Brain temperature by Biosensor Imaging of Redundant Deviation in Shifts (BIRDS): comparison between TmDOTP5- and TmDOTMA-.

Chemical shifts of complexes between paramagnetic lanthanide ions and macrocyclic chelates are sensitive to physiological variations (of temperature and/or pH). Here we demonstrate utility of a complex between thulium ion (Tm(3+)) and the macrocyclic chelate 1,4,7,10-tetramethyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (or DOTMA(4-)) for absolute temperature mapping in rat brain. The feasibility of TmDOTMA(-) is compared with that of another Tm(3+)-containing biosensor which is based on the macrocyclic chelate 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetrakis(methylene phosphonate) (or DOTP(8-)). In general, the in vitro and in vivo results suggest that Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) which originate from these agents (but exclude water) can provide temperature maps with good accuracy. While TmDOTP(5-) emanates three major distinct proton resonances which are differentially sensitive to temperature and pH, TmDOTMA(-) has a dominant pH-insensitive proton resonance from a -CH(3) group to allow higher signal-to-noise ratio (SNR) temperature assessment. Temperature (and pH) sensitivities of these resonances are practically identical at low (4.0T) and high (11.7T) magnetic fields and at nominal repetition times only marginal SNR loss is expected at the lower field. Since these resonances have extremely short relaxation times, high-speed chemical shift imaging (CSI) is needed to detect them. Repeated in vivo CSI scans with BIRDS demonstrate excellent measurement stability. Overall, results with TmDOTP(5-) and TmDOTMA(-) suggest that BIRDS can be reliably applied, either at low or high magnetic fields, for functional studies in rodents.

Brain temperature and pH measured by (1)H chemical shift imaging of a thulium agent.

Temperature and pH are two of the most important physiological parameters and are believed to be tightly regulated because they are intricately related to energy metabolism in living organisms. Temperature and/or pH data in mammalian brain are scarce, however, mainly because of lack of precise and non-invasive methods. At 11.7 T, we demonstrate that a thulium-based macrocyclic complex infused through the bloodstream can be used to obtain temperature and pH maps of rat brain in vivo by (1)H chemical shift imaging (CSI) of the sensor itself in conjunction with a multi-parametric model that depends on several proton resonances of the sensor. Accuracies of temperature and pH determination with the thulium sensor - which has a predominantly extracellular presence - depend on stable signals during the course of the CSI experiment as well as redundancy for temperature and pH sensitivities contained within the observed signals. The thulium-based method compared well with other methods for temperature ((1)H MRS of N-acetylaspartate and water; copper-constantan thermocouple wire) and pH ((31)P MRS of inorganic phosphate and phosphocreatine) assessment, as established by in vitro and in vivo studies. In vitro studies in phantoms with two compartments of different pH value observed under different ambient temperature conditions generated precise temperature and pH distribution maps. In vivo studies in alpha-chloralose-anesthetized and renal-ligated rats revealed temperature (33-34 degrees C) and pH (7.3-7.4) distributions in the cerebral cortex that are in agreement with observations by other methods. These results show that the thulium sensor can be used to measure temperature and pH distributions in rat brain in vivo simultaneously and accurately using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS).

Regional temperature changes in the brain during somatosensory stimulation.

Time-dependent variations in the brain temperature (Tt) are likely to be caused by fluctuations of cerebral blood flow (CBF) and cerebral metabolic rate of oxidative consumption (CMRO2) both of which are seemingly coupled to alterations in neuronal activity. We combined magnetic resonance, optical imaging, temperature sensing, and electrophysiologic methods in alpha-chloralose anesthetized rats to obtain multimodal measurements during forepaw stimulation. Localized changes in neuronal activity were colocalized with regional increases in Tt (by approximately 0.2%), CBF (by approximately 95%), and CMRO2 (by approximately 73%). The time-to-peak for Tt (42+/-11 secs) was significantly longer than those for CBF and CMRO2 (5+/-2 and 18+/-4 secs, respectively) with a 2-min stimulation. Net heat in the region of interest (ROI) was modeled as being dependent on the sum of heats attributed to changes in CMRO2 (Qm) and CBF (Qf) as well as conductive heat loss from the ROI to neighboring regions (Qc) and to the environment (Qe). Although tissue cooling because of Qf and Qc can occur and are enhanced during activation, the net increase in Tt corresponded to a large rise in Qm, whereas effects of Qe can be ignored. The results show that Tt increases slowly (by approximately 0.1 degrees C) during physiologic stimulation in alpha-chloralose anesthetized rats. Because the potential cooling effect of CBF depends on the temperature of blood entering the brain, Tt is mainly affected by CMRO2 during functional challenges. Implications of these findings for functional studies in awake humans and temperature regulation are discussed.

A multiparametric assessment of oxygen efflux from the brain.

A quantitative understanding of unidirectional versus net extraction of oxygen in the brain is required because an important factor in calculating oxidative metabolism by calibrated functional magnetic resonance imaging (fMRI) as well as oxygen inhalation methods of positron emission tomography (15O2-PET) and nuclear magnetic resonance (17O2-NMR)) is the degree of oxygen efflux from the brain back into the blood. Because mechanisms of oxygen transport from blood to brain are dependent on cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), and oxygen partial pressure (pO2) values in intravascular (Piv) and extravascular (Pev) compartments, we implemented multimodal measurements of these parameters into a compartmental model of oxygen transport and metabolism (i.e., hemoglobin-bound oxygen, oxygen dissolved in plasma and tissue spaces, oxygen metabolized in the mitochondria). In the alpha-chloralose anesthetized rat brain, we used magnetic resonance (7.0 T) and fluorescence quenching methods to measure CMRO2 (2.5+/-1.0 micromol/g min), CBF (0.7+/-0.2 mL/g min), Piv (74+/-10 mm Hg), and Pev (16+/-5 mm Hg) to estimate the degree of oxygen efflux from the brain. In the axially distributed compartmental model, oxygen molecules in blood had two possible fates: enter the tissue space or remain in the same compartment; while in tissue there were three possible fates: enter the blood or the mitochondrial space, or remain in the same compartment. The multiparametric results indicate that the probability of unmetabolized (i.e., dissolved) oxygen molecules reentering the blood from the tissue is negligible and thus its inclusion may unnecessarily complicate calculations of CMRO2 for 15O-PET, 17O-NMR, and calibrated fMRI methods.

Outcome of coma in children.

Coma following a hypoxic-ischemic event is a serious condition and common reason for admission to the pediatric intensive care unit. Because coma has a high rate of mortality and morbidity in children, and the clinician may be unsure of the outcome very early in the course, it is important to have strategies to define prognosis. Although most studies have been conducted in adults, we review factors predicting outcome from coma of nontraumatic causes in infants and children. We consider the relation between physical findings, commonly accessible laboratory tools, and outcome, and comment on some newer techniques that may become more available for clinical purposes.

Brain temperature measured by 1H-NMR in conjunction with a lanthanide complex.

In vivo data on temperature distributions in the intact brain are scarce, partly due to lack of noninvasive methods for the region of interest. NMR has been exploited for probing a variety of brain activities in vivo noninvasively within the region of interest. Here we report the use of a thulium-based thermometric sensor, infused through the blood, for monitoring absolute temperature in rat brain in vivo by (1)H-NMR and validated by direct temperature measurements with thermocouple wires. Because the (1)H chemical shifts also demonstrate pH sensitivity, detection of multiple resonances was used to measure both temperature and pH simultaneously with high sensitivity. Examination of blood plasma and cerebral spinal fluid samples removed from rats infused with the thermometric sensor suggests that the complex, despite its negative charge, crosses the blood-brain barrier to enter the extracellular milieu. In the future, the thulium-based thermometric sensor may be used for monitoring temperature (and pH) distributions throughout the entire brain, examining response to therapy and evaluating changes induced by alterations in neuronal activity.

Complicated nosocomial pneumonia due to Legionella pneumophila in an immunocompromised child.

An immunocompromised child developed necrotizing pneumonia with BAL cultures growing Legionella pneumophila resistant to treatment, including erythromycin and rifampicin. Ciprofloxacin and clarithromycin reversed the clinical course; their use as first-line drugs is justifiable and a high index of suspicion for the occurrence of legionellosis is warranted.