Excitatory cholecystokinin neurons of the midbrain integrate diverse temporal responses and drive auditory thalamic subdomains.

The central nucleus of the inferior colliculus (ICC) integrates information about different features of sound and then distributes this information to thalamocortical circuits. However, the lack of clear definitions of circuit elements in the ICC has limited our understanding of the nature of these circuit transformations. Here, we combine virus-based genetic access with electrophysiological and optogenetic approaches to identify a large family of excitatory, cholecystokinin-expressing thalamic projection neurons in the ICC of the Mongolian gerbil. We show that these neurons form a distinct cell type, displaying uniform morphology and intrinsic firing features, and provide powerful, spatially restricted excitation exclusively to the ventral auditory thalamus. In vivo, these neurons consistently exhibit V-shaped receptive field properties but strikingly diverse temporal responses to sound. Our results indicate that temporal response diversity is maintained within this population of otherwise uniform cells in the ICC and then relayed to cortex through spatially restricted thalamic subdomains.

Physiological diversity influences detection of stimulus envelope and fine structure in neurons of the medial superior olive.

The neurons of the medial superior olive (MSO) of mammals extract azimuthal information from the delays between sounds reaching the two ears (interaural time differences, or ITDs). Traditionally, all models of sound localization have assumed that MSO neurons represent a single population of cells with specialized and homogeneous intrinsic and synaptic properties that enable detection of synaptic coincidence on a time scale of tens to hundreds of microseconds. Here, using patch-clamp recordings from large populations of anatomically labeled neurons in brainstem slices from male and female Mongolian gerbils (Meriones unguiculatus), we show that MSO neurons are far more physiologically diverse than previously appreciated, with properties that depend regionally on cell position along the topographic map of frequency. Despite exhibiting a similar morphology, neurons in the MSO exhibit sub-threshold oscillations of differing magnitudes that drive action potentials at rates between 100-800 Hz. These oscillations are driven primarily by voltage-gated sodium channels and are distinct from resonant properties derived from other active membrane properties. We show that graded differences in these and other physiological properties across the MSO neuron population enable the MSO to duplex the encoding of ITD information in both fast, sub-millisecond time varying signals as well as slower envelopes.SIGNIFICANCE STATEMENTNeurons in the medial superior olive (MSO) encode sound localization cues by detecting microsecond differences in the arrival times of inputs from the left and right ears, and it has been assumed this computation is made possible by highly stereotyped structural and physiological specializations. Here we report using a large (>400) sample size that MSO neurons show a strikingly large continuum of functional properties despite exhibiting similar morphologies. We demonstrate that subthreshold oscillations mediated by voltage-gated Na+ channels play a key role in conferring graded differences in firing properties. This functional diversity likely confers capabilities of processing both fast, submillisecond-scale synaptic activity (acoustic "fine structure"), and slow-rising envelope information that is found in amplitude modulated sounds and speech patterns.

De novo sequencing and initial annotation of the Mongolian gerbil (Meriones unguiculatus) genome.

The Mongolian gerbil (Meriones unguiculatus) is a member of the rodent family that displays several features not found in mice or rats, including sensory specializations and social patterns more similar to those in humans. These features have made gerbils a valuable animal for research studies of auditory and visual processing, brain development, learning and memory, and neurological disorders. Here, we report the whole gerbil annotated genome sequence, and identify important similarities and differences to the human and mouse genomes. We further analyze the chromosomal structure of eight genes with high relevance for controlling neural signaling and demonstrate a high degree of homology between these genes in mouse and gerbil. This homology increases the likelihood that individual genes can be rapidly identified in gerbil and used for genetic manipulations. The availability of the gerbil genome provides a foundation for advancing our knowledge towards understanding evolution, behavior and neural function in mammals. ACCESSION NUMBER: The Whole Genome Shotgun sequence data from this project has been deposited at DDBJ/ENA/GenBank under the accession NHTI00000000. The version described in this paper is version NHTI01000000. The fragment reads, and mate pair reads have been deposited in the Sequence Read Archive under BioSample accession SAMN06897401.

Amplitude Normalization of Dendritic EPSPs at the Soma of Binaural Coincidence Detector Neurons of the Medial Superior Olive.

The principal neurons of the medial superior olive (MSO) encode cues for horizontal sound localization through comparisons of the relative timing of EPSPs. To understand how the timing and amplitude of EPSPs are maintained during propagation in the dendrites, we made dendritic and somatic whole-cell recordings from MSO principal neurons in brain slices from Mongolian gerbils. In somatic recordings, EPSP amplitudes were largely uniform following minimal stimulation of excitatory synapses at visualized locations along the dendrites. Similar results were obtained when excitatory synaptic transmission was eliminated in a low calcium solution and then restored at specific dendritic sites by pairing input stimulation and focal application of a higher calcium solution. We performed dual dendritic and somatic whole-cell recordings to measure spontaneous EPSPs using a dual-channel template-matching algorithm to separate out those events initiated at or distal to the dendritic recording location. Local dendritic spontaneous EPSP amplitudes increased sharply in the dendrite with distance from the soma (length constant, 53.6 µm), but their attenuation during propagation resulted in a uniform amplitude of ∼0.2 mV at the soma. The amplitude gradient of dendritic EPSPs was also apparent in responses to injections of identical simulated excitatory synaptic currents in the dendrites. Compartmental models support the view that these results extensively reflect the influence of dendritic cable properties. With relatively few excitatory axons innervating MSO neurons, the normalization of dendritic EPSPs at the soma would increase the importance of input timing versus location during the processing of interaural time difference cues in vivoSIGNIFICANCE STATEMENT The neurons of the medial superior olive analyze cues for sound localization by detecting the coincidence of binaural excitatory synaptic inputs distributed along the dendrites. Previous studies have shown that dendritic voltages undergo severe attenuation as they propagate to the soma, potentially reducing the influence of distal inputs. However, using dendritic and somatic patch recordings, we found that dendritic EPSP amplitude increased with distance from the soma, compensating for dendritic attenuation and normalizing EPSP amplitude at the soma. Much of this normalization reflected the influence of dendritic morphology. As different combinations of presynaptic axons may be active during consecutive cycles of sound stimuli, somatic EPSP normalization renders spike initiation more sensitive to synapse timing than dendritic location.

An essential role for modulation of hyperpolarization-activated current in the development of binaural temporal precision.

In sensory circuits of the brain, developmental changes in the expression and modulation of voltage-gated ion channels are a common occurrence, but such changes are often difficult to assign to clear functional roles. We have explored this issue in the binaural neurons of the medial superior olive (MSO), whose temporal precision in detecting the coincidence of binaural inputs dictates the resolution of azimuthal sound localization. We show that in MSO principal neurons of gerbils during the first week of hearing, a hyperpolarization-activated current (I(h)) progressively undergoes a 13-fold increase in maximal conductance, a >10-fold acceleration of kinetics, and, most surprisingly, a 30 mV depolarizing shift in the voltage dependence of activation. This period is associated with an upregulation of the hyperpolarization-activated and cyclic nucleotide-gated (HCN) channel subunits HCN1, HCN2, and HCN4 in the MSO, but only HCN1 and HCN4 were expressed strongly in principal neurons. I(h) recorded in nucleated patches from electrophysiologically mature MSO neurons (>P18) exhibited kinetics and an activation range nearly identical to the I(h) found in whole-cell recordings before hearing onset. These results indicate that the developmental changes in I(h) in MSO neurons can be explained predominantly by modulation from diffusible intracellular factors, and not changes in channel subunit composition. The exceptionally large modulatory changes in I(h), together with refinements in synaptic properties transform the coding strategy from one of summation and integration to the submillisecond coincidence detection known to be required for transmission of sound localization cues.

Dynamic interaction of Ih and IK-LVA during trains of synaptic potentials in principal neurons of the medial superior olive.

In neurons of the medial superior olive (MSO), voltage-gated ion channels control the submillisecond time resolution of binaural coincidence detection, but little is known about their interplay during trains of synaptic activity that would be experienced during auditory stimuli. Here, using modeling and patch-clamp recordings from MSO principal neurons in gerbil brainstem slices, we examined interactions between two major currents controlling subthreshold synaptic integration: a low-voltage-activated potassium current (I(K-LVA)) and a hyperpolarization-activated cation current (I(h)). Both I(h) and I(K-LVA) contributed strongly to the resting membrane conductance and, during trains of simulated EPSPs, exhibited cumulative deactivation and inactivation, respectively. In current-clamp recordings, regular and irregular trains of simulated EPSCs increased input resistance up to 60%, effects that accumulated and decayed (after train) over hundreds of milliseconds. Surprisingly, the mean voltage and peaks of EPSPs increased by only a few millivolts during trains. Using a model of an MSO cell, we demonstrated that the nearly uniform response during modest depolarizing stimuli relied on changes in I(h) and I(K-LVA), such that their sum remained nearly constant over time. Experiments and modeling showed that, for simplified binaural stimuli (EPSC pairs in a noisy background), spike probability gradually increased in parallel with the increasing input resistance. Nevertheless, the interplay between I(h) and I(K-LVA) helps to maintain a nearly uniform shape of individual synaptic responses, and we show that the time resolution of synaptic coincidence detection can be maintained during trains if EPSC size gradually decreases (as in synaptic depression), counteracting slow increases in excitability.

Synaptic integration in dendrites: exceptional need for speed.

Some neurons in the mammalian auditory system are able to detect and report the coincident firing of inputs with remarkable temporal precision. A strong, low-voltage-activated potassium conductance (g(KL)) at the cell body and dendrites gives these neurons sensitivity to the rate of depolarization by EPSPs, allowing neurons to assess the coincidence of the rising slopes of unitary EPSPs. Two groups of neurons in the brain stem, octopus cells in the posteroventral cochlear nucleus and principal cells of the medial superior olive (MSO), extract acoustic information by assessing coincident firing of their inputs over a submillisecond timescale and convey that information at rates of up to 1000 spikes s(-1). Octopus cells detect the coincident activation of groups of auditory nerve fibres by broadband transient sounds, compensating for the travelling wave delay by dendritic filtering, while MSO neurons detect coincident activation of similarly tuned neurons from each of the two ears through separate dendritic tufts. Each makes use of filtering that is introduced by the spatial distribution of inputs on dendrites.

Perisomatic voltage-gated sodium channels actively maintain linear synaptic integration in principal neurons of the medial superior olive.

Principal neurons of the medial superior olive (MSO) compute azimuthal sound location by integrating phase-locked inputs from each ear. While previous experimental and modeling studies have proposed that voltage-gated sodium channels (VGSCs) play an important role in synaptic integration in the MSO, these studies appear at odds with the unusually weak active backpropagation of action potentials into the soma and dendrites. To understand the spatial localization and biophysical properties of VGSCs, we isolated sodium currents in MSO principal neurons in gerbil brainstem slices. Nucleated and cell-attached patches revealed that VGSC density at the soma is comparable to that of many other neuron types, but channel expression is largely absent from the dendrites. Further, while somatic VGSCs activated with conventional voltage dependence (V(1/2) = -30 mV), they exhibited an unusually negative range of steady-state inactivation (V(1/2) = -77 mV), leaving approximately 92% of VGSCs inactivated at the resting potential (approximately -58 mV). In current-clamp experiments, non-inactivated VGSCs were sufficient to amplify subthreshold EPSPs near action potential threshold, counterbalancing the suppression of EPSP peaks by low voltage-activated potassium channels. EPSP amplification was restricted to the perisomatic region of the neuron, and relatively insensitive to preceding inhibition. Finally, computational modeling showed that the exclusion of VGSCs from the dendrites equalizes somatic EPSP amplification across synaptic locations and lowered the threshold for bilateral versus unilateral excitatory synaptic inputs. Together, these findings suggest that the pattern of sodium channel expression in MSO neurons contributes to these neurons' selectivity for coincident binaural inputs.

Glycinergic axonal inhibition subserves acute spatial sensitivity to sudden increases in sound intensity.

Locomotion generates adventitious sounds which enable detection and localization of predators and prey. Such sounds contain brisk changes or transients in amplitude. We investigated the hypothesis that ill-understood temporal specializations in binaural circuits subserve lateralization of such sound transients, based on different time of arrival at the ears (interaural time differences, ITDs). We find that Lateral Superior Olive (LSO) neurons show exquisite ITD-sensitivity, reflecting extreme precision and reliability of excitatory and inhibitory postsynaptic potentials, in contrast to Medial Superior Olive neurons, traditionally viewed as the ultimate ITD-detectors. In vivo, inhibition blocks LSO excitation over an extremely short window, which, in vitro, required synaptically evoked inhibition. Light and electron microscopy revealed inhibitory synapses on the axon initial segment as the structural basis of this observation. These results reveal a neural vetoing mechanism with extreme temporal and spatial precision and establish the LSO as the primary nucleus for binaural processing of sound transients.

Glycinergic Inhibitory Plasticity in Binaural Neurons Is Cumulative and Gated by Developmental Changes in Action Potential Backpropagation.

Utilization of timing-based sound localization cues by neurons in the medial superior olive (MSO) depends critically on glycinergic inhibitory inputs. After hearing onset, the strength and subcellular location of these inhibitory inputs are dramatically altered, but the cellular processes underlying this experience-dependent refinement are unknown. Here we reveal a form of inhibitory long-term potentiation (iLTP) in MSO neurons that is dependent on spiking and synaptic activation but is not affected by their fine-scale relative timing at higher frequencies prevalent in auditory circuits. We find that iLTP reinforces inhibitory inputs coactive with binaural excitation in a cumulative manner, likely well suited for networks featuring persistent high-frequency activity. We also show that a steep drop in action potential size and backpropagation limits induction of iLTP to the first 2 weeks of hearing. These intrinsic changes would deprive more distal inhibitory synapses of reinforcement, conceivably establishing the mature, soma-biased pattern of inhibition.

Posthearing developmental refinement of temporal processing in principal neurons of the medial superior olive.

In mammals, principal neurons of the medial superior olive (MSO) exhibit biophysical specializations that enable them to detect sound localization cues with microsecond precision. In the present study, we used whole-cell patch recordings to examine the development of the intrinsic electrical properties of these neurons in brainstem slices from postnatal day 14 (P14) to P38 gerbils. In the week after hearing onset (P14-P21), we observed dramatic reductions in somatic EPSP duration, input resistance, and membrane time constant. Surprisingly, somatically recorded action potentials also dramatically declined in amplitude over a similar period (38 +/- 3 to 17 +/- 2 mV; tau = 5.2 d). Simultaneous somatic and dendritic patch recordings revealed that these action potentials were initiated in the axon, which primarily emerged from the soma. In older gerbils, the rapid speed of membrane voltage changes and the attenuation of action potential amplitudes were mediated extensively by low voltage-activated potassium channels containing the Kv1.1 subunit. In addition, whole-cell voltage-clamp recordings revealed that these potassium channels increase nearly fourfold from P14 to P23 and are thus a major component of developmental changes in excitability. Finally, the electrophysiological features of principal neurons of the medial nucleus of the trapezoid body did not change after P14, indicating that posthearing regulation of intrinsic membrane properties is not a general feature of all time-coding auditory neurons. We suggest that the striking electrical segregation of the axon from the soma and dendrites of MSO principal neurons minimizes spike-induced distortion of synaptic potentials and thus preserves the accuracy of binaural comparisons.

Serotonin modulates spike probability in the axon initial segment through HCN channels.

The axon initial segment (AIS) serves as the site of action potential initiation in most neurons, but difficulties in isolating the effects of voltage-gated ion channels in the AIS from those of the soma and dendrites have hampered understanding how AIS properties influence neural coding. Here we have combined confocal microscopy, patch-clamp recordings and light-sensitive channel blockers ('photoswitches') in binaural auditory gerbil neurons to show that hyperpolarization and cyclic-nucleotide-gated (HCN) channels are expressed in the AIS and decrease spike probability, in a manner distinct from that of HCN channels in the soma and dendrites. Furthermore, the control of spike threshold by HCN channels in the AIS can be altered through serotonergic modulation of 5-hydroxytryptamine 1A (5-HT1A) receptors, which hyperpolarizes the activation range of HCN channels. As release of serotonin signals changes in motivation and attention states, axonal HCN channels provide a mechanism to translate these signals into changes in the threshold for sensory stimuli.

In vivo coincidence detection in mammalian sound localization generates phase delays.

Sound localization critically depends on detection of differences in arrival time of sounds at the two ears (acoustic delay). The fundamental mechanisms are debated, but all proposals include a process of coincidence detection and a separate source of internal delay that offsets the acoustic delay and determines neural tuning. We used in vivo patch-clamp recordings of binaural neurons in the Mongolian gerbil and pharmacological manipulations to directly compare neuronal input to output and to separate excitation from inhibition. Our results cannot be accounted for by existing models and reveal that coincidence detection is not an instantaneous process, but is instead shaped by the interaction of intrinsic conductances with preceding synaptic activity. This interaction generates an internal delay as an intrinsic part of the process of coincidence detection. The multiplication and time-shifting stages thought to extract synchronous activity in many brain areas can therefore be combined in a single operation.

Effects of sodium bicarbonate on striated muscle metabolism and intracellular pH during endotoxic shock.

The effects of HCO3Na load on acid-base balance and muscle intracellular bioenergetics have been investigated using 31P-magnetic resonance spectroscopy in an experimental model of endotoxinic shock. Anesthetized, mechanically ventilated, and paralyzed rats (n = 16) were given an intravenous bolus of Escherichia coli lipopolysaccharide (15 mg/kg). When shock was established they were randomly assigned to receive either HCO3Na intravenously (2 mmol/kg in 2 min) or an equimolar saline injection. Lipopolysaccharide induced a significant decrease in the levels of mean arterial pressure (58 +/- 6 vs. 120 +/- 8 mmHg), arterial pH (7.20 +/- .03 vs. 7.35 +/- .01), intracellular pH (6.86 +/- .04 vs. 7.08 +/- .01), a marked hyperlactatemia (7 +/- 3 vs. 1.2 +/- .2 mmol/L) and a drop in the phosphocreatine-inorganic phosphate ratio. In the bicarbonate-loaded rats, mean arterial pressure further decreased whereas it remained unchanged in the saline group. Bicarbonate increased arterial pH and PaCO2 transiently. In the saline group, arterial pH decreased and PaCO2 remained stable. In both groups, intracellular pH and high energy phosphates had a similar evolution. In this model of septic shock, partial correction of arterial pH using HCO3Na did not reduce the metabolic cellular injury in skeletal muscle. Based on these results, HCO3Na may be of limited therapeutic value in severe septic metabolic acidosis.

Hemodynamic and metabolic effects of rapid correction of hypophosphatemia in patients with septic shock.

STUDY OBJECTIVE: To examine the hemodynamic and metabolic short-term effects of hypophosphatemia correction in patients with septic shock receiving catecholamine therapy. DESIGN: Prospective, single cohort study. SETTING: ICU, university hospital. PATIENTS: Ten patients with septic shock and hypophosphatemia below 2 mg/dL. INTERVENTIONS: Infusion of glucose-1-phosphate solution (20 mmol of elemental phosphorus) for 60 min. MEASUREMENTS AND RESULTS: Hemodynamic, oxygen-derived, acid-base, and electrolyte parameters before and immediately after phosphate infusion. Left ventricular stroke work index increased significantly (22%) from a mean low value of 24 +/- 10 g/m2 without changes in filling pressures. Systolic arterial pressure improved by 12%. Arterial pH improved slightly but significantly. Ionized calcium level slightly decreased within the normal range values. Other parameters remained unchanged. CONCLUSIONS: Severe hypophosphatemia may be considered as a superimposed cause of myocardial depression, inadequate peripheral vasodilatation, and acidosis in septic shock. A rapid correction of hypophosphatemia is well tolerated and may have both myocardial and vascular beneficial effects. The magnitude of the response, however, is variable and unpredictable on the basis of serum phosphorus levels.

Prognosis of stroke patients undergoing mechanical ventilation.

OBJECTIVE: to determine the outcome of stroke patients undergoing mechanical ventilation. DESIGN: retrospective chart review and follow-up telephone interview. SETTING: medical ICU in a multidisciplinary university hospital. PATIENTS AND PARTICIPANTS: 199 stroke patients from 1984-1989 where the final diagnosis was stroke. INTERVENTIONS: all patients were admitted for the need of mechanical ventilation. MEASUREMENTS AND RESULTS: demographic information, previous relevant diseases, stroke type, general clinical and neurological data, biochemical variables, severity of illness were recorded for the first 24 h following ICU admission. A 1-year follow-up was performed, including mortality and functional status of survivors. Of 170 eventually analyzable patients, 123 (72.4%) died during their ICU stay and 156 (91.8%) during the first year. Three variables were independently associated with one-year mortality: Glasgow score < 10 (p < 0.03), bradycardia (p < 0.001), absence of brainstem reflexes (p < 0.0004). CONCLUSION: overall prognosis of stroke needing mechanical ventilation is poor, strongly linked to symptoms of neurological impairment.

Comparison of systemic and regional effects of dobutamine and dopexamine in norepinephrine-treated septic shock.

OBJECTIVES: To compare the effects of dobutamine and dopexamine on systemic hemodynamics, lactate metabolism, renal function and the intramucosal-arterial PCO(2) gap in norepinephrine-treated septic shock. DESIGN: A prospective, interventional, randomized clinical trial. SETTING: Adult medical/surgical intensive care unit in a university hospital. PATIENTS: After volume resuscitation, 24 patients were treated with norepinephrine alone titrated to obtain a mean arterial pressure of 75 mmHg and a cardiac index greater than 3. 5 l/min(-1). m(-2). INTERVENTIONS: Patients were randomized to receive an infusion of dobutamine (n = 12) (5 microg/kg per min) or dopexamine (n = 12) (1 microg/kg per min). MEASUREMENTS AND MAIN RESULTS: Baseline measurements included: hemodynamic parameters, renal parameters (diuresis, creatinine clearance and urinary sodium excretion), gastric mucosal-arterial PCO(2) gap, arterial and mixed venous gases and arterial lactate and pyruvate levels. These measurements were repeated after 1 (H(1)), 4 (H(4)) and 24 (H(24)) h. No difference was found between dobutamine and dopexamine among H(0) and H(1), H(4) and H(24) values for hemodynamics. Dobutamine and dopexamine at low doses had no significant effect on mean arterial pressure, heart rate, cardiac index, oxygen delivery, oxygen consumption and pulmonary artery occlusion pressure. No patients developed arrhythmia or electrocardiographic signs of myocardial ischemia. After 4 and 24 h lactate concentration decreased in the dobutamine group from 2.4 +/- 1 mmol/l to 1.7 +/- 0. 7 mmol/l and 1.5 +/- 0.4 mmol/l, respectively, while it increased in the dopexamine group from 2.3 +/- 1 mmol/l to 2.7 +/- 1 mmol/l after 4 h and returned to baseline values after 24 h (2.2 +/- 0.6). After 24 h the lactate/pyruvate ratio decreased in the dobutamine group from 15 +/- 5 to 12 +/- 3 (p < 0.05) while it was unchanged in the dopexamine group (from 16 +/- 6 to 17 +/- 4). Arterial pH increased in the dobutamine group from 7.35 +/- 0.05 to 7.38 +/- 0.07 (p < 0. 05) while it was unchanged in the dopexamine group (from 7.34 +/- 0. 01 to 7.35 +/- 0.10). The PCO(2) gap decreased after 1 and 4 h in both the dobutamine and dopexamine groups (p < 0.05 with respect to baseline). When looking at individual responses, however, patients from both groups exhibited an increased gastric PCO(2) gap. No difference was found between dobutamine and dopexamine for renal parameters. CONCLUSIONS: In norepinephrine-treated septic shock, low doses of neither dobutamine nor dopexamine caused significant effects on systemic hemodynamics and renal function and both dobutamine and dopexamine inconsistently improved the PCO(2) gap. The present results support the need for individual measurement of the effects of catecholamine on the PCO(2) gap.

Parenteral with enteral nutrition in the critically ill.

OBJECTIVE: To determine whether nutrient intake by early enteral nutrition with parenteral nutrition improves levels of retinol-binding protein and prealbumin (primary endpoint) and reduce morbidity and mortality (secondary endpoint) in ICU patients. DESIGN: Prospective, double-blind, and randomized, placebo-controlled study. SETTING: Two intensive care units in a tertiary institution. PATIENTS AND PARTICIPANTS: 120 patients in two groups of 60. INTERVENTIONS: Patients received either enteral plus parenteral nutrition (treatment group) or enteral nutrition plus placebo (placebo group) for 4-7 days after initiation of nutritional support. MEASUREMENTS AND RESULTS: Retinol-binding protein (P = 0.0496) and prealbumin (P = 0.0369) increased significantly in the treatment group from day 0 to day 7. There was no reduction in morbidity in ICU. There was no difference in OMEGA score (263 vs. 244) and length of stay in the ICU (16.9 vs. 17.3), but a reduction in length of stay at hospital (31.2+/-18.5 vs. 33.7+/-27.7, P = 0.0022). Mortality on day 90 (17 vs. 18) and after 2 years (24 vs. 24) was identical. CONCLUSIONS: Although it enhances nutrient intake and corrects nutritional parameters such as RBP and prealbumin more rapidly, within 1 week, supplemental parenteral nutrition has no clinically relevant effect on outcome in ICU patients at the early phase of nutritional support.

Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study.

OBJECTIVES: To compare the effects of norepinephrine and dobutamine to epinephrine on hemodynamics, lactate metabolism, and gastric tonometric variables in hyperdynamic dopamine-resistant septic shock. DESIGN: A prospective, intervention, randomized clinical trial. SETTING: Adult medical/surgical intensive care unit in a university hospital. PATIENTS: 30 patients with a cardiac index (CI) > 3.51 x min(-1) x m(-2) and a mean arterial pressure (MAP) < or = 60 mmHg after volume loading and dopamine 20 microg/kg per min and either oliguria or hyperlactatemia. INTERVENTIONS: Patients were randomized to receive an infusion of either norepinephrine-dobutamine or epinephrine titrated to obtain an MAP greater than 80 mmHg with a stable or increased CI. MEASUREMENTS AND MAIN RESULTS: Baseline measurements included: hemodynamic and tonometric parameters, arterial and mixed venous gases, and lactate and pyruvate blood levels. These measurements were repeated after 1, 6, 12, and 24 h. All the patients fulfilled the therapeutic goals. No statistical difference was found between epinephrine and norepinephrine-dobutamine for systemic hemodynamic measurements. Considering metabolic and tonometric measurements and compared to baseline values, after 6 h, epinephrine infusion was associated with an increase in lactate levels (from 3.1 +/- 1.5 to 5.9 +/- 1.0 mmol/l;p < 0.01), while lactate levels decreased in the norepinephrine-dobutamine group (from 3.1 +/- 1.5 to 2.7 +/- 1.0 mmol/l). The lactate/pyruvate ratio increased in the epinephrine group (from 15.5 +/- 5.4 to 21 +/- 5.8; p < 0.01) and did not change in the norepinephrine-dobutamine group (13.8 +/- 5 to 14 +/- 5.0). Gastric mucosal pH (pHi) decreased (from 7.29 +/- 0.11 to 7.16 +/- 0.07; p < 0.01) and the partial pressure of carbon dioxide (PCO2) gap (tonometer PCO2-arterial PCO2) increased (from 10 +/- 2.7 to 14 +/- 2.7 mmHg; p < 0.01) in the epinephrine group. In the norepinephrine-dobutamine group pHi (from 7.30 +/- 0.11 to 7.35 +/- 0.07) and the PCO2 gap (from 10 +/- 3.0 to 4 +/- 2.0 mmHg) were normalized within 6 h (p < 0.01). The decrease in pHi and the increase in the lactate/pyruvate ratio in the epinephrine group was transient, since it returned to normal within 24 h. CONCLUSIONS: Considering the global hemodynamic effects, epinephrine is as effective as norepinephrine-dobutamine. Nevertheless, gastric mucosal acidosis and global metabolic changes observed in epinephrine-treated patients are consistent with a markedly inadequate, although transient, splanchnic oxygen utilization. The metabolic and splanchnic effects of the combination of norepinephrine and dobutamine in hyperdynamic dopamine-resistant septic shock appeared to be more predictable and more appropriate to the current goals of septic shock therapy than those of epinephrine alone.