Behavioral and histopathologic effects following intrathecal administration of butorphanol, sufentanil, and nalbuphine in sheep.

A large number of opioids and nonopioids have been administered epidurally and intrathecally in the hope of providing segmental analgesia without serious adverse effects. However, neurotoxicity data are generally unavailable for many of these drugs. The present study evaluated the behavioral, motor, electroencephalographic, and histopathologic changes following intrathecal injection of large and small doses of butorphanol, sufentanil, and nalbuphine in sheep. Thirty-two sheep (20-32 kg) were anesthetized and catheters placed intrathecally after hemilaminectomy. The large doses of butorphanol, sufentanil and nalbuphine were 0.375 mg/kg (4.4-5.2 ml), 7.5 micrograms/kg (3.6-4.8 ml) and 0.75 mg/kg (1.5-2.4 ml), and the small doses were 0.075 mg/kg (0.9-1.1 ml), 1.5 micrograms/kg (0.7-0.9 ml) and 0.15 mg/kg (0.38-0.5 ml), respectively. The opioids were administered intrathecally every 6 h for 3 days and the above-mentioned parameters studied. Five sheep received intrathecal saline (1.1 or 5.2 ml) and served as controls. Histopathologic changes were evaluated by a neuropathologist blinded to the study protocol. Irrespective of dose, intrathecal injection of butorphanol was associated with severe behavioral responses such as agitation, rigidity, vocalization, and restlessness, as well as prolonged or irreversible hindlimb paralysis. Electroencephalography showed increased cortical activity or seizure activity. One sheep died because of severe respiratory depression that did not respond to naloxone. Spinal cord histologic changes consisted of suppurative meningitis and myelitis as well as neuronal changes such as spongiosis and chromatolysis. Large doses of intrathecal sufentanil were associated with similar though somewhat less severe responses. The behavioral and motor changes following the small dose of intrathecal sufentanil were of mild to moderate nature. Following intrathecal nalbuphine, the above-mentioned changes were similar to those seen in control animals. We conclude that butorphanol in doses of 0.075 and 0.375 mg/kg intrathecally and sufentanil 7.5 micrograms/kg intrathecally are neurotoxic in sheep.

Osteomyelitis complicating fracture: pitfalls of 111In leukocyte scintigraphy.

111In-labeled leukocyte imaging has shown greater accuracy and specificity than alternative noninvasive methods in the detection of uncomplicated osteomyelitis. Forty patients with suspected osteomyelitis complicating fractures (with and without surgical intervention) were evaluated with 111In-labeled leukocytes. All five patients with intense focal uptake, but only one of 13 with no uptake, had active osteomyelitis. However, mild to moderate 111In leukocyte uptake, observed in 22 cases, indicated the presence of osteomyelitis in only four of these; the other false-positive results were observed in noninfected callus formation, heterotopic bone formation, myositis ossificans, and sickle-cell disease. These results suggest that 111In-labeled leukocyte imaging is useful for the evaluation of suspected osteomyelitis complicating fracture but must be used in conjunction with clinical and radiographic correlation to avoid false-positive results.

Long-term anticonvulsant therapy and intestinal calcium absorption.

Twelve patients on anticonvulsant therapy were studied to determine whether or not the drugs induced alterations in gastrointestinal absorption of calcium, response to parathyroid hormone (PTH), or serum 25-hydroxy vitamin D (25-OHD) concentrations. Fractional calcium absorption (FCaA) was determined by giving 45Ca intravenously and orally. The short-term response to PTH was assessed by giving 200 U of parathyroid extract (PTE) intravenously over 15 min and measuring hourly urine cyclic adenosine monophosphate (cAMP) and tubular reabsorption of phosphate (TRP). Calcemic response to PTH was followed by giving intramuscular injections of PTE, 200 U every 6 hr. FCaA was 30.8 +/- 3.7% lower than the normal of 42.2 +/- 2.5% (P less than 0.025), and baseline 25-OHD levels were 30.5 +/- 3.4 ng/ml (normal 15 to 50 ng/ml). Anticonvulsant drugs did not alter renal response to PTE. There was a rise in urinary cAMP from 3.7 +/- 0.23 to 6.1 +/- 0.47 mumol/gm creatinine (P less than 0.005) with a fall in TRP from 87.8 +/- 1.2% to 78.8 +/- 1.6% (P less than 0.005). Serum calcium rose from 9.4 +/- 0.1 to 11.1 +/- 0.3 mg/dl (P less than 0.005). We conclude that FCaA is low in patients receiving anticonvulsant drugs, even when serum 25-OHD levels and the response of bone and kidney to PTH remain normal.

Organ distribution of 99mTc- and 51Cr-labeled autologous peripheral blood lymphocytes in rabbits.

The present series of experiments was designed to compare 99mTc with 51Cr as a lymphocyte label in rabbits and to correlate organ distribution patterns as determined by postmortem counting with those observed by 99mTc gamma imaging. The distribution of 51Cr and 99mTc-labeled, viable and nonviable, unreduced or SnCl2-reduced autologous lymphocytes was determined 2 hr following intravenous injection. Viable 99mTc-labeled lymphocytes localized primarily in the liver, lungs, and kidneys or remained circulating in the blood. These compartments accounted for 34-54% of the injected radioactivity. One to three percent of the injected dose was recovered from the spleen, thyroid, bladder, and stomach, and all remaining organs accounted for less than 1%. Reduced, nonviable cells showed increased localization in the lungs and liver (48%) compared to viable unreduced cells (15%). Chromium-51-labeled lymphocytes were distributed primarily to the liver, lungs, and spleen or remained circulating in the blood. Hepatic localization differed from that observed with viable, unreduced 99mTc-labeled lymphocytes (32 vs. 12%), but vascular compartmentalization was similar (18 vs. 15%). The distribution of pertechnetate and reduced 99mTc was different from that of 99mTc-labeled cells. The urine and blood accounted for 84% of the recovered radioactivity, and for 43-45% of the injected dose, indicating that the patterns we observed with 99mTc-labeled lymphocytes truly represented cell-associated radioactivity. Similarly, the distribution of Na251CrO4 differed from that of 51Cr-labeled cells. The kidneys and urine accounted for 26% of the injected dose, compared with 5% for 51Cr-labeled lymphocytes, and only trace amounts of radioactivity were found in the lungs and spleen. The distribution of 99mTc-labeled cells, as determined by scintigraphy 90 min after injection, correlated well with data obtained by postmortem counting, suggesting that 99mTc may be applicable as a lymphocyte label for diagnostic gamma-imaging procedures.