Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury

OBJECTIVES: To define optimal cerebral perfusion pressure (CPPOPT) in individual head-injured patients using continuous monitoring of cerebrovascular pressure reactivity. To test the hypothesis that patients with poor outcome were managed at a cerebral perfusion pressure (CPP) differing more from their CPPOPT than were patients with good outcome. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: A total of 114 head-injured patients admitted between January 1997 and August 2000 with continuous monitoring of mean arterial blood pressure (MAP) and intracranial pressure (ICP). MEASUREMENTS AND MAIN RESULTS: MAP, ICP, and CPP were continuously recorded and a pressure reactivity index (PRx) was calculated online. PRx is the moving correlation coefficient recorded over 4-min periods between averaged values (6-sec periods) of MAP and ICP representing cerebrovascular pressure reactivity. When cerebrovascular reactivity is intact, PRx has negative or zero values, otherwise PRx is positive. Outcome was assessed at 6 months using the Glasgow Outcome Scale. A total of 13,633 hrs of data were recorded. CPPOPT was defined as the CPP where PRx reaches its minimum value when plotted against CPP. Identification of CPPOPT was possible in 68 patients (60%). In 22 patients (27%), CPPOPT was not found because it presumably lay outside the studied range of CPP. Patients' outcome correlated with the difference between CPP and CPPOPT for patients who were managed on average below CPPOPT (r =.53, p <.001) and for patients whose mean CPP was above CPPOPT (r = -.40, p <.05). CONCLUSIONS: CPPOPT could be identified in a majority of patients. Patients with a mean CPP close to CPPOPT were more likely to have a favorable outcome than those whose mean CPP was more different from CPPOPT. We propose use of the criterion of minimal achievable PRx to guide future trials of CPP oriented treatment in head injured patients.     

Physician and public opinions on quality of health care and the problem of medical errors

BACKGROUND: The 1999 Institute of Medicine report on medical errors proposed major changes to the health care system and gained widespread media attention, yet there is limited information on physician or public opinion regarding recommendations from that report. METHODS: Mail survey of 1000 Colorado physicians (n = 594) and 1000 national physicians (n = 304), and telephone survey of 500 Colorado households to assess agreement with several proposals and conclusions from the 1999 Institute of Medicine report. RESULTS: Most physicians believed that reduction of medical errors should be a national priority (69.7% of Colorado physicians). However, physicians were much less likely than the public to believe that quality of care is a problem (29.1% vs 67.6%; P<.001) or that a national agency is needed to address the problem of medical errors (24.1% vs 59.8%; P<.001). Uniformly, physicians believed that fear of medical malpractice is a barrier to reporting of errors and that greater legal safeguards are necessary for a mandatory reporting system to be successful. Nearly all physicians (92.9%) believed that more training in how to handle medical errors is needed, and 60.1% agreed that it is difficult to differentiate errors due to negligence from unintended errors. CONCLUSIONS: There appears to be widespread concern among physicians regarding medical errors, but only a minority in this survey believed that the problem is as significant as the Institute of Medicine and the public believe it to be. Our results suggest that physicians see several barriers to successful error reduction including difficulty defining errors, the need for more training in handling errors, and fear of malpractice litigation. Addressing these barriers will be a necessary step to increasing physician support for many of the changes proposed by the Institute of Medicine.     

A model of the cerebral and cerebrospinal fluid circulations to examine asymmetry in cerebrovascular reactivity.

The authors examined the steal phenomenon using a new mathematical model of cerebral blood flow and the cerebrospinal fluid circulation. In this model, the two hemispheres are connected through the circle of Willis by an anterior communicating artery (ACoA) of varying size. The right hemisphere has no cerebrovascular reactivity and the left is normally reactive. The authors studied the asymmetry of hemispheric blood flow in response to simulated changes in arterial blood pressure and carbon dioxide concentration. The hemispheric blood flow was dependent on the local regulatory capacity but not on the size of the ACoA. Flow through the ACoA and carotid artery was strongly dependent on the size of the communicating artery. A global interhemispheric "steal effect" was demonstrated to be unlikely to occur in subjects with nonstenosed carotid arteries. Vasoreactive effects on intracranial pressure had a major influence on the circulation in both hemispheres, provoking additional changes in blood flow on the nonregulating side. A method for the quantification of the crosscirculatory capacity has been proposed.     

Subcellular distribution of 5-HT(1B) and 5-HT(7) receptors in the mouse suprachiasmatic nucleus

The suprachiasmatic nucleus (SCN), a circadian oscillator, receives glutamatergic afferents from the retina and serotonergic (5-HT) afferents from the median raphe. 5-HT(1B) and 5-HT(7) receptor agonists inhibit the effects of light on SCN circadian activity. Electron microscopic (EM) immunocytochemical procedures were used to determine the subcellular localization of 5-HT(1B) and 5-HT(7) receptors in the SCN. 5-HT(1B) receptor immunostaining was associated with the plasma membrane of thin unmyelinated axons, preterminal axons, and terminals of optic and nonoptic origin. 5-HT(1B) receptor immunostaining in terminals was almost never observed at the synaptic active zone. To a much lesser extent, 5-HT(1B) immunoreaction product was noted in dendrites and somata of SCN neurons. 5-HT(7) receptor immunoreactivity in gamma-aminobutyric acid (GABA), vasoactive intestinal polypeptide (VIP), and vasopressin (VP) neuronal elements in the SCN was examined by using double-label procedures. 5-HT(7) receptor immunoreaction product was often observed in GABA-, VIP-, and VP-immunoreactive dendrites as postsynaptic receptors and in axonal terminals as presynaptic receptors. 5-HT(7) receptor immunoreactivity in terminals and dendrites was often associated with the plasma membrane but very seldom at the active zone. In GABA-, VIP-, and VP-immunoreactive perikarya, 5-HT(7) receptor immunoreaction product was distributed throughout the cytoplasm often in association with the endoplasmic reticulum and the Golgi complex. The distribution of 5-HT(1B) receptors in presynaptic afferent terminals and postsynaptic SCN processes, as well as the distribution of 5-HT(7) receptors in both pre- and postsynaptic GABA, VIP, and VP SCN processes, suggests that serotonin plays a significant role in the regulation of circadian rhythms by modulating SCN synaptic activity.     

Age dependence of cerebrospinal pressure-volume compensation in patients with hydrocephalus

OBJECT: The dynamics of both drainage and storage capacity become altered during the sequential pathological processes that lead to hydrocephalus. Cerebrospinal fluid (CSF) formation and drainage rate have been reported to be age dependent. The aim of this study was to investigate whether CSF compensatory parameters are dependent on age in patients who have symptoms of hydrocephalus and apparently normal intracranial pressure (ICP). METHODS: Forty-six patients who presented with ventriculomegaly, the clinical symptoms of hydrocephalus, and normal ICPs underwent a computerized CSF infusion test. Parameters used to describe CSF compensation were calculated and correlated with the age of each patient. The mean ICPs were found to be independent of the age of the patient. Resistance to CSF outflow (Rcsf), however, demonstrated a nonlinear increase with advancing age (r = -0.57; p < 0.0001) and was associated with a decrease in the CSF production rate, which also occurred with increasing age (r = 0.49; p < 0.002). Both the pulse amplitude of the ICP waveform and the slope of the amplitude-ICP regression line increased significantly with advancing age (r = 0.39; p < 0.01 and r = 0.43, p < 0.004, respectively). The nonlinear increase in the elastance coefficient indicated increasing brain stiffness, which acompanies older ages (r = -0.31; p < 0.04). CONCLUSIONS: In a study of patients with symptoms of hydrocephalus, but normal ICPs, the increase in Rcsf and decrease in CSF production were most pronounced in patients who were older than 56 years of age. This relationship was more significant than previously suggested.     

Laboratory evaluation of the phoenix CRx diamond valve

OBJECTIVE: To assess the long-term hydrodynamic properties of a new cerebrospinal fluid flow-regulating hydrocephalus shunt called the CRx Diamond valve (Phoenix Biomedical Corp., Valley Forge, PA). METHODS: Three samples of a Diamond valve were tested in the United Kingdom Shunt Evaluation Laboratory during a 40-day period. Tests were performed for long-term pressure-flow performance, overdrainage, susceptibility to ambient temperature changes, external pressure, reflux, presence of small particles in the reagent, mechanical durability, and magnetic resonance imaging compatibility. RESULTS: Tests demonstrated that the Diamond valve stabilized flow within the range of 0.36 to 0.62 ml/min when pressure varied from 14 to 23 mm Hg. Hydrodynamic resistance demonstrated pressure-dependent variability from 20 to 78 mm Hg/(ml/min). The time drift of hydrodynamic parameters was significant (P < 0.001). The valve was insensitive to changes in temperature, external pressure, rapid fluctuations of differential pressure, small particles in fluid, and reflux. CONCLUSION: The Diamond valve demonstrated the intended variable resistance, which increased as the pressure increased. This property may help it limit overdrainage related to body posture as well as nocturnal vasogenic waves. Flow through the valve stabilizes within a wide range, which may contribute to the prevention of excessive pressure buildup after implantation. However, shunt placement should be avoided in patients who present with normal baseline intracranial pressure but an increased incidence of high vasogenic intracranial pressure waves.     

Aeromedical decision-making for aviators with malignant melanoma: an update and review

A review of the recent medical literature on malignant melanoma yielded sufficient information to correlate readily identifiable tumor characteristics to disease-free intervals, and in turn to subsequent risk of cerebral metastasis and neurologic incapacitation. These data were used to construct a new decision table to help guide flight surgeons considering a flying waiver for aviators with a history of melanoma.     

The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome

Abstract A numeric scoring system for the assessment of hypoxic ischaemic encephalopathy during the neonatal period was tested. The value of the score in predicting neurodevelopmental outcome at 1 y of age was assessed. Forty-five infants who developed hypoxic ischaemic encephalopathy after birth were studied prospectively. In addition to the hypoxic ischaemic encephalopathy score all but two infants had at least one cranial ultrasound examination. Thirty-five infants were evaluated at 12 months of age by full neurological examination and the Griffiths Scales of Mental Development. Five infants were assessed at an earlier stage, four who died before 6 months of age and one infant who was hospitalized at the time of the 12 month assessment. Twenty-three (58%) of the infants were normal and 17 (42%) were abnormal, 16 with cerebral palsy and one with developmental delay. The hypoxic ischaemic encephalopathy score was highly predictive for outcome. The best correlation with outcome was the peak score; a peak score of 15 or higher had a positive predictive value of 92% and a negative predictive value of 82% for abnormal outcome, with a sensitivity and specificity of 71% and 96%, respectively. For the clinician working in areas where sophisticated technology is unavailable this scoring system will be useful for assessment of infants with hypoxic ischaemic encephalopathy and for prognosis of neurodevelopmental outcome.     

Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to DNA damage.

The inherent or acquired (induced) resistance of certain tumours to cytotoxic drug therapy is a major clinical problem. There are many categories of cytotoxic agent: the antimetabolites, e.g. methotrexate (MTX), N-phosphonacetyl-L-aspartate (PALA), 5-fluorouracil (5-FU), 6-mercaptopurine (6-TG), hydroxyurea (HU) and 1-beta-D-arabinofuranosylcytosine (AraC); the alkylating agents, e.g. the nitrogen mustards and nitrosoureas; the antibiotics, e.g. doxorubicin and mitomycin C; the plant alkaloids, e.g. vincristine and vinblastine; and miscellaneous compounds, such as cisplatin. There are also many mechanisms of drug resistance elucidated principally from in vitro studies. These include mutation of target genes, amplification of target and mutated genes, differences in repair capacity, altered drug transport and differences in nucleoside and nucleobase salvage pathways (Fox et al, 1991). The aim of the present review is to evaluate in detail the mechanisms of response of both normal and tumour cells to three chemotherapeutic antimetabolites, MTX, PALA and 5-FU, which are routinely used in the clinic either alone or in combination to treat some of the commonest solid tumours, e.g. breast, colon, gastric and head and neck. The normal and tumour cell response to these agents will be discussed in relation to the operation of the known alternative ''salvage pathways'' of DNA synthesis and current theories of DNA damage response.     

Current practice in dietary management of diabetic children. A transatlantic comparison

Dietary therapy practice in 18 British clinics for diabetic children is reviewed, and contrasted with Canadian and American practice. Values for dietary composition expressed as energy are presented for small groups of British and Canadian children. Fat is often the principal energy source in British diabetic children; protein intake is much higher in the Canadian. It is suggested that British practice might be improved by the adoption of a simple uniform exchange system. Reported differences in growth characteristics may reflect differences in protein intake.