Robert W. McPherson

Placebo-controlled pilot study of centromedian thalamic stimulation in treatment of intractable seizures.

Summary: Stimulation of centromedian (CM) thalamic nuclei has been proposed as a treatment for seizures. We implanted programmable subcutaneous (s.c.) stimulators into CM bilaterally in 7 patients with intractable epilepsy to test feasibility and safety. Stimulation was on or off in 3‐month blocks, with a 3‐month washout period in a double‐blind, cross‐over protocol. Stimuli were delivered as 9O‐μs pulses at 65 pulses/s, 1 min of each 5 min for 2 h/day, with voltage set to half the sensory threshold. Stimulation was safe and well‐tolerated, with a mean reduction of tonic‐clonic seizure frequency of 30% with respect to baseline when stimulator was on versus a decrease of 8% when the stimulator was off. There was no improvement in total number of generalized seizures with stimulation, and treatment differences were not statistically significant. Stimulation at low intensity did not alter the EEG acutely, but high‐intensity stimulation induced slow waves or 2–3 Hz spike‐waves with ipsilateral frontal maximum. In an open‐label follow‐up segment with stimulator trains continuing for 24 h/day, 3 of 6 patients reported at least a 50% decrease in seizure frequency. There were no side effects. This pilot project demonstrated the feasibility of controlled study of thalamic stimulation in epilepsy, but further study will be needed to demonstrate efficacy.

Cervicomedullary compression in young patients with achondroplasia: Value of comprehensive neurologic and respiratory evaluation

We studied prospectively 26 young patients with achondroplasia to test two hypotheses: that respiratory problems may be the result of occult spinal cord compression, and that achondroplastic patients with cord compression might have occult respiratory abnormalities. Respiratory abnormalities were present in 85%, the majority caused by a primary problem of the pulmonary system, such as small thoracic cage or obstructed airway. Three patients had hypoxemia, recurrent cyanotic spells, and episodes of respiratory distress explainable only by cervicomedullary cord compression; in each patient, respiratory problems were alleviated by decompressive surgery. Another six patients with cervicomedullary compression had, in addition, at least one primary pulmonary cause of respiratory problems. After decompressive surgery the respiratory problems improved in three and were unchanged in three. Reconstructed sagittal CT images proved the most sensitive technique for detecting craniocervical stenosis as a cause of cervicomedullary cord compression, although some degree of stenosis was present in nearly all of the patients.

Effects of Enflurane, Isoflurane, and Nitrous Oxide on Somatosensory Evoked Potentials during Fentanyl Anesthesia

The effects of nitrous oxide, enflurane, and isoflurane on cortical somatosensory evoked potentials (SEPs) were studied in 29 patients undergoing intracranial or spinal operations. Anesthesia was induced with fentanyl (25 μg/kg, iv) plus thiopental (0.5–1.0 mg/kg, iv). In one group of patients (n = 12), nitrous oxide (50%) was compared with enflurane (0.25–1.0%), and in another group (n = 12) nitrous oxide (50%) was compared with enflurane (0.25–1.0%). In all third group of patients (n = 5) with preexisting neurologic deficits, nitrous oxide (50%) was compared with enflurane (0.25–1.0%). In all three groups, one gas was administered for 30 min, and then the alternate gas was administered for 30 min; then the cycle was repeated for a total of two administrations of each of the two anesthetics. SEPs were determined before and after induction of anesthesia and at the end of each 30-min study period. The latencies and amplitudes of the early cortical components of the upper- and lower-extremity SEP were examined. Induction of anesthesia resulted in increases of latency in both upper- and lower-extremity SEPs-without any alteration of amplitude. Nitrous oxide, enflurane, and isoflurane each decreased the amplitude of the upper-extremity SEPs compared with the postinduction value. The amplitude of the upper-extremity SEPs was less during nitrous oxide than with either enflurane or isoflurane. Nitrous oxide decreased the amplitude of lower-extremity SEPs below postinduction value, while enflurane and isoflurane had no effect. Isoflurane and enflurane increased the latency of both upper- and lower-extremity SEPs slightly, while nitrous oxide had no effect. In patients with preexisting neurologic deficits, nitrous oxide decreased amplitude more than enflurane. The authors conclude that during fentanyl-based anesthesia either enflurane or isoflurane (0.25–1.0%) results in less alteration of cortical SEPs than does nitrous oxide (50%), and these concentrations of enflurane or isoflurane are compatible with the generation of waves that are adequate for evaluation.

Expanding uterotonic protection following childbirth through community-based distribution of misoprostol: Operations research study in Nepal

To determine feasibility of community‐based distribution of misoprostol for preventing postpartum hemorrhage (PPH) to pregnant woman through community volunteers working under government health services.

Effects of Isoflurane on Cerebral Auto regulation in Dogs

The effect of decreased cerebral perfusion pressure (CPP) on regional cerebral blood flow (CBF) with radiolabeled microspheres in dogs receiving either 1.4% or 2.8% isoflurane following anesthesia induction with thiopental (12 mg/kg, iv bolus) was studied. Mean arterial blood pressure (MABP), cerebrospinal fluid pressure (Pcsf), and sagittal sinus pressure (Pss) were measured. CPP of 83, 63, 53, 43, 33, and 23 mmHg were studied in three groups of animals. In group 1 (n = 6, isoflurane 1.4%) CPP was decreased by hemorrhage, in group 2 (n = 6, isoflurane 1.4%) CPP was decreased by increasing Pcsf while MABP was maintained constant, and in group 3 (n = 6; isoflurane 2.8%) CPP was decreased by hemorrhage. Control total CBF in groups 1, 2, and 3 was 69 ± 8, 72 ± 7, and 150 ± 25 ml · min-1 · 100 g-1, respectively, at CPP of 84 ± 1 mmHg. Flow to both cerebral hemispheres and brain stem in animals receiving 2.8% isoflurane was approximately twice that found with 1.4% isoflurane while CMRO2 was similar (about 3.5 ml · min-1 · 100 g-1). In groups 1 and 2 flow in all brain areas was maintained as CPP decreased to 43 mmHg and then flow decreased as CPP decreased further (P < 0.05). In group 3 flow to all brain areas decreased progressively as CPP decreased from 83 to 23 mmHg. At CPP of 43 mmHg and below, flow to cerebrum was similar in the three groups; however, flow to brain stem in group 3 animals remained elevated above groups 1 and 2 until CPP was decreased to 23 mmHg. Control cerebrovascular resistance (CVR) was 1.4 ± 0.2, 1.6 ± 0.2, and 0.8 ± 0.1 mmHg ml-1·min·100 g in groups 1, 2, and 3, respectively. In groups 1 and 2 CVR continuously declined as CPP decreased. In group 3 control CVR was less than groups 1 and 2 (P < 0.05) and was unchanged from control as CPP decreased from 83 to 23 mmHg. CMRO2 was 3.5, 3.8, and 3.1 ml·min-1·100 g-1 in groups 1, 2, and 3, respectively and was unchanged as CPP decreased. Cerebral autoregulation to decreased CPP is preserved with 1.4% isoflurane, whereas autoregulation is eliminated by 2.8% isoflurane. The increased CBF produced by 2.8% isoflurane maintains cerebral O2 delivery at or greater than that with 1.4% isoflurane as CPP is decreased.

Relationship of somatosensory evoked potentials and cerebral oxygen consumption during hypoxic hypoxia in dogs.

The effects of hypoxic hypoxia on cerebral hemodynamics and somatosensory evoked potential (SEP) were studied in 10 pentobarbital anestheteized dogs. Cerebral blood flow (CBF) was measured using the venous outflow technique and cerebral oxygen consumption (CMRO2) was calculated from the arterio-cerebro-venous oxygen difference times CBF. SEP was evaluated by percutaneous stimulation of an upper extremity nerve and was recorded over the contralateral somatosensory cortex. The latencies of the initial negative wave (N1), second positive wave (P2) and the amplitude of the primary complex (P1N1) were measured. Animals were breathed sequentially with oxygen concentrations of 21, 10, 6, 5, and 4.5% for five minutes each. Animals were returned to room air breathing when the amplitude of the SEP decreased to less than 20% of control and were observed for 30 minutes following reoxygenation. Severe hypoxia (4.5% O2) increased CBF to 200% of control, decreased CMRO2 to 45% of control, decreased amplitude and increased latency of SEP. Following reoxygenation, as CMRO2 increased toward control, latency of SEP decreased and amplitude increased and CBF returned to baseline within 30 min. During hypoxia and reoxygenation, the latencies of N1 and P2 and the amplitude of P1N1 were correlated with CMRO2 in individual animals. We conclude that changes in SEP amplitude and latency reflect changes in CMRO2 despite high CBF during rapidly progressive hypoxic hypoxia and following reoxygenation.

Effect of Nitric Oxide Synthase Inhibition on the Cerebral Vascular Response to Hypercapnia in Primates

BACKGROUND AND PURPOSE The role of nitric oxide in cerebrovascular response to changes in PCO2 is unclear. In the present study, we assessed responses at two levels of hypercapnia in a primate model before and after blockade of nitric oxide synthesis. METHODS We compared the effects of two levels of hypercapnia, defined as PCO2 of approximately 70 mm Hg (high-CO2 group, n = 5) and PCO2 of approximately 50 mm Hg (moderate-CO2 group, n = 6), on increases in regional cerebral blood flow (microspheres) before and after inhibition of nitric oxide synthase with N omega-nitro-L-arginine methyl ester (L-NAME; 60 mg.kg-1) in isoflurane-anesthetized cynomolgus monkeys (1.0% end-tidal concentration). RESULTS Before L-NAME administration, hypercapnia increased flow in all regions (eg, forebrain, high-CO2 group 69 +/- 10 to 166 +/- 15 mL.min-1.100 g-1; moderate-CO2 group, 49 +/- 7 to 93 +/- 15 mL.min-1.100 g-1) and decreased cerebral vascular resistance (high-CO2, 1.1 +/- 0.1 to 0.4 +/- 0.1 mm Hg.mL-1.min.100 g; moderate-CO2, 1.4 +/- 0.1 to 0.7 +/- 0.1 mm Hg.mL-1.min.100 g). During normocapnia, L-NAME decreased cerebral blood flow (high-CO2, 37 +/- 9%; moderate-CO2, 40 +/- 6%) and increased cerebral vascular resistance (high-CO2, 93 +/- 33%; moderate-CO2, 88 +/- 20%). After L-NAME, hypercapnia still increased blood flow in all regions (eg, forebrain: high-CO2, 56 +/- 7 to 128 +/- 3 mL.min-1.100 g-1, moderate-CO2, 36 +/- 5 to 57 +/- 8 mL.min-1.100 g-1) and decreased vascular resistance (high-CO2, 1.5 +/- 0.1 to 0.6 +/- 0.1 mm Hg.mL-1.min.100 g; moderate-CO2, 2.0 +/- 0.3 to 1.2 +/- 0.1 mm Hg.mL-1.min.100 g). In both groups L-NAME attenuated hypercapnia hyperemia by approximately 30% in cortex but not in other regions. CONCLUSIONS Nitric oxide contributes to basal vascular tone but is not a major contributor to the mechanism of hypercapnia-induced cerebral vasodilation, except in cortex, in primates.

Dexmedetomidine Decreases Seizure Threshold in a Rat Model of Experimental Generalized Epilepsy

Background:Dexmedetomidine (DEX) is a highly selective α2 agonist with marked sedative and analgesic properties thought to be mediated via reduction of central noradrenergic transmission. Because an anticonvulsant effect is associated with increased noradrenergic activity, we investigated the possible proconvulsant effects of DEX in an experimental model of generalized seizures. Methods:Male rats (n=82) were administered 0.9% saline as placebo (n=18) or pretreatment drug(s) before initiation of an infusion of pentylenetetrazol (PTZ) at 5.5 mg · kg-1 · min-1. The total dose of PTZ required to elicit electroencephalographic (EEG) and behavioral seizure activity was assessed. Blood samples were obtained 15 min after initiation of Infusion (82.5 mg/kg) for determination of serum PTZ concentrations by gas chromatography. Pretreatment drug groups included DEX (20 µg/kg [n=11], 100 µg/kg [n=14], and 500 µg/kg [n=10]); L-medetomidine (500 µg/kg [n=7]); the α2 antagonist atipamezole (500 µg/kg [n - 9]); and atlpamezole (500 µg/kg) before DEX (100 µg/kg [n=7] and 500 µg/kg [n - 6]). Results:In control animals, PTZ 25-35 mg/kg induced EEG evidence of epileptiform activity. The mean dose to EEG epileptiform activity and clonic convulsions was 30 ± 5.8 (SE) and 59 ± 3.2 mg/kg, respectively. Infusion of DEX at 100 and 500 µg/kg resulted in a marked sedative response and reduced the EEG seizure threshold of PTZ to 18 ± 1.5 and 7 ± 1.8 mg/ kg, respectively (P<0.05 at both doses). The clonic convulsant threshold also was significantly decreased In both groups, to 37 ± 3.2 and 28 ± 2.3 mg/kg (P<0.01 at each dose). Before clonic convulsion, a significantly greater number of motor seizure manifestations were scored in the DEX-treated animals at all three dose levels compared with the number scored in control animals. The proconvulsant action of DEX was not a result of alteration of PTZ kinetics, because serum concentrations did not differ between control and DEX-treated animals. Animals treated with L-medetomidine demonstrated more paroxysmal motor phenomena before clonic seizures than controls (P<0.01) although the clonic seizure threshold was not altered. Atlpamezole alone did not alter background EEG, nor did it affect the clonic convulsant threshold. Atipamezole did, however, block the proconvulsant behavioral action at both doses of DEX, raising clonic seizure threshold from 37 ± 3.2 to 59 ± 5.8 mg/kg (100 µg/kg DEX, P<0.05) and from 28 ± 2.3 to 59 ± 6.9 mg/kg (500 µg/kg DEX, P<0.01). Conclusions:DEX exerted a significant proconvulsant action In the PTZ experimental seizure model. The pharmacodynamlc effect was dose-dependent and stereospeclfic and was blocked by the selective α2-receptor antagonist atlpamezole. These data are consistent with previous data demonstrating that Inhibition of central noradrenergic transmission facilitates seizure expression. Further evaluation of DEX for possible clinical proconvulsant effects may be warranted.

Pneumocephalus: Effects of patient position on the incidence and location of aerocele after posterior fossa and upper cervical cord surgery

The incidence of pneumocephalus and factors contributing to its occurrence were studied retrospectively in 100 consecutive patients who underwent posterior fossa or cervical cord surgery in the sitting, park-bench, and prone positions. Supine skull x-ray films taken immediately postoperatively were used to determine the presence of intracranial air. Surgery in the sitting position uniformly resulted in pneumocephalus (32/32 patients). Pneumocephalus also occurred frequently among patients in the park-bench (29/40) and prone positions (16/28). Intraventricular air occurred more frequently when patients were in the sitting position (25/32) than in the two other surgical positions (3/29 and 4/16, respectively, P < 0.001). The high incidence of pneumocephalus and of intraventricular air that occurred when patients were in the sitting position is attributed to the large amount of cerebrospinal fluid drained due to gravitational effect. When surgical position is considered one of the contributing factors, only position significantly affected the frequencies of pneumocephalus and intraventricular air accumulation. None of the 77 patients with pneumocephalus suffered neurologic change related to the presence of intracranial air. We conclude the following: pneumocephalus commonly occurs after posterior fossa or cenvical cord surgeries, particularly when the surgery is performed in the sitting position; neurologic change caused by pneumocephalus is a rare complication after posterior fossa craniotomy; when a patient with coexisting hydrocephalus undergoes surgery, if the patient is in the sitting position, there is an increased risk of trapping a large amount of intracranial air.

N omega-nitro-L-arginine methyl ester prevents cerebral hyperemia by inhaled anesthetics in dogs.

The mechanism by which halothane, isoflurane, and nitrous oxide increase cerebral blood flow (CBF) is unknown. We assessed the cerebrovascular effects of nitrous oxide (70%; n = 6), isoflurane (1 minimum alveolar anesthetic concentration: 1.4%; n = 6) or halothane (1 minimum alveolar anesthetic concentration: 0.8%; n = 6) before and after blockade of nitric oxide (NO) synthase with 40 mg/kg N omega-nitro-L-arginine methyl ester (L-NAME) intravenously in dogs with baseline pentobarbital anesthesia. Baseline CBF (microspheres) was determined after 1 h of pentobarbital anesthesia. Cerebral perfusion pressure (CPP) was maintained during inhaled anesthetic or L-NAME by either hemorrhage or inflation of an intra-aortic balloon. Before L-NAME, halothane and isoflurane increased CBF (40 +/- 4 to 56 +/- 6 mL.min-1 x 100 g-1 and 43 +/- 6 to 78 +/- 12 mL.min-1 x 100 g-1, respectively) with no change in cerebral oxygen consumption (baseline: halothane, 2.6 +/- 0.2; isoflurane, 2.0 +/- 0.2 mL.min-1 x 100 g-1). On the contrary, nitrous oxide increased CBF similarly (40 +/- 6 to 57 +/- 8 mL.min-1 x 100 g-1), but increased cerebral oxygen consumption (2.2 +/- 0.3 to 3.0 +/- 0.3 mL.min-1 x 100 g-1). L-NAME decreased blood flow in the neurohypophysis by 80% with no change in blood flow in other brain regions. After L-NAME, reexposure to nitrous oxide, halothane, or isoflurane resulted in no change in CBF.(ABSTRACT TRUNCATED AT 250 WORDS)