Time course and role of morphine dose and concentration in intrathecal granuloma formation in dogs: a combined magnetic resonance imaging and histopathology investigation.

BACKGROUND: Intrathecal morphine infusion leads to intrathecal granulomas. In dogs, the authors examined time course of granuloma formation and the role of concentration in granuloma development. METHODS: Dogs were prepared with lumbar intrathecal catheters and vest-mounted pumps. To define the time course of granuloma formation, serial magnetic resonance imaging was performed in animals receiving 10 or 31 days of morphine infusion (12.5 mg/ml at 40 microl/h). At these times, morphine was removed from the infusate, and further magnetic resonance images were acquired over 14-35 additional days. To assess dose versus concentration, dogs received 28-day infusions of vehicle, 12 mg morphine/day as 12.5 mg/ml at 40 microl/h, or 1.5 mg/ml at 334 microl/h (12 mg/day) for 28 days. Additional dogs received 3 mg/day as 12.5 mg/ml at 10 mul/h. RESULTS: Serial magnetic resonance images in dogs receiving morphine (12.5 mg/ml at 40 microl/h) revealed pericatheter-enhancing tissues as early as 3 days with a prominent signal by 10 days. Removal of morphine reduced the mass volume within 7 days. At a fixed infusion rate, the incidence of granuloma formation with the continuous intrathecal infusion of morphine ranged from 0 in vehicle-treated dogs to 100% in dogs treated with 12.5 mg/ml at 40 microl/h (12 mg/day). Infusion of 12 mg/day at 1.5 mg/ml (334 microl/h) resulted in granuloma in one of four animals. The authors found that infusion of morphine in different concentrations at a fixed rate resulted in a dose-dependent increase in concentration, with the granuloma-producing, dose-yielding lumbar cerebrospinal fluid morphine concentrations around 40 microg/ml. CONCLUSIONS: Serial magnetic resonance imaging showed a rapid formation and regression of the masses initiated by intrathecal morphine infusion. These masses are dependent on local concentration.

Gadolinium-DTPA-dextran: a macromolecular MR blood pool contrast agent.

RATIONALE AND OBJECTIVES: Magnetic resonance (MR) imaging blood pool agents offer numerous advantages for vascular and tumor imaging. The purpose of this study was to test gadolinium-diethylenetriaminepentaacetate-dextran ([Gd]DTPA-dextran) as a new water soluble macromolecular blood pool agent for MR imaging. MATERIALS AND METHODS: [Gd]DTPA-dextran (187 gadolinium atoms per dextran, molecular weight 165 kD, diameter 17.6 nm) was synthesized. Fifteen anesthetized New Zealand White rabbits with thigh VX2 tumors were scanned in a knee coil at 1.5T. Coronal 3D MR angiographic sequences were obtained before and at several time points up to 72 hours after the intravenous bolus injection of [Gd]DTPA-dextran providing gadolinium at either 0.05 (n = 4) or 0.1 mmol/kg (n = 8) or [Gd]DTPA-bismethylamide (BMA) providing gadolinium at 0.1 mmol/kg (n = 3). Time enhancement curves for aorta, cava, and tumor rim were compared by univariate General Linear Model. RESULTS: Contrast enhancement of cava and aorta relative to a water phantom were significantly greater at all time points after either dose of [Gd]DTPA-dextran than after [Gd]DTPA-BMA (P < 0.01). Tumor rim enhancement was less intense for either dose of [Gd]DTPA-dextran at peak than for [Gd]DTPA-BMA (P < 0.05). Tumor rim enhancement with both doses of [Gd]DTPA-dextran became equivalent to that of [Gd]DTPA-BMA at one hour and was greater at 24 hours (P < 0.05). CONCLUSION: [Gd]DTPA-dextran is a new macromolecular MR contrast agent that can be synthesized to carry a high density of gadolinium atoms without intra-molecular cross-linking. It provides significantly greater vascular residence time than a conventional gadolinium chelate and shows promise for MR blood pool imaging.