P. Prithvi Raj

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.

Comparison of insulated and uninsulated needles for locating peripheral nerves with a peripheral nerve stimulator.

This study was designed to compare the use of insulated and uninsulated needles with a peripheral nerve stimulator for locating a peripheral nerve in an anesthetized cat. The needles were mounted on a one-dimensional manipulator and both the saphenous and sciatic nerves were located. The tip of the insulated needle was consistently placed on the sciatic nerve. The tip of the uninsulated needle was placed 0.1–0.9 cm past the sciatic nerve. Injecting saline to assess the position of the tip of the needle relative to the sciatic nerve did not detect the needle being past the nerve. With the saphenous nerve preparation, both the needle and nerve were visible through the tissue. Using an insulated needle, the minimum current required to stimulate the nerve occurred when the tip of the needle touched the saphenous nerve. Using an uninsulated needle, the minimum current occurred when the tip was 0.1–0.8 cm past the nerve. The conclusion is that insulated needles more precisely locate the peripheral nerve than uninsulated needles.

Comparison of continuous epidural infusion of a local anesthetic and administration of systemic narcotics in the management of pain after total knee replacement surgery

Continuous bupivacaine epidural analgesia was compared with conventional methods of systemic analgesic administration in the management of postoperative pain in 30 patients for 3 days following total knee replacement surgery. Patients given continuous epidural analgesia had significantly better pain relief (visual analogue scale, global evaluation), needed significantly fewer supplementary analgesics, and had significantly fewer side effects. In the epidural group, sensory block averaged six dermatomes on day 1 and four dermatomes on day 3. The number of patients with complete (or almost complete) motor block of the lower limbs decreased from eight on day 1 to five on day 3. The mean dosage of bupivacaine decreased from 21.0 ± 5.7 (SD) mg/hr on day 1 to 15.1 ± 8.5 mg/hr on day 3. No signs of accumulation of or toxic reactions to bupivacaine were seen.

Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes. DOI: http://dx.doi.org/10.7554/eLife.12089.001

Differential Peripheral Nerve Block by Local Anesthetics in the Cat

Controversy still surrounds the differential susceptibility of nerve fibers to local anesthetic conduction block. In order to help resolve this controversy, we developed an in vivo model of peripheral nerve blockade in the cat that closely reproduced the clinical state. Using this model, differential rate of nerve blockade of A-alpha, A-delta, and C fibers by 2-chloroprocaine, lidocaine, bupivacaine, and etidocaine was observed and quantitated. C fibers were blocked first by 2-chloroprocaine, lidocaine and bupivacaine. Etidocaine blocked A-delta fibers first. A-alpha fibers always were blocked last. Of the four local anesthetics tested, 2-chloroprocaine produced the greatest differential rate of block of the nerve fibers, and etidocaine produced the least.

DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA:DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.

Neural Blockade and Pharmacokinetics following Subarachnoid Lidocaine in the Rhesus Monkey I. Effects of Epinephrine

A sensitive and reliable animal model for the objective physiologic and pharmacokinetic evaluation of spinal anesthesia has been developed. Using this model, spinal anesthesia using lidocaine (30 mg) in 7.5% dextrose with and without epinephrine was compared. Epinephrine did not alter the degree or duration of time to achieve maximum motor block. However, epinephrine did significantly increase the time for complete motor recovery. A significantly higher dermatome level of sensory block was achieved in the epinephrine-containing solutions, as well as a significantly longer time for complete recovery. This reflects a latent effect of epinephrine, as the time for two-segment regression was independent of epinephrine. Pharmacokinetic analysis showed no effect of epinephrine on absorption and elimination constants. The maximum plasma concentration and time to reach maximum plasma concentration were equal with and without epinephrine.

Continuous intravenous infusion of methadone for control of burn pain.

Seventeen patients with acute, severe burns were treated with a two-stage continuous, intravenous infusion of methadone to control pain. An initial loading infusion was run for 2 hours at 0.1 mg/kg/hr of methadone; then a maintenance infusion was continued at 0.01 mg/kg/hr of methadone. Median visual analog scale scores were 70% pain relief after the 2-hour loading infusion and 80% after 24 hours. Cardiovascular parameters were stable. There was a significant decrease in the respiratory rate of the patients. It appears that continuous intravenous methadone is an effective analgesic agent for the patient with acute, severe burns. Administration of the drug should be on an individualized basis with conservative dosing in a well-monitored environment because somnolence and respiratory depression can occur.

Primary osteomyelitis caused by hypervirulent Klebsiella pneumoniae

Klebsiella pneumoniae is the most clinically relevant species of this genus, known to cause both community-acquired and nosocomial infections worldwide. In the past two decades, a distinct hypervirulent strain of K pneumoniae, characterised by its hypermucoviscous phenotype, has emerged as a clinically significant pathogen responsible for highly invasive infections. We present a case of osteomyelitis due to hypervirulent K pneumoniae reported in the USA. Genomic testing of the K pneumoniae isolate was performed due to the striking clinical presentation of the infection as well as the hypermucoid nature of the isolates, raising the suspicion for possible infection with the hypervirulent strain. Whole-genome sequencing and additional PCR testing demonstrated the isolate to be a K1 serotype, sequence type 23 strain expressing rmpA and rmpA2. Given the multiple reports of this pathogen causing invasive infections, clinicians should be aware of the possible presentation of metastatic and severe infection, including osteomyelitis, due to the hypervirulent strain of K pneumoniae not typical of classic K pneumoniae variants. In this Grand Round, we review the clinical features of hypervirulent K pneumoniae and its link to invasive infections, and discuss the need for improved awareness and identification of the pathogen.

Multi-disciplinary Management of Reflex Sympathetic Dystrophy

The diagnosis and definition of reflex sympathetic dystrophy has already been well addressed in this text. It is also apparent from previous chapters that treatment is not always successful and that further comparative studies are required, in order to better our patient evaluation and treatment methods. A number of scales have also been proposed to confirm early diagnosis and initiate appropriate therapy (1,2). Although a small number of these cases of RSD obtain resolution spontaneously or with minimal therapy, most of those cases presenting to major treatment centers, suffer prolonged pain which is difficult or impossible to fully resolve.