Klaus Ulrich Klein

Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis-associated delirium

IntroductionSepsis-associated delirium (SAD) increases morbidity in septic patients and, therefore, factors contributing to SAD should be further characterized. One possible mechanism might be the impairment of cerebrovascular autoregulation (AR) by sepsis, leading to cerebral hypo- or hyperperfusion in these haemodynamically unstable patients. Therefore, the present study investigates the relationship between the incidence of SAD and the status of AR during sepsis.MethodsCerebral blood flow velocity was measured using transcranial Doppler sonography and was correlated with the invasive arterial blood pressure curve to calculate the index of AR Mx (Mx>0.3 indicates impaired AR). Mx was measured daily during the first 4 days of sepsis. Diagnosis of a SAD was performed using the confusion assessment method for ICU (CAM-ICU) and, furthermore the predominant brain electrical activity in electroencephalogram (EEG) both at day 4 after reduction of sedation to RASS >-2.Results30 critically ill adult patients with severe sepsis or septic shock (APACHE II 32 ± 6) were included. AR was impaired at day 1 in 60%, day 2 in 59%, day 3 in 41% and day 4 in 46% of patients; SAD detected by CAM-ICU was present in 76 % of patients. Impaired AR at day 1 was associated with the incidence of SAD at day 4 (p = 0.035).ConclusionsAR is impaired in the great majority of patients with severe sepsis during the first two days. Impaired AR is associated with SAD, suggesting that dysfunction of AR is one of the trigger mechanisms contributing to the development of SAD.Trial registrationclinicalTrials.gov ID NCT01029080

Influence of respiratory rate and end-expiratory pressure variation on cyclic alveolar recruitment in an experimental lung injury model

IntroductionCyclic alveolar recruitment/derecruitment (R/D) is an important mechanism of ventilator-associated lung injury. In experimental models this process can be measured with high temporal resolution by detection of respiratory-dependent oscillations of the paO2 (ΔpaO2). A previous study showed that end-expiratory collapse can be prevented by an increased respiratory rate in saline-lavaged rabbits. The current study compares the effects of increased positive end-expiratory pressure (PEEP) versus an individually titrated respiratory rate (RRind) on intra-tidal amplitude of Δ paO2 and on average paO2 in saline-lavaged pigs.MethodsAcute lung injury was induced by bronchoalveolar lavage in 16 anaesthetized pigs. R/D was induced and measured by a fast-responding intra-aortic probe measuring paO2. Ventilatory interventions (RRind (n = 8) versus extrinsic PEEP (n = 8)) were applied for 30 minutes to reduce Δ paO2. Haemodynamics, spirometry and Δ paO2 were monitored and the Ventilation/Perfusion distributions were assessed by multiple inert gas elimination. The main endpoints average and Δ paO2 following the interventions were analysed by Mann-Whitney-U-Test and Bonferronis correction. The secondary parameters were tested in an explorative manner.ResultsBoth interventions reduced Δ paO2. In the RRind group, ΔpaO2 was significantly smaller (P < 0.001). The average paO2 continuously decreased following RRind and was significantly higher in the PEEP group (P < 0.001). A sustained difference of the ventilation/perfusion distribution and shunt fractions confirms these findings. The RRind application required less vasopressor administration.ConclusionsDifferent recruitment kinetics were found compared to previous small animal models and these differences were primarily determined by kinetics of end-expiratory collapse. In this porcine model, respiratory rate and increased PEEP were both effective in reducing the amplitude of paO2 oscillations. In contrast to a recent study in a small animal model, however, increased respiratory rate did not maintain end-expiratory recruitment and ultimately resulted in reduced average paO2 and increased shunt fraction.

Laparoscopic inguinal hernia repair does not impair testicular perfusion.

BACKGROUND Laparoscopic inguinal hernia repair techniques close the internal ring with a suture. Concern has been raised whether or not the testicular vessels are compromised with this technique. This study was undertaken to evaluate pre- and postoperative testicular perfusion and to compare it with healthy controls. PATIENTS AND METHOD Sixty-five boys (aged 6 weeks to 11 years; median, 1.4 years) with unilateral (n = 52) or bilateral (n = 13) inguinal hernias were treated laparoscopically. Testicular perfusion was measured using a recently developed neuromonitoring device (O2C; LEA Medizintechnik GmbH, Giessen, Germany), which combines light spectroscopy and laser Doppler technique. An optical probe was placed on the surface of each scrotal pouch for measurements at 2 depths (2 and 8 mm). Measurements involved oxygen (O(2)) saturation at the venous end of capillaries, the amount of hemoglobin within microvessels, the blood flow within microcirculation, and the velocity of the blood in microcirculation. Measurements were conducted before and after anesthesia, before and after surgery, and 6 weeks later. Twenty-one healthy boys of similar ages served as controls. RESULTS Measurements at 2-mm depth were unreliable. At 8-mm depth, the oxygen saturation of hemoglobin was between 62% and 75% (hypoxia would be <10%). The relative blood flow was between 160 to 235 arbitrary units, better than in healthy awake controls. Values were solely influenced by the administered fraction of inspired oxygen. Relative hemoglobin volume of the testes and blood flow velocity remained unchanged after surgery. Values were also normal when measured during early and long-term follow-up. CONCLUSION Laparoscopic inguinal hernia repair using suture closure of the internal inguinal ring does not impair testicular perfusion.

Intraoperative monitoring of cerebral microcirculation and oxygenation--a feasibility study using a novel photo-spectrometric laser-Doppler flowmetry.

Background The present study assesses the utility of a novel invasive device (O2C-, oxygen-to-see-device) for intraoperative measurement of the cerebral microcirculation. CO2 vasoreactivity during 2 different propofol concentrations was used to investigate changes of capillary venous cerebral blood flow (rvCBF), oxygen saturation (srvO2), and hemoglobin concentration (rvHb) during craniotomy. Methods Thirty-four patients were randomly assigned to a low propofol (4 mg/kg/h) versus a high propofol (6 mg/kg/h) group. A fiberoptic probe was applied on the cortex next to the surgical site. Measurements were performed during lower (35 mm Hg) and higher (45 mm Hg) levels of partial pressure of carbon dioxide (paCO2). Arterio-venous difference in oxygen concentration (avDO2) and approximated cerebral metabolic rate of oxygen (aCMRO2) were calculated for each paCO2 state. Linear models were fitted to test changes of end points in response to paCO2 and propofol concentration. Results In comparison to the lower levels of paCO2, higher levels of paCO2 increased rvCBF (P<0.001), and srvO2 (P=0.002). RvHb remained unchanged during measurements (P=0.325). Calculated avDO2 decreased with increasing paCO2 (P<0.001), whereas aCMRO2 did not change during the study (P=0.999). Propofol concentration had no effect on measured or calculated end points. Conclusions Increase of rvCBF by paCO2 indicates a preserved CO2 reactivity independent of propofol anesthesia. The consecutive rise in srvO2 implies enhanced oxygen availability due to vasodilatation. Unchanged rvHb represents constant venous hemoglobin concentration. As expected, calculated avDO2 decreases with increased paCO2, whereas aCMRO2 remains unchanged. Despite the promising technical approach, the technology needs validation and further investigation for usage during neurosurgery.

Human cerebral microcirculation and oxygen saturation during propofol-induced reduction of bispectral index

BACKGROUND Propofol reduces cerebral blood flow (CBF) secondary to cerebral metabolic depression. However, in vitro and in vivo studies demonstrate that propofol directly dilates the vascular smooth muscle. This study investigates the effects of propofol-induced changes in bispectral index (BIS) on cerebral microcirculation and oxygenation during craniotomies. METHODS In 21 craniotomy patients undergoing routine craniotomy, anaesthesia was maintained with propofol 4-10 mg kg⁻¹ h⁻¹ and remifentanil 0.1-0.4 µg kg⁻¹ min⁻¹. Propofol concentration was adjusted to achieve higher BIS (target 40) or lower BIS (target 20). Regional measurements of capillary venous blood flow (rvCBF), oxygen saturation (srvO₂), and haemoglobin amount (rvHb) at 2 mm (grey matter) and 8 mm (white matter) cerebral depth were randomly performed at higher and lower BIS by combined laser-Doppler flowmetry and spectroscopy. Calculations: approximated arteriovenous difference in oxygen content (avDO₂) and cerebral metabolic rate of oxygen (aCMRO₂). RESULTS mean values (sd). STATISTICS Mann-Whitney test (*P<0.05). Results Human cerebral microcirculation and oxygen saturation were assessed at propofol dosages 5.1 (2.3) mg kg⁻¹ h⁻¹ [BIS 40 (9)] and 7.8 (2.1) mg kg⁻¹ h⁻¹ [BIS 21 (7)]. Propofol-induced reduction in BIS resulted in increased srvO₂ (P=0.018), and decreased avDO₂ (P=0.025) and aCMRO(2) (P=0.022), in 2 mm cerebral depth, while rvCBF and rvHb remained unchanged. In 8 mm cerebral depth, srvO₂, rvCBF, rvHb, and also calculated parameters avDO₂ and aCMRO₂ remained unaltered. CONCLUSIONS Findings suggest alteration of the CBF/CMRO₂ ratio by propofol in cortical brain regions; therefore, it might be possible that propofol affects coupling of flow and metabolism in the cerebral microcirculation.

Serial Measurement of Static and Dynamic Cerebrovascular Autoregulation After Brain Injury

Background In patients with neuronal injury, the knowledge of the status of cerebrovascular autoregulation can help to optimize the management of the cerebral perfusion pressure. This study characterizes dynamic and static cerebrovascular autoregulation during the first 7 days after severe traumatic brain injury or intracranial hemorrhage. Methods After approval from the IRB, 16 patients were studied. Cerebral blood flow velocity (CBFV) was measured daily for the assessment of dynamic (10 patients) and static (16 patients) cerebrovascular autoregulation in both the middle cerebral arteries using the transcranial Doppler sonography. Dynamic cerebrovascular autoregulation (dAR) was measured using the cuff-deflation method and was expressed by the index of the dAR. The index of the static cerebrovascular autoregulation (sAR) was calculated from changes in the CBFV in relation to drug-induced alterations of the arterial blood pressure. For statistical analyses, t test and mixed effect model were used. Results Both dAR and sAR after brain injury were impaired in most of the patients. The chronologic sequence of the dAR at the ipsilateral injured hemisphere showed a significant decrease until day 4 followed by an incomplete recovery (P<0.002). Changes in sAR were similar, however, they did not gain statistical significance. CBFV was lower at day 1-2 after injury in comparison with day 4 to 7 (P<0.02). Conclusion Daily measured dAR and sAR were impaired after brain injury with a nadir on day 4 and consecutive incomplete recovery over time.

An inhaled tumor necrosis factor‐alpha‐derived TIP peptide improves the pulmonary function in experimental lung injury

The lectin‐like domain of TNF‐α enhances the fluid clearance across the alveolar barrier. For experimental purposes, the lectin‐like domain can be mimicked by a synthetic peptide representing the TIP‐motif of TNF‐α. The present study aims to assess the acute effect of TIP on the pulmonary function in a porcine model of acute respiratory distress syndrome (ARDS).

The effects of arterial carbon dioxide partial pressure and sevoflurane on capillary venous cerebral blood flow and oxygen saturation during craniotomy

BACKGROUND: Intraoperative routine monitoring of cerebral blood flow and oxygenation remains a technological challenge. Using the physiological principle of carbon dioxide reactivity of cerebral vasculature, we investigated a recently developed neuromonitoring device (oxygen-to-see, O2C™ device) for simultaneous measurements of regional cerebral blood flow (rvCBF), blood flow velocity (rvVelo), oxygen saturation (srvO2), and hemoglobin amount (rvHb) at the capillary venous level in patients subjected to craniotomy. METHODS: Twenty-six neurosurgical patients were randomly assigned to anesthesia with 1.4% or 2.0% sevoflurane end-tidal concentration. After craniotomy, a fiberoptic probe was applied on a macroscopically healthy surface of cerebral tissue next to the site of surgery. Simultaneous measurements in 2 and 8 mm cerebral depth were performed in each patient during lower (35 mm Hg) and higher (45 mm Hg) levels (random order) of arterial carbon dioxide partial pressure (Paco2). The principle of these measurements relies on the combination of laser-Doppler flowmetry (rvCBF, rvVelo) and photo-spectrometry (srvO2, rvHb). Linear models were fitted to test changes of end points (rvCBF, rvVelo, srvO2, rvHb) in response to lower and higher levels of Paco2, 1.4% and 2.0% sevoflurane end-tidal concentration, and 2 and 8 mm cerebral depth. RESULTS: RvCBF and rvVelo were elevated by Paco2 independent of sevoflurane concentration in 2 and 8 mm depth of cerebral tissue (P < 0.001). Higher Paco2 induced an increase in mean srvO2 from 50% to 68% (P < 0.001). RvVelo (P < 0.001) and srvO2 (P = 0.007) were higher in 8 compared with 2 mm cerebral depth. RvHb was not influenced by alterations in Paco2 but positively correlated to sevoflurane concentration (P = 0.005). CONCLUSIONS: Increases in rvCBF and rvVelo by Paco2 suggest preserved hypercapnic vasodilation under anesthesia with sevoflurane 1.4% and 2.0% end-tidal concentration. A consecutive increase in srvO2 implies that cerebral arteriovenous difference in oxygen was decreased by elevated Paco2. Unchanged levels of rvHb signify that there was no blood loss during measurements. Data suggest that the device allows detection of local changes in blood flow and oxygen saturation in response to different Paco2 levels in predominant venous cerebral microvessels.

Measurement of cortical microcirculation during intracranial aneurysm surgery by combined laser-Doppler flowmetry and photospectrometry.

BACKGROUND:Accidental vessel occlusion is one major risk of intracranial aneurysm surgery potentially causing cerebral ischemia. The intraoperative assessment of cerebral ischemia remains a technological challenge. OBJECTIVE:As a novel approach, cortical tissue integrity was monitored using simultaneous measurements of regional capillary-venous cerebral blood flow (rvCBF), oxygen saturation (Srvo2), and hemoglobin amount (rvHb) during aneurysm surgery. METHODS:Fifteen patients scheduled for aneurysm surgery of the anterior and posterior circulation were included. A fiber optic probe was placed on the cortex associated with the distal branch of the aneurysmatic vessel. Blinded measurements by combined laser-Doppler flowmetry (rvCBF) and photospectrometry (Srvo2, rvHb) were performed before and after surgical clipping or trapping of the aneurysm. Data were correlated with postoperative imaging and neurological outcome. RESULTS:Cortical measurements could be successfully performed in all patients. Significant increase (>25% change from baseline) or decrease (<25% change from baseline) of rvCBF, Srvo2, and rvHb was detectable in 33 to 46% of patients after surgical intervention. Severe decrease (>50% change from baseline) of all parameters or solitary of rvCBF was correlated to reduced cerebral perfusion and neurological deficits in 2 patients. CONCLUSION:Combined laser-Doppler flowmetry and photospectrometry provides real-time information on cortical microcirculation. Intraoperative alterations of parameters (rvCBF, Srvo2, rvHb) might reflect changes of cerebral tissue integrity during intracranial aneurysm surgery.

Intermittent Hypoxia Causes Inflammation and Injury to Human Adult Cardiac Myocytes.

BACKGROUND:Intermittent hypoxia may occur in a number of clinical scenarios, including interruption of myocardial blood flow or breathing disorders such as obstructive sleep apnea. Although intermittent hypoxia has been linked to cardiovascular and cerebrovascular disease, the effect of intermittent hypoxia on the human heart is not fully understood. Therefore, in the present study, we compared the cellular responses of cultured human adult cardiac myocytes (HACMs) exposed to intermittent hypoxia and different conditions of continuous hypoxia and normoxia. METHODS:HACMs were exposed to intermittent hypoxia (0%–21% O2), constant mild hypoxia (10% O2), constant severe hypoxia (0% O2), or constant normoxia (21% O2), using a novel cell culture bioreactor with gas-permeable membranes. Cell proliferation, lactate dehydrogenase release, vascular endothelial growth factor release, and cytokine (interleukin [IL] and macrophage migration inhibitory factor) release were assessed at baseline and after 8, 24, and 72 hours of exposure. A signal transduction pathway finder array was performed to determine the changes in gene expression. RESULTS:In comparison with constant normoxia and constant mild hypoxia, intermittent hypoxia induced earlier and greater inflammatory response and extent of cell injury as evidenced by lower cell numbers and higher lactate dehydrogenase, vascular endothelial growth factor, and proinflammatory cytokine (IL-1&bgr;, IL-6, IL-8, and macrophage migration inhibitory factor) release. Constant severe hypoxia showed more detrimental effects on HACMs at later time points. Pathway analysis demonstrated that intermittent hypoxia primarily altered gene expression in oxidative stress, Wnt, Notch, and hypoxia pathways. CONCLUSIONS:Intermittent and constant severe hypoxia, but not constant mild hypoxia or normoxia, induced inflammation and cell injury in HACMs. Cell injury occurred earliest and was greatest after intermittent hypoxia exposure. Our in vitro findings suggest that intermittent hypoxia exposure may produce rapid and substantial damage to the human heart.