Correction: Evaluating Mechanisms of Postoperative Delirium and Cognitive Dysfunction Following Elective Spine Surgery in Elderly Patients (CONFESS): Protocol for a Prospective Observational Trial.

[This corrects the article DOI: 10.2196/15488.].

Evaluating Mechanisms of Postoperative Delirium and Cognitive Dysfunction Following Elective Spine Surgery in Elderly Patients (CONFESS): Protocol for a Prospective Observational Trial.

BACKGROUND: Elderly people are at particular high risk for postoperative delirium (POD) following spine surgery, which is associated with longer hospital stays, higher costs, risk for delayed complications, long-term care dependency, and cognitive dysfunction (POCD). It is insufficiently understood which mechanisms and risk factors contribute to the development of POD and POCD following these major but plannable surgeries. OBJECTIVE: This study aims to identify modifiable risk factors in spine surgery. A better understanding thereof would help adapt medical management and surgical strategies to individual risk profiles. METHODS: This is a single-center observational study jointly conducted by the departments of neurosurgery, neurology, and anesthesiology at a tertiary care hospital in Germany. All patients aged 60 years and older presenting to the neurosurgery outpatient clinic or ward for elective spine surgery are screened for eligibility. Exclusion criteria include presence of neurodegenerative or history of psychiatric disease and medication with significant central nervous system activity (eg, antidepressants, antipsychotics, sedatives). Surgical and anesthetic procedures including duration of surgery as primary end point of this study are thoroughly documented. All patients are furthermore evaluated for their preoperative cognitive abilities by a number of tests, including the Consortium to Establish a Registry for Alzheimer's Disease Plus test battery. Physical, mental, and social health and well-being are assessed using the Patient-Reported Outcome Measurement Information System Profile 29 and Hospital Anxiety and Depression Scale. Patients additionally receive preoperative cerebrovascular ultrasound and structural and functional brain imaging. The immediate postoperative period includes screening for POD using the Nursing Delirium Screening Scale and validation through Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria. We furthermore investigate markers of (neuro)inflammation (eg, interleukins, C-reactive protein, tumor necrosis factor alpha). Preoperative examinations are repeated 3 months postoperatively to investigate the presence of POCD and its mechanisms. Statistical analyses will compare delirious and nondelirious patients for predictors of immediate (POD) and delayed (POCD) cognitive dysfunction. RESULTS: This is the first study to prospectively evaluate risk factors for POD and POCD in spine surgery. Recruitment is ongoing, and data collection is estimated to be finished with the inclusion of 200 patients by mid-2020. CONCLUSIONS: The identification of mechanisms, possibly common, underlying POD and POCD would be a major step toward defining effective interventional strategies early in or even before the postoperative period, including the adaptation of surgical strategies to individual risk profiles. TRIAL REGISTRATION: ClinicalTrials.gov NCT03486288; https://clinicaltrials.gov/ct2/show/NCT03486288. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15488.

Anemia tolerance during normo-, hypo-, and hypervolemia.

BACKGROUND: Restrictive intraoperative fluid management has been demonstrated to improve outcome of visceral and lung surgery in several studies. However, subsequent hypovolemia (HOV) may be accompanied by a decrease of anemia tolerance, resulting in increased transfusion needs. We therefore investigated the effect of volume status on anemia tolerance. STUDY DESIGN AND METHODS: Eighteen domestic pigs of either sex (mean weight, 23.5 ± 4.8 kg) were anesthetized, ventilated, and randomized into three experimental groups: normovolemia (no intervention), HOV (blood loss of 40% of blood volume), and hypervolemia (HEV; volume infusion of 40% of blood volume). The animals were then hemodiluted until their individual critical hemoglobin concentrations (Hbcrit ) were reached by the exchange of whole blood for hydroxyethyl starch (HES; 130:0.4). Subsequently, organ-specific hypoxia was assessed using pimonidazole tissue staining in relevant organs. Hemodynamic and metabolic variables were also investigated. RESULTS: Despite significant differences in exchangeable blood volume, Hbcrit was the same in all groups (2.3 g/dL, NS). During HOV, tissue hypoxia was aggravated in the myocardium, brain, and kidneys, whereas tissue oxygenation of the liver and intestine was not influenced by volume status. HEV increased tissue hypoxia in the lungs, but did not impact tissue oxygenation of other organs. CONCLUSIONS: The combination of hemorrhagic HOV with subsequent anemia leads to accentuated tissue hypoxia, revealed by a significant increase in pimonidazole binding at Hbcrit , in heart, lungs, brain, and kidney. The lungs were the only organ that showed increased tissue hypoxia after pretreatment of HES infusion and subsequent anemia by normovolemic hemodilution.

Influence of clonidine induced sympathicolysis on anaemia tolerance in anaesthetized pigs.

BACKGROUND: Clonidine effectively decreases perioperative mortality by reducing sympathetic tone. However, application of clonidine might also restrict anaemia tolerance due to impairment of compensatory mechanisms. Therefore, the influence of clonidine induced, short-term sympathicolysis on anaemia tolerance was assessed in anaesthetized pigs. We measured the effect of clonidine on anaemia tolerance and of the potential for macrohemodynamic alterations to constrain the acute anaemia compensatory mechanisms. METHODS: After governmental approval, 14 anaesthetized pigs of either gender (Deutsche Landrasse, weight (mean ± SD) 24.1 ± 2.4 kg) were randomly assigned to intravenous saline or clonidine treatment (bolus: 20 µg · kg-1, continuous infusion: 15 µg · kg-1 · h-1). Thereafter, the animals were hemodiluted by exchange of whole blood for 6 % hydroxyethyl starch (MW 130.000/0.4) until the individual critical haemoglobin concentration (Hbcrit) was reached. Primary outcome parameters were Hbcrit and the exchangeable blood volume (EBV) until Hbcrit was reached. RESULTS: Hbcrit did not differ between both groups (values are median [interquartile range]: saline: 2.2 (2.0-2.5) g · dL-1 vs. clonidine: 2.1 (2.1-2.4) g · dL-1; n.s.). Furthermore, there was no difference in exchangeable blood volume (EBV) between both groups (saline: 88 (76-106) mL · kg-1 vs. clonidine: 92 (85-95) mL · kg-1; n.s.). CONCLUSION: Anaemia tolerance was not affected by clonidine induced sympathicolysis. Consequently, perioperative clonidine administration probably has not to be omitted in view of acute anaemia.

Determination of organ-specific anemia tolerance.

OBJECTIVE: Utilization of anemia tolerance reduces the need for and risks of perioperative transfusion. Recent publications indicate that the critical limit for oxygen supply might not be the same for each organ system. Therefore, we investigated the effects of acute dilutional anemia on heart, brain, kidneys, liver, small intestine, and skeletal muscle to quantify organ-specific tolerance of different levels of acute anemic hypoxia. We hypothesized that, in some organs, tissue hypoxia occurs before the critical limits of systemic oxygen supply are reached. DESIGN: Laboratory animal experiments. SETTING: Animal research laboratory at university medical school. SUBJECTS: A total of 18 domestic pigs of either sex (average weight: 19.6 kg). INTERVENTIONS: Animals were anesthetized, ventilated, and randomized into three groups and then hemodiluted by exchange of 6% hydroxyethyl starch (130,000:0.4) for whole blood to the group-specific endpoint: Sham (no hemodilution), Hb4 (hemoglobin 4.3 g/dL), Hbcrit (2.7 g/dL). Subsequently, 10 mg/kg pimonidazole (which forms protein adducts in hypoxic cells) was injected. One hour after injection, tissue samples were collected and analyzed for pimonidazole-protein adduct quantification (dot blot) and as a surrogate for transcriptional activation during hypoxia the expression of vascular endothelial growth factor messenger RNA. Relevant hemodynamic and metabolic parameters were collected. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, metabolic parameters, or oxygen consumption did not indicate that tissue oxygenation was restricted before reaching Hbcrit. However, kidneys and skeletal muscle showed enhanced pimonidazole binding and vascular endothelial growth factor expression at Hb4. By contrast, liver oxygenation was actually improved at Hb4. Heart, brain, and liver showed no signs of tissue hypoxia at Hb4. CONCLUSIONS: Heart, brain, kidneys, liver, small intestine, and skeletal muscle experience tissue hypoxia at different degrees of acute anemia, as assessed by the pimonidazole method and vascular endothelial growth factor expression. Further studies are needed to elucidate the mechanisms that determine organ-specific anemia tolerance.

Hyperoxia reversibly alters oxygen consumption and metabolism.

AIM: Ventilation with pure oxygen (hyperoxic ventilation: HV) is thought to decrease whole body oxygen consumption (VO(2)). However, the validity and impact of this phenomenon remain ambiguous; until now, under hyperoxic conditions, VO(2) has only been determined by the reverse Fick principle, a method with inherent methodological problems. The goal of this study was to determine changes of VO(2), carbon dioxide production (VCO(2)), and the respiratory quotient (RQ) during normoxic and hyperoxic ventilation, using a metabolic monitor. METHODS: After providing signed informed consent and institutional acceptance, 14 healthy volunteers were asked to sequentially breathe room air, pure oxygen, and room air again. VO(2), VCO(2), RQ, and energy expenditure (EE) were determined by indirect calorimetry using a modified metabolic monitor during HV. RESULTS: HV reduced VO(2) from 3.4 (3.0/4.0) mL/kg/min to 2.8 (2.5/3.6) mL/kg/min (P < 0.05), whereas VCO(2) remained constant (3.0 [2.6/3.6] mL/kg/min versus 3.0 [2.6/3.5] mL/kg/min, n.s.). After onset of HV, RQ increased from 0.9 (0.8/0.9) to 1.1 (1.0/1.1). Most changes during HV were immediately reversed during subsequent normoxic ventilation. CONCLUSION: HV not only reduces VO(2), but also increases the respiratory quotient. This might be interpreted as an indicator of the substantial metabolic changes induced by HV. However, the impact of this phenomenon requires further study.

The choice of the intravenous fluid influences the tolerance of acute normovolemic anemia in anesthetized domestic pigs.

INTRODUCTION: The correction of hypovolemia with acellular fluids results in acute normovolemic anemia. Whether the choice of the infusion fluid has an impact on the maintenance of oxygen (O2) supply during acute normovolemic anemia has not been investigated so far. METHODS: Thirty-six anesthetized and mechanically ventilated pigs were hemodiluted to their physiological limit of anemia tolerance, reflected by the individual critical hemoglobin concentration (Hbcrit). Hbcrit was defined as the Hb-concentration corresponding with the onset of supply-dependency of total body O2-consumption (VO2). The hemodilution protocol was randomly performed with either tetrastarch (6% HES 130/0.4, TS-group, n = 9), gelatin (3.5% urea-crosslinked polygeline, GEL-group, n = 9), hetastarch (6% HES 450/0.7, HS-group, n = 9) or Ringer's solution (RS-group, n = 9). The primary endpoint was the dimension of Hbcrit, secondary endpoints were parameters of central hemodynamics, O2 transport and tissue oxygenation. RESULTS: In each animal, normovolemia was maintained throughout the protocol. Hbcrit was met at 3.7 ± 0.6 g/dl (RS), 3.0 ± 0.6 g/dl (HS P < 0.05 vs. RS), 2.7 ± 0.6 g/dl (GEL, P < 0.05 vs. RS) and 2.1 ± 0.4 g/dl (TS, P < 0.05 vs. GEL, HS and RS). Hemodilution with RS resulted in a significant increase of extravascular lung water index (EVLWI) and a decrease of arterial oxygen partial pressure (paO2), and O2 extraction ratio was increased, when animals of the TS-, GEL- and HS-groups met their individual Hbcrit. CONCLUSIONS: The choice of the intravenous fluid has an impact on the tolerance of acute normovolemic anemia induced by acellular volume replacement. Third-generation tetrastarch preparations (e.g., HES 130/0.4) appear most advantageous regarding maintenance of tissue oxygenation during progressive anemia. The underlying mechanism includes a lower degree of extravasation and favourable effects on microcirculatory function.

Hyperoxic ventilation improves survival in pigs during endotoxaemia at the critical hemoglobin concentration.

AIM OF THE STUDY: Recently it has been demonstrated that short term hyperoxic ventilation (HV) can improve glucose metabolism, reduce pulmonary and hepatic apoptosis, and improve gastrointestinal perfusion during acute sepsis. However, it is unknown whether additional O(2) improves survival. Therefore we investigated the effects of increased plasma O(2) on survival during extreme anaemia and concomitant endotoxaemia in order to quantify the efficacy of HV. METHODS: Endotoxaemia (Salmonella abortus equi-LPS) was induced in 14 anesthetized pigs ventilated with room air (FiO(2)=0.21). Simultaneously, animals were haemodiluted by exchange of whole blood for 6% hydroxyethyl starch (200,000:0.5) until the individual critical hemoglobin concentration (Hb(crit)) was achieved (outermost limit of tissue oxygenation). Subsequently, animals were either ventilated with an FiO(2) of 0.21 (NOX, n=7) or an FiO(2) of 1.0 (HOX, n=7), and observed thereafter for 6 h without further intervention. RESULTS: HV significantly prolonged survival time at Hb(crit) (NOX, 30 [27/35] min; HOX, 172 [111/235] min, p<0.05). In contrast to the NOX group, HV maintained MAP, and improved DO(2) and tissue oxygenation in the HOX group. CONCLUSION: The improvement of survival, oxygen transport and tissue oxygenation seems to underline the efficacy of HV during endotoxaemia and concomitant acute anaemia. Further studies are needed to transfer these results into daily clinical practice.

Low hemoglobin levels during normovolemia are associated with electrocardiographic changes in pigs.

We studied whether low hemoglobin concentrations during normovolemia change the myocardial electrical current (electrocardiogram) in a pig model. Normovolemic anemia was achieved by stepwise replacing blood with colloids (hydroxyethyl starch 6%). We measured the length of the PQ-, QT-, QTc, and the ST interval as well as the amplitude of the Q wave and T wave at hemoglobin concentrations of 9.5, 8.0, 5.5, 3.8, and 3.3 g·dL. Normovolemic anemia is accompanied by a gradual prolongation of the QT and QTc interval and a reduction in the amplitude of the T wave. The QRS complex is partly diminished in amplitude. Results were verified performing a time-frequency analysis on single heartbeats. During severe anemia and normovolemia, electrocardiographic changes can be detected. Further investigations are warranted to elucidate whether these changes indicate myocardial hypoxia.

Improved short-term survival with polyethylene glycol modified hemoglobin liposomes in critical normovolemic anemia.

OBJECTIVE: To investigate the efficacy of a polyethylene glycol (PEG) modified formulation of liposome-encapsulated hemoglobin (LEH) as an oxygen-carrying blood substitute in the treatment of critical normovolemic anemia. DESIGN AND SETTING: Prospective, controlled, randomized experimental study in a university research facility. SUBJECTS: 14 anesthetized and mechanically ventilated beagle dogs. INTERVENTIONS: Animals were splenectomized and hemodiluted by exchange of whole blood for iso-oncotic hetastarch (HES). Target parameter of the hemodilution protocol was the individual critical hemoglobin concentration (Hb(crit)) corresponding with the onset of O(2) supply dependency of total body O(2) consumption. At Hb(crit) animals were randomized to receive a bolus infusion (20[Symbol: see text]ml/kg) of either LEH (n = 7) or normal saline (NS; n = 7). Subsequently animals were observed without further intervention. MEASUREMENTS AND RESULTS: The primary endpoint was survival time after the completion of treatment; secondary endpoints were parameters of central hemodynamics, O(2) transport and tissue oxygenation. Animals in the LEH group survived significantly longer after completion of treatment (149 +/- 109 vs. 43+/- 56 min). Immediately after treatment LEH-treated animals presented with a more stable cardiovascular condition. After 30 min tissue O(2) tension on the surface of a skeletal muscle was significantly higher in the LEH group (23+/-8 vs. 9 +/- 2 mmHg). Nevertheless, treatment with LEH did not decrease mortality within the observation period. CONCLUSIONS: In this present experimental study the infusion of a PEG-modified LEH provided adequate tissue oxygenation, hemodynamic stability, and a prolongation of survival time after critical anemia. However, these effects were sustained for only a short period of time.

Norepinephrine increases tolerance to acute anemia.

OBJECTIVE: Extreme anemia threatens myocardial oxygen supply by 1) a decline of arterial oxygen content and 2) by a decline of mean aortic pressure (MAP) and thus coronary perfusion pressure. Standard treatment of low arterial oxygen content includes ventilation with pure oxygen and the transfusion of red blood cells. However, it is unknown whether the stabilization of MAP and coronary perfusion pressure with norepinephrine as the sole therapeutic modality may also increase tolerance to extreme anemia and thus improve outcome. DESIGN: Prospective, randomized, controlled study. SETTING: Experimental animal laboratory of a university hospital. SUBJECTS: A total of 28 anesthetized, mechanically ventilated pigs. INTERVENTIONS AND MEASUREMENTS: In the first protocol, 14 anesthetized pigs were hemodiluted by exchange of whole blood for 6% hydroxyethyl starch (200,000:0.5) until the individual critical hemoglobin concentration was reached. For the next 6 hrs, animals were either observed without any further intervention (control group) or their MAP was maintained by adapted infusion of norepinephrine (norepinephrine group). The main outcome variable of this protocol was the 6-hr mortality in both groups. In the second protocol, 14 anesthetized pigs received hemodilution until death. In seven animals, no intervention was performed during the hemodilution procedure, whereas in the other seven animals, MAP was maintained at >60 mm Hg by adapted infusion of norepinephrine. The main outcome variable of this protocol was the maximum exchangeable blood volume until death. MAIN RESULTS: MAP stabilization with norepinephrine reduced the 6-hr mortality at the critical hemoglobin concentration from 100% to 14%. Maintaining MAP by adapted norepinephrine infusion during the hemodilution procedure allowed for the exchange of 125 (110/126) (median [quartile 1/quartile 3]) mL/kg blood (163% of blood volume) in the norepinephrine group, whereas only 76 (73/91) mL/kg blood (104% of blood volume) could be exchanged in the control group. CONCLUSIONS: Application of norepinephrine can be judged a first-line intervention to bridge acute anemia via a stabilization of MAP and coronary perfusion pressure. However, due to the relevant side effects of norepinephrine, its sole long-term use during extreme anemia without concomitant transfusion of erythrocytes is not advised.