinogen and the procoagulant activity of BAL fluid were reduced by AT III or hirudin during lung injury caused by pulmonary overdistention. Future investigations should determine whether tangible clinical benefits result from this reduced potential for fibrin deposition in the injured lung.

Delivery of metered dose inhaler aerosols to paralyzed and nonparalyzed rabbits

OBJECTIVE To assess whether paralysis alters pulmonary deposition of albuterol delivered by metered dose inhaler and spacer to small animals. DESIGN A parallel group study of intubated and ventilated rabbits. INTERVENTIONS Animals in group 1 (n = 7) were paralyzed with intravenous pancuronium, and ventilated at a rate of 30 breaths/ min. The animals in group 2 (n = 6) were ventilated at a rate of 10 breaths/min under light anesthesia without paralysis. In this latter group, spontaneous respiration continued at a rate of 40 to 50 breaths/min. Both groups were maintained at PaCO2 of 35 to 40 torr (4.7 to 5.3 kPa), and other ventilatory settings were identical. MEASUREMENTS AND MAIN RESULTS Technetium-99m labeled albuterol aerosol was delivered by metered dose inhaler via a spacer device to both groups. Pulmonary deposition of the aerosol, determined by measuring the radioactivity in the lung tissues at autopsy, was expressed as percent of the total radioactivity dispensed by the metered dose inhaler. Group 2 showed significantly greater lung deposition than group 1 (0.510 +/- 0.076 [SEM]% vs. 0.226 +/- 0.054%, p = .0094). Deposition in the airway, the endotracheal tube, and the ventilator circuit did not differ significantly. CONCLUSION Metered dose inhaler delivery of aerosolized medications to ventilated rabbits is significantly enhanced if respiration is not controlled. This observation might have implications for the delivery of therapeutic aerosols to newborns and young infants receiving slow, intermittent, mandatory ventilation.

Quantitative ventilation-perfusion lung scans in infants and children: utility of a submicronic radiolabeled aerosol to assess ventilation.

The quantitative assessment of regional pulmonary ventilation and perfusion provides useful information regarding lung function. Its use in infants and young children, however, has been minimal because of practical and technical limitations when the distribution of ventilation is assessed by radioactive gases. In 16 infants and children we used an inexpensive commercially available nebulizer to produce a submicronic aerosol labeled with 99mtechnetium-diethylenetriamine pentacetic acid to assess ventilation quantitatively, and intravenous injections of 99mtechnetium-labeled macroaggregates of albumin to assess pulmonary perfusion quantitatively. Studies were safely completed in both ambulatory and critically ill patients, including two premature infants who had endotracheal tubes in place for ventilatory support. No sedation or patient cooperation is required. This technique enables any department of nuclear medicine to measure regional pulmonary ventilation and perfusion in infants and children.

Ventilation scanning with technetium labeled aerosols. DTPA or sulfur colloid

We have compared the distribution in the lungs of submicronic aerosols of either Tc-99m sulfur colloid or Tc-99m DTPA immediately after inhalation with the distribution 20 minutes later in 83 patients. Thirty-two of the 83 patients were active smokers. Of the 28 smokers who received Tc-99m DTPA aerosol, the total lung count fell by a mean of 27 ± 14% between the 0 and 20 minute image. Eleven of these patients also had a major change in distribution of isotope during this time. In the nonsmoking patients total lung counts from Tc-99m DTPA fell by only 16 ± 8% and none had a major change in distribution pattern. None of the smoking or nonsmoking patients who received Tc-99m sulfur colloid had a significant change in count rate or distribution pattern over 20 minutes. The effects on the ventilation images of these rapid changes in count rate and distribution pattern after Tc-99m DTPA aerosol can be minimized by completing the ventilation study as quickly as possible after inhaling Tc-99m DTPA or by using a nondiffusible agent such as Tc-99m sulfur colloid.

Lung clearance of 99mTc-DTPA in patients with acute lung injury and pulmonary edema.

Several acute and chronic conditions that alter the integrity of the pulmonary epithelium increased the rate of absorption or clearance into the circulation of small solutes deposited in the alveoli. Technetium 99m diethylenetriamine pentaacetic acid can be deposited in the lungs as a submicronic aerosol and its rate of clearance measured with a gamma camera or simple probe. This clearance technique is currently being used to evaluate patients who have developed pulmonary edema and also to detect those patients from a high risk group who are likely to develop adult respiratory distress syndrome (ARDS). Its role in the evaluation of patients with pulmonary edema is still under active investigation. It is clear that a single measurement in patients who smoke is not useful, but repeated measurements may provide important information. The lung clearance measurement is very sensitive to changes in epithelial integrity but is not specific for ARDS. It may be most useful in combination with other predictive tests or when the clearance rate is normal.