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Objective: To test the hypothesis that either decreased ventilatory drive or decreased CO2 responsiveness accounts for the hypoventilation observed in patients during acute ventilatory failure from myasthenia gravis or Guillain-Barré syndrome., Design: Prospective, consecutive case series evaluating trials of ventilatory muscle performance, ventilatory drive, and CO2 response in patients during recovery from ventilatory failure until they were weaned from mechanical ventilation., Setting: Neurosciences critical care unit in a university hospital., Patients: Seven intubated, mechanically ventilated patients with myasthenia gravis or Guillain-Barré syndrome., Interventions: Patients repeatedly performed mechanically unsupported, spontaneous breathing trials to the limits of endurance. After spontaneous breathing trials, patients underwent CO2 rebreathing studies., Measurements and Main Results: Seventy-three breathing trials were performed in three patients with Guillain-Barré syndrome and four patients with myasthenia gravis. Patients were unable to sustain spontaneous ventilation in 55 trials averaging 27 +/- 5 mins. In these trials, significant increases occurred in mean end-tidal CO2 (41 +/- 1 to 44 +/- 1 torr [5.6 +/- 0.1 to 6.0 +/- 0.1 kPa]) and respiratory rate (31 +/- 1 to 35 +/- 1 breaths/min, p < .01). Ventilatory drive (as measured by airway occlusion pressure for 100 msecs) increased significantly p < .01 from 3.7 +/- 0.3 to 4.9 +/- 0.3 cm H2O. The response of airway occlusion pressure to CO2 rebreathing after these trials was 0.33 +/- 0.07 cm H2O/sec/mm Hg, while the minute ventilation response to CO2 rebreathing was only 0.30 +/- 0.06 L/min/mm Hg., Conclusions: These results suggest that ventilatory drive increases during acute hypoventilation, and the ventilatory drive response to CO2 remains intact, even when the minute ventilation response to CO2 is poor. Therefore, a decrease in ventilatory drive or CO2 response is unlikely to account for hypoventilation during ventilatory failure in patients with myasthenia gravis or Guillain-Barré syndrome.

The authors tested the hypothesis that cerebral blood flow (CBF) reactivity to CO2 was blunted following subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage was produced in five cats by performing four cisterna magna injections of blood in each (SAH Group). A second group of six cats was treated with an antifibrinolytic agent (AF) in addition to four cisterna magna blood injections (SAH+AF Group). Four cats received AF and four cisterna magna injections of saline (Control Group). The presence or absence of basilar artery vasospasm was determined by comparing baseline and follow-up selective angiograms. Cerebral blood flow reactivity was determined by randomly varying the concentration of inspired CO2 to alter PaCO2 from 20 to 75 mm Hg. Regional CBF was measured with radiolabeled microspheres. Basilar artery vasospasm was seen following subarachnoid injection of blood but not of saline. Normocapnic CBF was similar in all three groups in the brain stem (mean +/- standard error of the mean: SAH Group 46 +/- 6, SAH+AF Group 46 +/- 6, and Control Group 44 +/- 9 ml/min/100 gm) and in the supratentorial compartment (SAH Group 53 +/- 8, SAH+AF Group 61 +/- 9, and Control Group 51 +/- 13 ml/min/100 gm). At intermediate levels of hypercarbia (PaCO2 50 +/- 3 mm Hg), CBF increased similarly in all three groups (SAH Group 161% +/- 32%, SAH+AF Group 118% +/- 33%, and Control Group 174% +/- 19% compared to baseline); at higher levels of PaCO2 (60 +/- 3 mm Hg), CBF values were SAH Group 265% +/- 50%, SAH+AF Group 205% +/- 47%, and Control Group 159% +/- 30% of baseline. At the highest level of PaCO2 (75 +/- 6 mm Hg), supratentorial CBF did not increase as much in the SAH+AF Group as in the Control Group (179% +/- 59% vs. 463% +/- 58% of baseline, respectively). The authors conclude that, in this model of SAH, there is no change in normocapnic CBF; however, blood flow reactivity to hypercarbia is blunted. It is possible that this may result from a combination of narrowing of proximal large vessels and globally impaired reactivity of small vessels.

Moderate hypoglycemia (MH) may be associated with blunting of cerebral hypocapnic vasoconstriction. Coincident with this change, electroencephalogram (EEG) flattening occurs. Previous reports show that brain extracellular potassium activity ([K+]o) increases in association with the onset of isoelectricity during severe hypoglycemia and that K+ increases cause pial vessel vasodilation. Using a model of MH, we tested the hypothesis that increases in [K+]o (approximately 15 mM) correlate with blunting of cerebral hypocapnic vasoconstriction. Cerebral blood flow (CBF), [K+]o, and EEG were measured during normocapnia [arterial Pco2 (Paco2) = 35 Torr)] and hypocapnia (PaCO2 = 15 Torr) in MH (< 2 mM) and normoglycemic dogs. During MH, increases in [K+]o occurred in association with EEG flattening (from 4.2 +/- 0.5 to 13.8 +/- 3.8 mM). During normoglycemia and MH without [K+]o elevations, hypocapnic vasoconstriction occurred. [K+]o elevations with MH were associated with increased CBF and decreased vascular resistance (146 +/- 5 and 42 +/- 2% of control, respectively) during normocapnia, and blunting of cerebral hypocapnic vasoconstriction (93 +/- 16% normocapnic control) when [K+]o increased during hypocapnia. This study shows that increases in [K+]o during MH are necessary for both normocapnic increases in CBF and blunting of cerebral hypocapnic vasoconstriction. Increases in [K+]o may represent a mechanism for decreases in cerebral vascular resistance during MH.

Seven adult patients received human immune globulin intravenously as initial therapy for Guillain-Barré syndrome. Although all patients initially stabilized or improved, five patients deteriorated 1 to 16 days after completion of treatment. In all five patients, clinical worsening included loss of at least one functional grade together with a decreased forced vital capacity. We subsequently treated each patient with a course of plasma exchange, which led to varying degrees of clinical improvement in four. In contrast to previously reported relapse rates for Guillain-Barré syndrome, our experience suggests that clinically significant relapses may occur in patients more often following human immune globulin therapy than after either plasma exchange or no therapy.

Estimation of time-varying changes in evoked potentials (EP's) has important applications, such as monitoring high-risk neurosurgical procedures. We test the hypothesis that injury related changes in EP signals may be modeled by orthonormal basis functions. We evaluate two models of time-varying EP signals: the Fourier series model (FSM) and the Walsh function model (WFM). We estimate the Fourier and Walsh coefficients with the aid of an adaptive least-mean-squares technique. Results from computer simulations illustrate how selection of model order and of the adaptation rate of the estimator affect the signal-to-noise ratio (SNR). The FSM results in a somewhat higher steady-state SNR than does the WFM; however, the WFM is less computationally complex than is the FSM. We apply these two orthonormal functions to evaluate transient response to hypoxic hypoxia in anesthetized cats. Trends of the first five frequencies (Fourier) and sequencies (Walsh) show that the lower frequencies and sequencies may be sensitive indicators of hypoxic neurological injury.

Objective: To review the management and therapeutic approaches to severe acute Guillain-Barré syndrome, with emphasis on the ventilatory dysfunction, and cardiovascular instability seen in patients with this syndrome., Data Sources/study Selection: Clinical studies on Guillain-Barré syndrome patients, physiologic studies on animals and humans., Data Extraction/synthesis: Guillain-Barré syndrome is an acutely evolving, immune-mediated, inflammatory disorder of the peripheral nervous system, leading to demyelination and axonal loss. Clinical hallmarks are symmetric flaccid muscle paresis and areflexia in the presence of an increased cerebrospinal fluid protein content, and electrophysiologic studies demonstrating evolving demyelination. The only well-investigated, efficacious immunomodulatory therapy is plasmapheresis. Plasmapheresis has been shown to decrease ventilator dependence in severe Guillain-Barré syndrome. Ventilatory failure and cardiovascular instability are the main reasons for intensive care support. Ventilatory failure is caused by involvement of airway and respiratory muscles, particularly the diaphragm. Cardiovascular instability is due to involvement of the autonomic nervous system and results in labile blood pressure, cardiac arrhythmias, and hypovolemia. After admission to the intensive care unit, the most serious complications result from mechanical ventilation, circulatory disturbances, thrombosis, starvation, and sepsis. Special emphasis should be given to psychologic support and management of pain., Conclusions: With modern intensive care support, the outcome is excellent (> 80% recovery). In severe cases, a higher frequency of persistent residual paresis occurs; however, the majority of this group ultimately have a good functional recovery.

The absolute value of intracranial pressure (ICP) should be considered in conjunction with evaluation of a patient's clinical condition. In addition, other aspects of cranial vault mechanics may be important in multiple disease states. Among the important physiological measures of cranial vault sufficiency are hydrodynamic interaction between brain tissue, blood and cerebrospinal fluid (CSF)--volume-pressure relation, CSF dynamics--CSF outflow resistance, CSF production rate, sagittal sinus pressure, and appearance of ICP waves. Clinical and experimental studies brought together in this review provide an insight into the dynamics of ICP and the cranial vault.

We defined the extent of vasoactive intestinal polypeptide (VIP) and noradrenergic influences on isolated 100- to 200-microns-diameter vessels from the resistance arterial circulation of the neurohypophysis. A dual extracranial (inferior hypophysial) and intracranial (superior hypophysial) arterial supply to the neurohypophysis was confirmed. The inferior hypophysial artery demonstrates noradrenergic and VIP-like perivascular nerves, whereas the superior hypophysial artery shows primarily VIP-like innervation. Pharmacological sensitivity of the inferior hypophysial to VIP [mean effective dose (ED50) = 10(-8.2) M] and to norepinephrine (ED50 = 10(-5.7) M) was demonstrated. The superior hypophysial reacted only to VIP (ED50 = 10(-8.6) M). The physiological relevance of these findings was tested with transmural nerve stimulation. Frequency-dependent vasodilation of both inferior and superior hypophysial arteries was demonstrated. This dilation could not be blocked with atropine or propranolol. Frequency-dependent vasoconstriction was identified in extracranial vessels including the inferior hypophysial artery. This constriction is only partially blocked by prazosin, phentolamine, and guanethidine. When neurohypophysial resistance vessels are compared with larger circle of Willis arteries and similar-size pial vessels of other cerebral regions, they appear to have regionally unique neural mechanisms for regulating blood flow. Specifically whether controlled by periarterial nerves or other tissue influences, the inferior hypophysial artery appears to meet anatomic, pharmacological, and physiological definitions of neural control for both dilator and constrictor activities of flow to the neurohypophysis.

We studied 21 patients with Guillain-Barré syndrome who demonstrated multiple nutritional risk factors upon admission to an intensive care unit: ventilator dependence (71.4%), adynamic ileus (23.8%), significant weight loss in the 2 weeks before admission (53.0%), antecedent viral illness with gastrointestinal sequelae (43.0%), cranial nerve deficits impairing oral intake and gastrointestinal motility (60%), and depressed serum transferrin (85.7%). Patients are hypermetabolic and hypercatabolic because of endocrine, infectious, and inflammatory components of the disease. High-energy (40 to 45 nonprotein kcal/kg), high-protein (2.0 to 2.5 g/kg) nutrition support appears to exert a favorable effect on visceral protein repletion, nitrogen balance, and resistance to pulmonary infection. Immediate attainment of positive energy balance in these hypermetabolic patients, ideally assessed by indirect calorimetry and followed by high-energy, high-protein feedings, may promote positive nitrogen balance early and attenuate muscle wasting in Guillain-Barré syndrome.

This study tested the hypothesis that cerebral blood flow (CBF) is maintained by vasodilation, which manifests itself as a progressive increase in mean transit time (MTT) and cerebral blood volume (CBV) when cerebral perfusion pressure is reduced. Cerebral perfusion pressure was decreased in 10 pentobarbital-anesthetized dogs by controlled hemorrhage. Microsphere-determined CBF was autoregulated in all tested cerebral regions over the 40- to 130-mmHg cerebral perfusion pressure range but decreased by 50% at approximately 30 mmHg. MTT and CBV progressively and proportionately increased in the right parietal cerebral cortex over the 40- to 130-mmHg cerebral perfusion pressure range. Total hemoglobin content (Hb1), measured in the same area by an optical method, increased in parallel with the increases in CBV computed as the (CBF.MTT) product. At 30 mmHg cerebral perfusion pressure, CBV and Hb were still increased and MTT was disproportionately lengthened (690% of control). We conclude that within the autoregulatory range, CBF constancy is maintained by both increased CBV and MTT. Outside the autoregulatory range, substantial prolongation of the MTT occurs. When CBV is maximal, further reductions in cerebral perfusion pressure produce disproportionate increases in MTT that signal the loss of cerebral vascular dilatory hemodynamic reserve.

Hyponatremia is common following subarachnoid hemorrhage and has alternatively been attributed to either the inappropriate secretion of antidiuretic hormone or natriuresis causing intravascular volume contraction. We prospectively studied body sodium and intravascular volume regulation in 19 patients, beginning within 3 days after acute aneurysmal subarachnoid hemorrhage occurred, in order to determine the impact of hypervolemic therapy on both hyponatremia and volume contraction and to ascertain whether humoral factors account for hyponatremia. Serial measurements of plasma arginine vasopressin, atrial natriuretic factor, renin activity, aldosterone, and catecholamines were correlated with body sodium and fluid balance, change in blood volume, serum sodium concentration, and osmolality. Six patients (32%) developed hyponatremia, but only 2 had a negative sodium balance. In most patients, levels of atrial natriuretic factor were elevated, while plasma renin activity and aldosterone concentrations were generally suppressed. Plasma arginine vasopressin levels were not suppressed during hypo-osmolality and did not correlate with serum osmolality in hyponatremic patients. Only 1 patient had a decrease in blood volume, which was associated with marked rises in aldosterone and plasma renin activity, but normal serum sodium and plasma atrial natriuretic factor levels. We conclude that following subarachnoid hemorrhage: (1) Hypervolemic therapy prevents volume contraction but not hyponatremia, (2) humoral factors may favor both sodium loss and water retention, and (3) arginine vasopressin regulation is disturbed and may contribute to hyponatremia.

The mechanism(s) responsible for the onset of presyncope during a central hypovolaemic challenge have gone undefined for many years. It has been speculated that a decrease in cerebral blood flow initiates presyncopal responses, which in turn lead to greater decreases in cerebral oxygen delivery and unconsciousness. Somatosensory evoked potentials (SEP) were monitored as a measure of cerebral functioning in ten subjects during presyncopal symptom limiting lower body negative pressure (a central hypovolaemic challenge). SEP latency and amplitudes have been correlated with cerebral oxygen uptake, so SEP activity can serve as an indirect indicator of cerebral homeostasis. SEPs were generated by electrically stimulating the median nerve and recoding the resulting potentials over the contralateral cerebral cortex. While heart rate and mean blood pressure both fell at presyncope, there were no changes noted in either SEP latency or amplitude at any point before (latency = 22.9 +/- 9 ms; amplitude = 2.86 +/- 0.24 microV), during (22.6 +/- 0.9 ms; 2.68 +/- 0.2 microV), or after (22.7 +/- 0.9 ms; 2.37 +/- 0.23 microV) the occurrence of presyncope. We conclude that the onset of presyncope is not associated with a decrease in cerebral function.

Regional cerebral and neurohypophysial blood flow responses to isotonic extracellular fluid volume expansion were studied in pentobarbital-anesthetized dogs using radiolabeled microspheres. Measurements were made at baseline and after increasing pulmonary capillary wedge pressure by 8 +/- 2 mmHg. Plasma arginine vasopressin (AVP) decreased by 50%, and neural lobe blood flow (NLBF) decreased by 47%. Blood flow through median eminence and other brain regions was unchanged. We investigated potential mechanisms responsible for the NLBF changes. Following control vagotomy, AVP concentration increased during the first hour and then returned to control values for hours 2 and 3, whereas NLBF was unchanged for the first hour and fell after 2 and 3 h. Vagus section abolished the decrease in NLBF but not the AVP response to volume expansion. The contribution of left atrial and pulmonary baroreceptors to this response was tested by inflation of a balloon in the left atria to produce a 13 +/- 1 mmHg rise in atrial pressure. This led to a 20% reduction in NLBF, a 35% reduction in AVP concentration, and a 270% increase in plasma atrial natriuretic factor (ANF). However, ANF release does not account for the NLBF changes, since intravenous ANF infusion had no effect on NLBF or AVP concentration. These data suggest that the NLBF response to volume expansion is mediated by the vagus with input from multiple cardiopulmonary baroreceptors.

Objective: To test the hypothesis that preoperative lumbar epidural morphine improves postoperative pain control and ventilatory function after transsternal thymectomy in patients with myasthenia gravis., Design: The study design was randomized, placebo-controlled, and double-blind., Setting: After surgery, all patients were admitted to the Neuroscience Critical Care Unit for evaluation and treatment., Patients: All patients with myasthenia gravis who presented to the hospital for thymectomy were asked to participate in the study. Twenty patients were randomized to either the placebo or epidural morphine groups., Interventions: Patients received either epidural morphine (7 mg in 14 mL of sterile saline) or saline (14 mL) before induction of anesthesia. Supplemental iv opioids were administered intraoperatively, with need determined by the anesthesiologist., Main Outcome Measures: The main outcome measures were indicators of postoperative pain (e.g., Visual Analog Pain Score, requirement for supplemental opioid administration, respiratory rate) and ventilatory function (e.g., forced vital capacity, negative inspiratory pressure)., Results: Immediately after surgery, the Visual Analog Pain Score in the placebo group was twice as high as the score in the epidural morphine group (placebo 7.0 +/- 1.3; epidural morphine 3.5 +/- 1.2, p less than or equal to .05). During the first eight postoperative hours, the placebo group required more opioids (0.22 +/- 0.03 vs. 0.12 +/- 0.04 mg/kg morphine equivalents, p less than or equal to .06) than the epidural morphine group. Later, both groups received similar amounts of opioids. Patients receiving epidural morphine had better initial recovery of forced vital capacity (at 8 hrs: 55 +/- 6% [epidural morphine] vs. 34 +/- 5% [placebo] of preoperative value, p less than or equal to .05). Respiratory rate was lower for the first 12 postoperative hours in the epidural morphine group, without a difference in PaCO2. There was no difference between groups for the duration of postoperative intubation or ventilation., Conclusions: Preoperative lumbar epidural morphine facilitates postoperative analgesia and improves initial postoperative ventilatory performance.

Following subarachnoid hemorrhage, the plasma concentration of atrial natriuretic factor is elevated and appears to be independent of atrial stretch. While the hypothalamus and circumventricular organs contribute to sodium and intravascular volume regulation, their influence on atrial natriuretic factor is not known. We tested the hypothesis that, following subarachnoid hemorrhage, suprasellar cisternal blood, intraventricular blood, or ventricular enlargement would be associated with elevated plasma levels of atrial natriuretic factor. Computed tomograms of 26 patients performed less than or equal to 3 days after hemorrhage were analyzed to determine the presence of suprasellar or intraventricular blood and enlargement of the third or lateral ventricle. These results were correlated with the plasma atrial natriuretic factor and serum sodium concentrations. The initial atrial natriuretic factor concentration was elevated and was higher in patients with suprasellar or intraventricular blood than in those without (suprasellar: 131 +/- 20 and 54 +/- 10 pg/ml, respectively; intraventricular: 137 +/- 25 and 84 +/- 31 pg/ml, respectively). The atrial natriuretic factor concentration remained higher over the week following hemorrhage in patients with suprasellar blood than in those without (127 +/- 16 and 68 +/- 12 pg/ml, respectively). The atrial natriuretic factor concentration was not correlated with hyponatremia (125-134 meq/l) or age-corrected ventricular size. Hyponatremia did not correlate with the presence of intraventricular or suprasellar blood. Our data suggest that suprasellar and intraventricular blood disturb hypothalamic function, resulting in an elevated plasma atrial natriuretic factor concentration. The presence of a direct relation between atrial natriuretic factor and hyponatremia remains unclear.

Evoked potentials (EPs) have traditionally been analyzed in time domain, with amplitude and latency of various signal components used in clinical interpretation. A new approach, called adaptive Fourier series modeling (FSM), is presented here. Dynamic changes in magnitudes of Fourier coefficients are analyzed for diagnostic purposes. In order to estimate the time-varying changes in the Fourier coefficients of noisy signals, a least mean-square filtering algorithm is applied. Results of computer simulations as well as experimental data are presented. Time-varying trends are presented in a new compressed evoked spectrum format. These techniques are applied to the study of alterations in human somatosensory EPs caused by the intravenous administration of etomidate during neurosurgical procedures. Amplitude increases of the order of 200-500% occurring within a time span of about 100 sec were captured. Due to its superior convergence properties, the adaptive FSM technique estimates more rapid changes in amplitude and latency than exponentially weighted averaging or moving window averaging schemes.

While the in vitro reactivity of cerebral conducting vessels following subarachnoid hemorrhage has been extensively studied, in vivo cerebrovascular CO2 reactivity has not been systematically investigated. We tested the hypothesis that, in the canine model of subarachnoid hemorrhage, the rise in cerebral blood flow normally seen with hypercapnia is blunted during delayed vasospasm. Four groups of animals were studied: one received two 4-ml subarachnoid injections of nonheparinized arterial blood into the cisterna magna (n = 8), one received three subarachnoid injections of 5 ml blood (n = 5), one received two subarachnoid injections of 4 ml saline (n = 5), and a control group (n = 5) had no subarachnoid injections or angiography. Basilar artery diameter was measured from baseline and follow-up angiography. We determined CO2 reactivity by randomly varying the concentration of inspired CO2 and measuring regional cerebral blood flow with radiolabeled microspheres. Basilar artery diameter was not affected by saline injection and was reduced by 26 +/- 2.9% in the two-hemorrhage group and 55 +/- 1.9% in the three-hemorrhage group. Baseline cerebral blood flow and CO2 reactivity were similar in all four groups. We conclude that, in this model of delayed vasospasm, regional cerebral vascular CO2 reactivity is intact and extrapolation of in vitro data regarding basilar artery diameter and reactivity to cerebral blood flow must be done cautiously.

Diaphragmatic muscle performance during acute ventilatory failure due to Guillain-Barré syndrome and myasthenia gravis was assessed to evaluate (1) diaphragmatic function during weaning from ventilatory support and (2) diaphragmatic tension-time integral (TTdi) during ventilatory failure. We used a multilumen nasogastric tube and a pneumotachograph to measure transdiaphragmatic pressure per breath (Pdi), maximum transdiaphragmatic pressure (Pdimax), tidal volume (VT), and inspiratory time fraction during 74 spontaneous breathing trials in nine patients. Diaphragmatic performance was poor in all patients. The Pdi, Pdimax, and VT improved significantly, but values for Pdi and Pdimax remained low even after weaning. Improvement in Pdimax was the best predictor of recovery (r = 0.48; p less than 0.001). Maximal inspiratory force correlated with Pdimax (r = 0.48; p less than 0.005), but FVC did not. The TTdi rarely exceeded the expected fatigue threshold of 0.15 in spite of the patient's inability to sustain ventilation. Although our patients demonstrated diaphragmatic weakness, TTdi did not demonstrate diaphragmatic fatigue.

We tested the hypothesis that the concentration of atrial natriuretic factor in the cerebrospinal fluid is an indicator of brain injury in patients with intracranial disease. Atrial natriuretic factor concentration was measured in 72 samples of cerebrospinal fluid from 28 patients with intraventricular drains and in nine samples from outpatient controls undergoing diagnostic lumbar puncture. Levels were correlated with diagnosis; systemic fluid administration; concentration of atrial natriuretic factor in the plasma; intracranial pressure; sodium, glucose, and protein concentrations, osmolality, and cell count in the cerebrospinal fluid; sodium concentration in the serum; and hemodynamics. Atrial natriuretic factor concentration was highest in cerebrospinal fluid from patients with intracerebral hematoma, followed by those with obstructive hydrocephalus and subarachnoid hemorrhage (19 +/- 2, 13 +/- 3, and 8 +/- 2 pg/ml, respectively); atrial natriuretic factor concentration was less than 4 pg/ml in the controls. Patients treated with fluid restriction had significantly higher atrial natriuretic factor levels than those receiving maintenance or high-volume fluids (16 +/- 3, 8 +/- 2, 10 +/- 1 pg/ml, respectively). The concentration of atrial natriuretic factor in the plasma was significantly elevated in patients with intracerebral hematoma and subarachnoid hemorrhage (155 +/- 38 and 92 +/- 20 pg/ml, respectively) and did not correlate with fluid administration or the concentration of atrial natriuretic factor in the cerebrospinal fluid. Neither cerebrospinal fluid nor plasma concentrations of atrial natriuretic factor correlated with intracranial pressure; cerebrospinal fluid sodium, glucose, or protein concentrations, osmolality, or cell count; serum sodium concentration; or hemodynamics. We conclude that the concentration of atrial natriuretic factor in the cerebrospinal fluid is a nonspecific indicator of brain injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Orthopaedists and other physicians in Maine organized the Maine Medical Assessment Foundation to deal with the problem of variations in the rates of hospitalization for orthopaedic conditions. Five musculoskeletal injuries and five orthopaedic procedures were selected for study. The variation in decision-making by orthopaedists was least for fractures of the ankle and fractures of the hip and was greatest for fractures of the forearm, derangement of the knee, and lumbosacral sprain. The rates in an area tended to be consistently high or low for the same treatments. The major reasons for the variations appeared to be related to lack of agreement about optimum treatment. Feedback of data to physicians on variations in patterns of practice reduced the variations.

It would appear from the above that Pritchard agrees with the use of some agents other than magnesium sulfate that have known anticonvulsant properties. We believe that the subject at issue is whether magnesium sulfate should be used in treating the seizures of eclampsia. In our "Controversies" article, we do not address the issue of whether magnesium sulfate modifies pathophysiological factors leading to preeclampsia, but restrict ourselves to the treatment of the seizure per se, once seizures supervene, and the avoidance of their recurrence. The pathophysiological mechanisms and optimal treatment of preeclampsia and of eclampsia (excepting seizures) remain to be determined, as does the use of magnesium sulfate in this condition. Eclamptic seizures are clinically and electroencephalographically indistinguishable from generalized tonic-clonic seizures. Whether seizures arise in or out of the setting of preeclampsia, they should be treated as are other seizures, with known anticonvulsants. Controlled clinical trials are needed to address the effectiveness of alternative antiseizure regimens.

Survival from untreated herpes simplex type 1 encephalitis is well known to be accompanied by severe cognitive impairments. Recently, acyclovir has been proven to be the most effective available treatment for this disease, with the expectation that it would appreciably reduce morbidity. We performed detailed assessments of four consecutive patients who received acyclovir in the early stages of biopsy-proven herpes encephalitis and who now have been followed up for 1.5 to 4 years. All four patients showed definite residual on either clinical or formal neuropsychological testing, most commonly dysnomia and impaired new learning for both verbal and visual material, even though three had normal performance on a standard clinical mental status test. All four patients were unable to function at their prior level of achievement. Therefore, despite early administration of acyclovir in herpes encephalitis, long-lasting neuropsychological residua are likely. Furthermore, cognitive deficits of prognostic importance may not be detected by clinical screening.

Rapid scanning near-infrared spectroscopy (730-960 nm) was utilized to determine cat brain cytochrome-c oxidase copper band by blood-perfluorochemical emulsion (Oxypherol) exchange. Spectra were carried out before, during, and after the exchange transfusion on animals with preserved somatosensory-evoked potentials and microsphere-determined cerebral blood flow. Remaining hemoglobin (less than 4% of control) was converted to carboxyhemoglobin that does not absorb in this spectral region. Difference spectra, between an hypercapnic status (8% CO2-92% O2) and postmortem, demonstrated the presence of a broad absorption band centered around 820-845 nm that could be attributed to the oxidized low potential copper ion (CuA) of cytochrome-c oxidase. However, we were unable to further oxidize this band by adding CO2 to the inspired gas mixture, but this inconsistency may be due to the near-maximal cerebral blood flow levels present in this preparation. Cytochrome oxidation by CO2 is normally attributed to increased O2 delivery to the tissue, secondary to an increased cerebral perfusion. We were unable to induce further increases in cerebral blood flow. In contrast, the cytochrome band could be reduced both by lowering fractional O2 concentration and by inducing circulatory arrest. The spectral data support the hypothesis that it is possible to quantify the cytochrome-c oxidase copper band in the near-infrared spectral region.

Rapid scanning near infrared spectroscopy (730-960 nm) was utilized to determine cat brain cytochrome-c-oxidase after blood-perfluorocarbon (FC-43) exchange. Spectra were carried out before, during, and after the exchange transfusion on cats with preserved somatosensory evoked potentials and microsphere determined cerebral blood flow (CBF). Carbon dioxide (8%) did not produce an increase in CBF. Difference spectra between the hypercapnic state (8% CO2-92% O2) and post mortem, demonstrated the presence of a broad absorption band centered around 820-845 nm which could be attributed to the oxidized low potential copper ion of cytochrome-c-oxidase. We were unable to further oxidize this band by adding carbon dioxide to the inspired gas mixture. This may be due to the near maximal CBF levels present in this preparation. The spectral data support the hypothesis that near infrared spectroscopy can quantify changes in the redox state of cytochrome-c-oxidase.

In this article, we have reviewed the pathophysiology and several therapeutic strategies for cerebral ischemia. It seems likely that there will never be simple therapeutic answers to the complex pathophysiology of cerebral ischemia as we now understand it. Ultimate therapies will probably involve combinations of interventions designed to block several ongoing pathophysiologic processes in neuronal death. Progress in this field will likely be slow and difficult.

(D-ala2)-met5-encephalinamide (AM encephalinamide) and (D-ala2)-leu5-encephalinamide (AL encephalinamide) were administered into the cisterna magna in anesthetized dogs to determine whether these opiates effected the neurohypophyseal circulation differently than the circulation of other brain areas. At the beginning of the experimental protocol, animals were given either mock cerebral spinal fluid (CSF) or 5 or 25 mg of AM encephalinamide or 5 mg of AL encephalinamide in equal volumes of mock CSF into the cisterna magna. By 60 min after intracisternal injection, radiolabeled AM encephalinamide distributed throughout the brain with the highest concentration being in the area of the brainstem. Sixty minutes after intracisternal injection, heart rate was decreased 29.0 +/- 5.1%, 41.3 +/- 4.4%, and 36.0 +/- 3.6%, and MABP was decreased 25.2 +/- 8.0%, 26.4 +/- 2.4%, and 32.3 +/- 2.6% in animals treated with AL encephalinamide (5 mg), AM encephalinamide (5 mg), and AM encephalinamide (25 mg), respectively. Neither AL encephalinamide or AM encephalinamide altered CBF or CMRO2 when compared with animals treated with mock CSF, whereas both AL encephalinamide and AM encephalinamide reduced neurohypophyseal blood flow by 30 min (43 +/- 11%, AL encephalinamide; 35 +/- 7%, AM encephalinamide, 5 mg; 46 +/- 8%, AM encephalinamide, 25 mg); the reduction was sustained throughout the 60-min protocol (34 +/- 10%, AL encephalinamide; 37 +/- 3%, AM encephalinamide, 5 mg; 38 +/- 4% AM encephalinamide, 25 mg). Plasma arginine vasopressin was transiently elevated 15 (326 +/- 75%, AL encephalinamide; 323 +/- 109%, AM encephalinamide, 25 mg) and 30 min (271 +/- 68%, AL encephalinamide; 368 +/- 136%, AM encephalinamide, 25 mg) in animals treated with AL encephalinamide or AM encephalinamide (25 mg). Intravenous naloxone administered at the end of the 60-min encephalinamide protocol was associated with a rise toward control values in heart rate and MABP in the AL encephalinamide group and in heart rate, MABP, and neurohypophyseal blood flow in both the AM encephalinamide 5 mg and 25 mg groups. These data suggest that encephalinamides may play a role in the regulation of neurohypophyseal blood flow through their actions on opiate receptors.

The four patients presented here demonstrate the value of contrast enhanced CT in the diagnosis and serial evaluation of dural sinus thrombosis. Two patients were young women using oral contraceptives; another patient had lateral sinus thrombosis complicating mastoiditis; a fourth patient developed superior sagittal sinus thrombosis following hip surgery. Improvements in CT diagnosis, including the use of thin sections for evaluation of the deep venous structures and lateral sinuses complemented by multiplanar reconstruction or direct coronal scanning, are discussed. Sequential scans for following the progress of two patients treated by barbiturate coma added to the understanding of dural sinus occlusive disease.

Subarachnoid hemorrhage remains an important cause of mortality and morbidity despite recent attempts at aggressive surgical and medical therapy. This article reviews proposed mechanisms of brain injury following subarachnoid hemorrhage and rationale for therapy.

We measured neurohypophysial blood flow (NHBF) in dogs made hypotensive to study the time course of neurohypophysial autoregulation. We found that the neurohypophysis has a unique autoregulatory response in which blood flow increases transiently before establishing a stable perfusion level. During the "hyperemic" phase, the time course of the flow transient correlates with an increased plasma arginine vasopressin (pAVP) neurosecretory transient. However, unlike pAVP, blood flow does not remain elevated. The transitory nature of the flow response led us to evaluate the hypothesis that peripheral baroreceptor activity may be responsible for the hyperemic phase. Bilateral vagotomy and carotid sinus nerve denervation attenuated the increase in neural lobe blood flow (NLBF) to a standardized step to 80 mmHg mean arterial pressure. The pAVP response was enhanced both by vagotomy and carotid sinus denervation. Combined denervation abolished both the pAVP and the NLBF responses. We conclude that NHBF is autoregulated; however, control may be exerted at multiple levels, i.e., via nerves as well as local metabolic mechanisms. The peripheral baroreceptors influence NHBF primarily during periods of changing blood pressure. When blood pressure is stable, local mechanisms appear to be dominant.

An "in vivo" method for non-invasive determination of cerebral venous hemoglobin O2 saturation (SvO2) was developed. A specially designed spectrophotometer recorded the Td near IR spectra of transilluminated brain tissue surrounding the SS. The accuracy of the method, based on the principle of DNIRS was tested on eight pentobarbital anesthetized dogs during hypoxic hypoxia (inspired O2 6-21%). Spectral data were transformed into first derivative for correlation with SvO2 data measured from the SS. Linear regression analyses were applied using data from 5 dogs, with SvO2 ranging from 1.5%-70%, to build a 3 wavelength algorithm for predicting brain SvO2. In three dogs, this regression equation was employed to predict SvO2 in 31 separate spectra of varying HH intensity. The standard deviation of differences between SvO2 and predicted values was 3.2%. The predicted values, when regressed against the sampled SvO2, yielded an r value of 0.97. The results demonstrate that it is possible to noninvasively quantify SvO2 utilizing IR spectroscopy.

Vasopressin (prepropressophysin) mRNA is detected in neurons of the supraoptic, suprachiasmatic, and paraventricular nuclei of human postmortem hypothalamic specimens by quantitated in situ hybridization using 35S-labeled single-stranded cDNA probes directed against exon C of the human vasopressin gene. This hybridization displays the anticipated anatomic distribution, as well as several biochemical features supporting its specificity. Hybridization densities in supraoptic neurons, a measure of vasopressin gene expression, display substantial variability from brain-to-brain. We can attribute much of this brain-to-brain variability to differences in antemortem extracellular volume status. This conclusion is based on a) animal models of the human postmortem process, b) animal models of common agonal events, c) good correlations between antemortem volume status and neuronal vasopressin mRNA hybridization densities in human postmortem specimens matched for age and postmortem interval, and d) our inability to correlate human neuronal vasopressin mRNA hybridization densities with other clinical and postmortem features. These results provide an example of antemortem regulation of a human neuroendocrine gene using postmortem tissue.

A patient is reported in whom intraoperative somatosensory evoked potential (SEP) changes occurred in response to temporary clipping of the right middle cerebral artery. A period of 10 minutes elapsed before changes in SEP's in response to contralateral nerve stimulation were noted and, during the following 2 minutes, the waves decreased in amplitude and then were unrecordable. Waves of SEP, with amplitude similar to those recorded before clipping but with abnormal latency, returned within 45 seconds of removal of the clip, and the latency abnormalities persisted until the end of the operation. The patient awakened promptly at the end of the procedure with a dense left hemiparesis which resolved over 24 hours. At the end of 24 hours, the SEP's in response to median nerve stimulation were symmetrical in both latency and amplitude. This report demonstrates the accuracy of intraoperative evoked potential monitoring in demonstrating alterations of cerebral perfusion during aneurysm surgery. It also suggests that a prolonged period of observation may be necessary to assess the effects of temporary vessel occlusion during surgery on aneurysms or arteriovenous malformations.

The goal of the present study was to investigate the relationships among CBF, CMRO2, MTT and tissue/superior sagittal sinus hemoglobin saturations over a wide range of CPP using a canine model of hypotension. Microsphere-determined CBF was autoregulated in all tested cerebral regions over the 40-130 mmHg CPP range, but it decreased 50% around 30 mmHg. MTT, calculated by an indicator-dilution technique, progressively and proportionately increased over the 40-130 mmHg CPP range. The HbO2 content, measured in the same area by an optical method, parallely decreased. Around 30 mmHg CPP, MTT disproportionately lengthened (700% of control). CMRO2 maintenance was accompanied by a progressive decrease of tissue HbO2 and sagittal sinus hemoglobin saturation. In this framework, MTT measurement and tissue HbO2 monitoring by NIRS might give a sensitive evaluation of the hemodynamic reserve than CBF measurement in anesthesia and intensive care.

A total of 432 patients underwent brain biopsy for presumptive herpes simplex encephalitis. Three patient groups were identified. The first group, 195 patients (45%), had herpes simplex encephalitis confirmed by the isolation of herpes simplex virus from brain tissue at biopsy (193 patients) or autopsy (2 patients). The second group, 95 patients (22%), had diseases that were identified but that were not caused by herpes simplex virus. Three subgroups were recognized: (1) 38 patients (9%) with treatable disease, (2) 40 patients (9%) with nontreatable but diagnosed viral infection, and (3) 17 patients (4%) with identified diseases neither of viral etiology nor treatable. The third group, 142 patients (33%), remained without a diagnosis. Clinical presentation of patients in the second group was similar to that of those with herpes simplex encephalitis and those without a diagnosis. Patients in the subgroup with nontreatable but diagnosed viral infections had the greatest likelihood of returning to normal.

Hyponatremia, in patients with central nervous system disease, can be attributable to impaired free water excretion (syndrome of inappropriate secretion of antidiuretic hormone) or to excessive sodium excretion (cerebral salt wasting). We present a patient with a parietal glioma and hyponatremia characterized by salt wasting and dehydration. Rehydration and sodium repletion corrected the sodium and volume deficits; withdrawal of supplemental sodium resulted in recurrence of dehydration and hyponatremia. We determined sodium and water balance and measured plasma atriopeptin, antidiuretic hormone, and aldosterone. Plasma atriopeptin ranged from 8 to 44 pg/mL (normal, less than 45 pg/mL); antidiuretic hormone was not elevated at 4 to 5 pg/mL, and aldosterone was slightly elevated at 1040.25 pmol/L. The concentrations of these hormones could not directly explain the natriuresis; interactions with neural or other humoral factors may be involved. In evaluating such patients, careful attention to sodium and water balance is important to guide appropriate therapy.

Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy that may lead to quadriparesis, ventilatory failure, and autonomic dysfunction. While significant mortality due to ventilatory failure has been associated with this syndrome, this complication can now be readily managed. However, an estimated mortality of 5% to 20% remains attributable to medical complications (pulmonary embolus, sepsis) and to acute cardiovascular collapse due to autonomic failure. In this report, detailed sequential changes in hemodynamic parameters, as measured by Swan-Ganz catheter, associated with severe autonomic cardiovascular instability in a patient with GBS are described. Knowledge of changes in these hemodynamic parameters led to optimal therapy. Long-term Swan-Ganz monitoring in an intensive care setting may dramatically benefit the critically ill patient with GBS and cardiovascular autonomic dysfunction, and may help to eliminate the residual morbidity and mortality associated with this disease.

Neurohypophyseal blood flow responses to hypoxia and hypercapnia were studied in pentobarbital anesthetized, paralyzed dogs. Arterial O2 content was lowered from control (18 +/- 2 vol%) to 8 +/- 1 vol% by either decreasing O2 tension (hypoxic hypoxia, HH) or by increasing carboxyhemoglobin saturation (carbon monoxide hypoxia, COH) at normal O2 tension. In all animals HH and COH resulted in similar increases in total cerebral blood flow (239 and 300%, respectively). Regional cerebral blood flow showed a similar increase for all brain regions except the neurohypophysis (NH). The NH increased its blood flow with HH (approximately 320% of control) but was unchanged with COH (117% of control). The responsiveness of NH blood vessels was tested under conditions of hypercapnia (10% CO2) and HH with blood pressure controlled by concurrent hemorrhage. The response of NH vessels to altered arterial O2 tension occurs independently of blood pressure. Systemic [H+] or CO2 tension produce only small changes in NH blood flow. These data suggest that hypoxic and hypercapnic regulatory mechanisms for the NH are different from those of other brain regions. The precise mechanism by which the NH hypoxic response occurs remains unclear, but our data suggest an important role for systemic arterial O2 tension and chemoreceptors.

Concerns about the costs and effectiveness of drug testing in reducing drug use and abuse among athletes has sparked a debate about whether testing should be continued, expanded in scope, or discontinued. THE PHYSICIAN AND SPORTSMEDICINE has asked physicians Daniel F. Hartley, Herman Adlercreutz. K. D. Fitch, and E. C. Percy for their views on the subject. Their comments are preceded by an introduction by Allan J. Ryan. MD.

Two cases of complete sagittal sinus occlusion with multiple brain hemorrhages, elevated intracranial pressure, and disseminated intravascular coagulation are described. These patients were successfully managed using pentobarbital-induced coma to ameliorate intracranial pressure elevation. This therapy was combined with monitoring of intracranial pressure and intermittent drainage of cerebrospinal fluid to further control intracranial pressure elevations. Thrombus and coagulopathy resolved with pentobarbital alone in one patient and after pentobarbital plus heparin therapy in the second patient. It is suggested that cases of severe distal sagittal sinus thrombosis with brain hemorrhage and intracranial hypertension may benefit from combined pentobarbital coma and intraventricular drainage. This allows for stabilization of bleeding tendencies before instituting heparin therapy when necessary. Management of sagittal sinus thrombosis with barbiturates or ventricular drainage is best performed in an intensive care unit environment with continuous monitoring of intracranial pressure and substantial electrophysiologic and neuroradiologic support.

Twenty-four adults who were undergoing operations on the abdominal aorta were enrolled in a randomized, double-blind, placebo-controlled study in which epidural morphine sulfate (6 mg) was employed to attenuate the sympathoadrenal response to surgery to evaluate the possible contribution of sympathetic nervous system hyperactivity to postoperative hypertension. Patients who received epidural morphine required less parenteral morphine in the 24 hours following surgery, had lower analogue pain scores, and had markedly lower plasma norepinephrine levels when compared with patients in the control group who received an identical volume of saline in the epidural space. Epidural morphine had no effect on plasma epinephrine or arginine vasopressin levels. Fewer patients in the morphine group (4 of 12 vs 9 of 12 patients in the saline group) required treatment for hypertension (mean arterial blood pressure, greater than or equal to 110 mm Hg) in the 24 hours following surgery. In addition, patients in the morphine group had lower blood pressures in the 24 hours following surgery. These data suggest that sympathetic nervous system activity and not adrenal epinephrine or pituitary secretion of arginine vasopressin is responsible for the development of hypertension following aortic surgery. Furthermore, epidural narcotics appear to provide a means of attenuating this response.

An in vivo method utilizing derivative near-infrared spectroscopy was developed to noninvasively determine cerebral venous hemoglobin O2 saturation (SVO2). The method was tested on eight pentobarbital-anesthetized dogs ventilated with differing inspired O2 mixtures to force changes in SVO2 over a wide range. Spectral data obtained by transilluminating the tissues surrounding the superior sagittal sinus (SS) were transformed into first derivative units for correlation with SVO2 data measured from the SS. Linear regression analysis was applied to data obtained from five dogs and used to build a three-wavelength algorithm for predicting brain SVO2. In three dogs, SVO2 was varied to test this equation ability to predict SVO2. The standard deviation of differences between measured SVO2 and SVO2 predicted from 31 separate spectra was 3.2%. These predicted values, when regressed against the sampled SVO2, yielded an r value of 0.97. The results demonstrate that during hypoxic hypoxia (HH) it is possible to noninvasively quantify SVO2 with the use of infrared spectroscopy.