Prognostic impact of autonomic information flow in multiple organ dysfunction syndrome patients.

BACKGROUND: Multiple organ dysfunction syndrome (MODS) is the sequential failure of several organ systems after a trigger event, like cardiogenic shock or decompensated heart failure. Mortality is high, up to 70%. Autonomic dysfunction (AD) may substantially contribute to the development of MODS. In cardiology, it has recently been shown that nonlinear parameters could predict mortality. Our study aimed at 1. characterising the complex characteristics of AD of critically ill MODS patients by the nonlinear parameters of autonomic information flow (AIF), 2. comparing AIF with autonomic function of healthy controls, and 3. characterising the accuracy of this parameter in predicting mortality in MODS. METHODS: We enrolled 43 score-defined MODS patients who were consecutively admitted to a twelve-bed medical intensive care unit in a university centre into this prospective outcome study. Additionally, we assigned 50 healthy controls to the study. AIF was assessed as a complexity function of AD using 24-h ECG. Measures of AIF were introduced according to the standard HRV concept. The patients were followed up for 28-day mortality. RESULTS: MODS causes a disorganisation of short term AIF in favour of an enhanced (rigid) long term AIF. Concerning prognosis increased short term AIF was associated with survival. Short term AIF discriminated between MODS survivors and non-survivors at the level of APACHE II score. CONCLUSIONS: This is the first study providing evidence that complex AD of MODS patients is specifically assessed by AIF time scales and that AIF has significant prognostic impact.

Mutual information function assesses autonomic information flow of heart rate dynamics at different time scales.

The autonomic information flow (AIF) represents the complex communication within the Autonomic Nervous System (ANS). It can be assessed by the mutual information function (MIF) of heart rate fluctuations (HRF). The complexity of HRF is based on several interacting physiological mechanisms operating at different time scales. Therefore one prominent time scale for HRF complexity analysis is not given a priori. The MIF reflects the information flow at different time scales. This approach is defined and evaluated in the present paper. In order to aggregate relevant physiological time scales, the MIF of HRF obtained from eight adult Lewis rats during the awake state, under general anesthesia, with additional vagotomy, and additional betal-adrenergic blockade are investigated. Physiologically relevant measures of the MIF were assessed with regard to the discrimination of these states. A simulation study of a periodically excited pendulum is performed to clarify the influence of the time scale of MIF in comparison to the Kolmogorov Sinai entropy (KSE) of that well defined system. The general relevance of the presented AIF approach was confirmed by comparing mutual information, approximate entropy, and sample entropy at their respective time scales.

Effect of moderate hypercapnic hypoxia on cerebral dopaminergic activity and brain O2 uptake in intrauterine growth-restricted newborn piglets.

There is evidence that intrauterine growth restriction (IUGR) is associated with altered dopaminergic function in the immature brain. Compelling evidence exists that in the newborn brain, specific structures are especially vulnerable to O2 deprivation. The dopaminergic system is shown to be sensitive to O2 deprivation in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain after IUGR under hypercapnic hypoxia (H/H). Therefore, 18F-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography was used to estimate the aromatic amino acid decarboxylase activity of the brain of seven normal weight (body weight 2078 +/- 434 g) and seven IUGR newborn piglets (body weight 893 +/- 109 g). Two positron emission tomography scans were performed in each piglet. All animals underwent a period of normoxia and moderate H/H. Simultaneously, cerebral blood flow was measured with colored microspheres and cerebral metabolic rate of O2 was determined. In newborn normal-weight piglets, the rate constant for FDOPA decarboxylation was markedly increased in mesostriatal regions during H/H, whereas brain oxidative metabolism remained unaltered. In contrast, moderate H/H induced in IUGR piglets a marked reduction of clearance rates for FDOPA metabolites (p <0.05), which was accompanied by a tendency of lowering the rate constant for FDOPA conversion. Furthermore, IUGR piglets maintained cerebral O2 uptake in the early period of H/H, but during the late period of H/H, a significantly reduced cerebral metabolic rate of O2 occurred (p <0.05). Thus, IUGR is accompanied by a missing activation of dopaminergic activity and attenuated brain oxidative metabolism during moderate H/H. This may indicate endogenous brain protection against O2 deprivation.

Inhomogeneous propagation of cortical spreading depression-detection by electro- and magnetoencephalography in rats.

Spreading depression (SD) propagates in cortical regions that are different in their morphological and functional characteristics. We tested whether the propagation pattern of spreading depression was different between parts of the cortex. In six adult rats, we recorded the ECoG by a 4 x 4 electrode array that covered parts of the frontal, parietal cortex and the cingulate cortex. Simultaneously a 16-channel magnetoencephalogram was recorded to characterize the development and direction of intracortical ion movements accompanying this phenomenon. Spreading depression was initiated by occipital application of 0.3 molar KCl solution. Depolarization was observed, at first, at lateral cortical regions and then at medial cortical regions. Thereafter, the propagation velocity increased in medial cortical regions and was faster than in lateral regions. Negative potential shifts were detected by all electrodes, but the depolarization reached a maximum over lateral and caudal cortical regions. The recorded magnetic fields indicated the same orientation of currents underlying these fields, which was perpendicular to the wave front and points away from the depolarization region. Overall, the data indicated that propagation patterns of spreading depression differed between parts of the cortex and, thus, propagation was inhomogeneous. This propagation was accompanied by strong currents parallel to the cortical surface.

Intrauterine growth restriction ameliorates the effects of gradual hemorrhagic hypotension on regional cerebral blood flow and brain oxygen uptake in newborn piglets.

Data are scant regarding the development of cerebrovascular autoregulation in intrauterine growth-restricted (IUGR) newborns. We tested the hypothesis that IUGR improves the ability of neonates to withstand critical periods of gradual hemorrhagic hypotension by optimizing cerebrovascular autoregulation. Studies were conducted on 1-d-old anesthetized piglets divided into groups of normal weight (NW, n = 14, body weight = 1518 +/- 122 g) and IUGR (n = 14, body weight = 829 +/- 50 g) animals. Physiologic parameters, including regional cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO(2)), were similar in NW and IUGR piglets under baseline conditions. Controlled arterial blood loss [hemorrhagic hypotension (HH)] induced a stepwise reduction of the mean arterial blood pressure of 49 +/- 3 mm Hg (mild HH), 39 +/- 3 mm Hg (moderate HH), and 30 +/- 3 mm Hg (severe HH) in seven NW and seven IUGR piglets (p < 0.05). In NW piglets, cortical CBF and CMRO(2) was reduced already at moderate HH (p < 0.05). A similar CMRO(2) reduction occurred during severe HH in NW and IUGR piglets (p < 0.05). In addition, during mild and moderate HH, primarily in IUGR piglets, an increase in regional CBF of brainstem, cerebellum, and thalamus was shown compared with baseline values (p < 0.05). Furthermore, under these conditions, cerebral cortex blood flow was maintained in newborn IUGR animals. In contrast, NW piglets exhibited a significant reduction in CBF (p < 0.05) during moderate HH. Thus, IUGR resulted in an improved ability to withstand critical periods of gradual oxygen deficit as shown by improved cerebrovascular autoregulation during hemorrhagic hypotension.

Age-dependent effects of severe traumatic brain injury on cerebral dopaminergic activity in newborn and juvenile pigs.

There is evidence that the dopaminergic system is sensitive to traumatic brain injury (TBI). However, the age-dependency of this sensitivity has not been studied together with brain oxidative metabolism. We postulate that the acute effects of severe TBI on brain dopamine turnover are age-dependent. Therefore 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with Positron-Emission-Tomography (PET) was used to estimate the activity of the aromatic amino acid decarboxylase (AADC) in the brain of 11 newborn piglets (7-10 days old) and nine juvenile pigs (6-7 weeks old). Six newborn and five juvenile animals were subjected to a severe fluid-percussion (FP) induced TBI. The remaining animals were used as sham operated untreated control groups. Simultaneously, the regional cerebral blood flow (CBF) was measured with colored microspheres and the cerebral metabolic rates of oxygen and glucose were determined. At 1 h after FP-TBI, [18F]FDOPA was infused and PET scanning was performed for 2 h. At 2 h after FP-TBI administration, a second series of measurements of physiological values including CBF and brain oxidative metabolism data had been obtained. Severe FP-TBI elicited a marked increase in the rate constant for fluorodopamine production (k3FDOPA) in all brain regions of newborn piglets studied by between 97% (mesencephalon) and 143% (frontal cortex) (p < 0.05). In contrast, brain hemodynamics and cerebral oxidative metabolism remained unaltered after TBI. Furthermore, the permeability-surface area product of FDOPA (PSFDOPA) was unchanged. In addition, regional blood flow differences between corresponding ipsi- and contralateral brain regions did not occur after TBI. Thus, it is suggested that severe FP-TBI induces an upregulation of AADC activity of newborn piglets that is not related to alterations in brain oxidative metabolism.

Marked reduction of brainstem blood flow in artificially ventilated newborn piglets during normoxia and normocapnic hypoxia.

OBJECTIVE: To estimate the effect of artificial ventilation on regional cerebral blood flow, cardiovascular regulation, and cerebral oxidative metabolism in newborns. DESIGN AND SUBJECTS: Comparison of three randomized treatment groups of newborn piglets: Group 1 (artificially ventilated sham-operated group; n =7); group 2 (artificially ventilated group with normoxia and moderate normocapnic hypoxia; n =7); group 3 (spontaneously breathing group with normoxia and moderate normocapnic hypoxia; n =6). MEASUREMENTS AND RESULTS: Animals were anesthetized with 0.5% isoflurane in 70% nitrous oxide and 30% oxygen. Groups 1 and 2 were artificially ventilated. Animals in group 3 breathed spontaneously. Moderate normocapnic hypoxia was induced in groups 2 and 3 for 1 h by lowering the inspiratory oxygen fraction from 0.35 to 0.11. Mode of ventilation induced at most marginal effects on global cerebrovascular response, cardiovascular regulation, and cerebral oxidative metabolism. However, under normoxic conditions, regional cerebral blood flow of the medulla oblongata, pons, mesencephalon, thalamus, and cerebellum were markedly reduced in artificially ventilated piglets ( P <0.05). Moderate normocapnic hypoxia led to a marked increase in regional cerebral blood flow, which was significantly lower in the medulla oblongata, pons, mesencephalon, thalamus, and cerebellum of artificially ventilated piglets ( P <0.05). CONCLUSION: Artificial ventilation clearly induces reduced neuronal activity in the brain stem and cerebellum of newborn piglets. This is suggested by a considerably reduced blood flow in these regions under normoxia and moderate normocapnic hypoxia. However, there is no relevant detrimental effect on cardiovascular regulation and brain oxidative metabolism.

Impact of asymmetric intrauterine growth restriction on organ function in newborn piglets.

Fetal malnutrition may induce asymmetric intrauterine growth restriction (aIUGR) with long-lasting consequences. Understanding the organ-specific structural and functional effects aIUGR may have on the newborn, and understanding the potential impact on the neonatal response to compromising conditions, appears to be essential for adequate treatment. Therefore, a survey is given of some organ-specific alterations in newborns, which have suffered from aIUGR. We studied these effects in a model of asymmetric intrauterine growth restriction based on the spontaneous occurrence of runting in pigs. We wish to demonstrate that experimental studies in animal models are necessary and helpful to elucidate pathogenetic mechanisms. aIUGR seems to have both beneficial and detrimental effects on the newborn. The development of skeletal muscles (conversion to oxidative type I fibers) and of their vascular supply as well as of the brain dopaminergic activity is accelerated. Also, aIUGR apparently improves the ability to withstand critical periods of gradual oxygen deficit as shown by the maintenance of renal blood flow during severe systemic hypoxia, and by improved cerebrovascular autoregulation in hemorrhagic hypotension. On the other hand, aIUGR leads to the reduction of the number of nephrons and to impaired renal excretory functions with arterial hypertension and chronic renal failure.

Effect of hypoxia/hypercapnia on metabolism of 6-[(18)F]fluoro-L-DOPA in newborn piglets.

There is evidence that the dopaminergic system is sensitive to altered p(O(2)) in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain together with brain oxidative metabolism. Therefore 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography (PET) was used to estimate the activity of the aromatic amino acid decarboxylase (AADC) in the brain of fifteen newborn piglets (2-5 days old). Two PET scans were performed in each piglet. Eleven animals underwent a period of normoxia and moderate hypoxia/hypercapnia (H/H). The remaining four animals were used as an untreated control group. Simultaneously, the brain tissue p(O(2)) was recorded, the regional cerebral blood flow (CBF) was measured with colored microspheres and the cerebral metabolic rate of oxygen (CMRO(2)) was determined. In addition, in four untreated and six H/H treated piglets the relative amounts of fluorodopamine and the respective metabolites were determined in brain tissue samples using HPLC analysis. H/H conditions were induced by lowering the inspired fraction of oxygen from 0.35 to 0.10 and adding CO(2) to the inspired gas resulting in an arterial p(CO(2)) between 74 and 79 mmHg. H/H elicited a more than 3-fold increase of the CBF (P<0.05) so that the CMRO(2) remained unchanged throughout the H/H period. Despite this, the brain tissue p(O(2)) was reduced from 19+/-4 to 6+/-3 mmHg (P<0.05). The permeability-surface area product of FDOPA (PS(FDOPA)) was unchanged. However, the transfer rate of FDOPA (k(3)(FDOPA)) of the nigrostriatal dopaminergic system and the relative amounts of fluorodopamine and the respective metabolites were significantly increased (P<0.05). It is suggested that H/H induces an increase of AADC activity. However, an H/H-induced CBF increase maintains bulk O(2) delivery and preserves CMRO(2).

Mutual information and phase dependencies: measures of reduced nonlinear cardiorespiratory interactions after myocardial infarction.

The heart rate variability (HRV) is related to several mechanisms of the complex autonomic functioning such as respiratory heart rate modulation and phase dependencies between heart beat cycles and breathing cycles. The underlying processes are basically nonlinear. In order to understand and quantitatively assess those physiological interactions an adequate coupling analysis is necessary. We hypothesized that nonlinear measures of HRV and cardiorespiratory interdependencies are superior to the standard HRV measures in classifying patients after acute myocardial infarction. We introduced mutual information measures which provide access to nonlinear interdependencies as counterpart to the classically linear correlation analysis. The nonlinear statistical autodependencies of HRV were quantified by auto mutual information, the respiratory heart rate modulation by cardiorespiratory cross mutual information, respectively. The phase interdependencies between heart beat cycles and breathing cycles were assessed basing on the histograms of the frequency ratios of the instantaneous heart beat and respiratory cycles. Furthermore, the relative duration of phase synchronized intervals was acquired. We investigated 39 patients after acute myocardial infarction versus 24 controls. The discrimination of these groups was improved by cardiorespiratory cross mutual information measures and phase interdependencies measures in comparison to the linear standard HRV measures. This result was statistically confirmed by means of logistic regression models of particular variable subsets and their receiver operating characteristics.