The hip fracture surgery in elderly patients (HIPELD) study to evaluate xenon anaesthesia for the prevention of postoperative delirium: a multicentre, randomized clinical trial.

BACKGROUND: Postoperative delirium occurs frequently in elderly hip fracture surgery patients and is associated with poorer overall outcomes. Because xenon anaesthesia has neuroprotective properties, we evaluated its effect on the incidence of delirium and other outcomes after hip fracture surgery. METHODS: This was a phase II, multicentre, randomized, double-blind, parallel-group, controlled clinical trial conducted in hospitals in six European countries (September 2010 to October 2014). Elderly (≥75yr-old) and mentally functional hip fracture patients were randomly assigned 1:1 to receive either xenon- or sevoflurane-based general anaesthesia during surgery. The primary outcome was postoperative delirium diagnosed through postoperative day 4. Secondary outcomes were delirium diagnosed anytime after surgery, postoperative sequential organ failure assessment (SOFA) scores, and adverse events (AEs). RESULTS: Of 256 enrolled patients, 124 were treated with xenon and 132 with sevoflurane. The incidence of delirium with xenon (9.7% [95% CI: 4.5 -14.9]) or with sevoflurane (13.6% [95% CI: 7.8 -19.5]) were not significantly different (P=0.33). Overall SOFA scores were significantly lower with xenon (least-squares mean difference: -0.33 [95% CI: -0.60 to -0.06]; P=0.017). For xenon and sevoflurane, the incidence of serious AEs and fatal AEs was 8.0% vs 15.9% (P=0.05) and 0% vs 3.8% (P=0.06), respectively. CONCLUSIONS: Xenon anaesthesia did not significantly reduce the incidence of postoperative delirium after hip fracture surgery. Nevertheless, exploratory observations concerning postoperative SOFA-scores, serious AEs, and deaths warrant further study of the potential benefits of xenon anaesthesia in elderly hip fracture surgery patients. CLINICAL TRIAL REGISTRATION: EudraCT 2009-017153-35; ClinicalTrials.gov NCT01199276.

Influence of gravitational sympathetic stimulation on the Surgical Plethysmographic Index.

Surgical Plethysmographic Index (SPI), calculated from pulse photo-plethysmographic amplitude oscillations, has been proposed as a tool to measure nociception anti-nociception balance during general anesthesia, but it is affected by several confounding factor that alter the autonomic nervous system (ANS) modulation. We hypothesized that SPI may be mainly affected by sympathetic stimulation independently from nociception. We studied the effects of two sympathetic stimuli on SPI, delivered through passive head-up tilt at 45 and 90 degrees angles, in nine awake healthy adults. The sympathetic modulation was assessed by means of heart rate variability (HRV) analysis. Mean (SD) SPI significantly increased from baseline to 45 degrees [from 38.6 (13.7) to 60.8 (7.6), p<0.001)] and to 90 degrees angle tilt [82.3 (5.4), p<0.001]. The electrocardiographic mean R-to-R interval significantly shortened during both passive tilts, whereas systolic arterial pressure did not change during the study protocol. HRV changed significantly during the study protocol towards a predominance of sympathetic modulation during passive tilt. Gravitational sympathetic stimulation at two increasing angles, in absence of any painful stimuli, affects SPI in awake healthy volunteers. SPI seems to reflect the sympathetic outflow directed to peripheral vessels.

Preoperative autonomic nervous system analysis may stratify the risk of hypotension after spinal anesthesia.

BACKGROUND: Studies on pregnant women undergoing cesarean delivery or elderly men scheduled for prostate brachytherapy have demonstrated the predictive value of heart rate variability (HRV) analysis for hypotension during spinal anesthesia. We conducted a prospective observational study to investigate if preoperative HRV analysis may have a role in identifying the risk of hypotension following spinal anesthesia in otherwise healthy patients. METHODS: The study investigated 47 ASA physical status I-II patients aged between 18-50 years that underwent subarachnoid anesthesia for lower abdominal or orthopedic scheduled surgery. ECG was recorded from all subjects before the subarachnoid block. We analysed the autonomic nervous system modulation, measured by HRV analysis. The variables that were be considered were preoperative HRV total power, low frequency (LF) and high frequency (HF) heart beat oscillations and LF/HF ratio. The LF/HF ratio was dichotomized according to the median for sensitivity analysis. The lowest arterial pressure value between spinal anesthesia and the end of surgery was recorded. RESULTS: The median LF/HF before anesthesia was 2.3. We considered two groups of 23 (LF/HF<2.3, group LOW) and 24 (LF/HF>2.3, group HIGH) patients respectively. Both groups had similar baseline demographic and hemodynamic variables. A high preoperative sympathetic outflow and loss of vagal modulation, as stated by LF/HF>2.3, was correlated with a relative risk of 7.7 (95%CI 1.04 to 56.6, p=0.023) of post-spinal hypotension. CONCLUSIONS: Preoperative analysis of autonomic nervous system modulation might be useful to stratify the risk of post-spinal hypotension and it might indicate the need for careful monitoring or prophylactic fluids.

Surgical Pleth Index guided analgesia blunts the intraoperative sympathetic response to laparoscopic cholecystectomy.

BACKGROUND: Surgical noxious stimuli generate a stress response with an increased sympathetic activity, potentially affecting the perioperative outcome. Surgical Pleth Index (SPI), derived from the pulse plethysmogram, has been proposed as a tool to assess nociception-antinociception balance. The relationship between SPI and autonomic nervous system (ANS) during general anesthesia is poorly understood and it is doubtful if SPI-guided analgesia may offer advantages over the standard clinical practice. The study was designed to evaluate if SPI-guided analgesia leads to a lower sympathetic modulation compared with standard clinical practice. METHODS: Electrocardiographic wave, non-invasive blood pressure and SPI were recorded in ASA I-II patients undergoing elective laparoscopic cholecystectomy, randomized to receive SPI-guided analgesia or standard analgesia. Hemodynamic parameters, SPI, mean and variance of heart rate, low (LF) and high frequency (HF) spectral components of heart rate variability were measured at four time points: (T0) baseline, (T1) after induction of general anesthesia, (T2) after pneumoperitoneum insufflation and (T3) after pneumoperitoneum withdrawal. RESULTS: SPI, hemodynamic and ANS parameters changed significantly in both groups during the study period (P<0.0001). At T2 SPI and markers of sympathetic modulation were significantly lower in SPI group (mean [SD] SPI 38.1 [15.3] vs. 48.1 [16.2] normalized units, P<0.05; LF 38 [8.6] vs. 56.2 [20.6] normalized units, P<0.01; LF/HF 1.01 [1.1] vs. 2.68 [2.07], P<0.01). There was no difference in remifentanil consumption, recovery time from anesthesia, or postoperative pain and complications. CONCLUSION: SPI-guided analgesia led to a more stable sympathetic modulation but didn't seem to offer clinically relevant advantages over the standard clinical practice for laparoscopic cholecystectomy.

Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing mitochondrial antioxidant protection.

Generation of free radicals is often associated with the induction and progression of apoptosis. Therefore, antioxidants can prove anti-apoptotic, and can help to elucidate specific apoptotic pathways. Here we studied whether coenzyme Q, present in membranes in reduced (ubiquinol) or oxidised (ubiquinone) forms, can affect apoptosis induced by various stimuli. Exposure of Jurkat cells to alpha-tocopheryl succinate (alpha-TOS), hydrogen peroxide, anti-Fas IgM or TRAIL led to induction of apoptosis. Cell death due to the chemical agents was suppressed in cells enriched with the reduced form of coenzyme Q. However, coenzyme Q did not block cell death induced by the immunological agents. Ubiquinol-10 inhibited reactive oxygen species (ROS) generation in cells exposed to alpha-TOS, and a mitochondrially targeted coenzyme Q analogue also blocked apoptosis triggered by alpha-TOS or hydrogen peroxide. Therefore, it is plausible that ubiquinol-10 protects cells from chemically-induced apoptosis by acting as an antioxidant in mitochondria. Our results also indicate that generation of free radicals may not be a critical step in induction of apoptosis by immunological agents.

Identification of novel low M(r) glutenin subunits in the high quality bread wheat cv Salmone and their effects on gluten quality.

Southern-blot hybridization with a probe specific for genes encoding for low M(r) glutenin subunits showed that the high quality bread wheat cv Salmone contains two DNA fragments designated as SF720 and SF750. These fragments were found to occur on the chromosome-1B satellite, and to be associated with the presence of two strongly staining low M(r) glutenin subunits in the two-dimensional A-PAGE x SDS-PAGE pattern of cv Salmone. Comparison of 65 F(6) random lines derived from the cross between cv Salmone and the medium quality line FAP74809 revealed that the presence of fragments SF720 and SF750 had significant positive effects on several quality related parameters such as SDS sedimentation volume, Farinograph stability and Alveograph strength (W), tenacity (P) and elasticity (L). Additive effects of high M(r) glutenin subunits 1 and 7+9 on gluten quality were found as well. Fragments SF720 and SF750 were suggested to occur at a locus other than Glu-B3, as indicated by their relatively high frequency of recombination with the Gli-B1 locus.

From low hematocrit physiology to isovolemic hemodilution.

The aim of this study, starting from some concepts of physiology, was to deal with the ever growing question of intentional anemia. Physiology suitably expresses the linear relationship between hematocrit and blood fluidity, and at the same time explains how viscosity and aggregability are important co-factors in the circulation, in disease and in thromboembolic complications. The need to understand how a low hematocrit level, compared to the volemia, is a fundamental requirement in surgery, and even more so in surgery with a high risk of embolism, like orthopedic traumatology surgery. Normovolemic hemodilution was analyzed both for the risks it involves and for how much it sticks to the changes induced by a similar situation on the various organs and apparatus. The authors, based on their experience in the field of anesthesiology, propose an operating schedule to safely perform intentional normovolemic hemodilution, describing the preoperative, intraoperative and finally the postoperative period. In conclusion, the authors advocate a wider use of this technique, confirming its safety in relation to volemia.

Blood saving program: a multicenter Italian experience.

To assess the causes of failure in a blood saving program and the consequent need for homologous transfusions during major orthopedic surgery, data were collected from six orthopedic centers where an autotransfusion program was carried out from 1992-1994. The 1,576 (1,016 female and 560 male) patients studied (average age 63.6 +/- 10 years) were treated either for total hip prosthesis (1,144 pts) total knee prosthesis (212 pts), plate and screw removal plus hip prosthesis (8 pts), hip revision (cup 48 pts, stem 10 pts, cup plus stem 146 pts) and total knee revision (8 pts). Ninety percent of patients did not undergo homologous transfusions, which was significantly connected to: male sex (8% versus 11.7% p = 0.02), younger age (63.2 vs 66.9 years, p = 0.0001), higher weight (male 76 vs 70.7 Kg. p = 0.003, female 65.6 vs 61.9 Kg. p = 0.0003); higher baseline Hb (13.9 vs 12.8 g/dl, p = 0.0041), shorter operation time (110 vs 128 minutes, p = 0.0001); use of indobufen for antithromboembolic prophylaxis (indobufen 4.6% vs heparin calcium 15.2% vs low molecular weight heparin 9% p = 0.0001). On the contrary, the factors favoring homologous transfusions were: peripheral anesthesia (spinal and epidural 15.3% vs general 9.3% vs integrated 9.8% p = 0.016), total hip or knee revision, fixation device removal before hip prosthesis, systemic hypertension and coronary heart disease.

Autotransfusion with predeposit-haemodilution and perioperative blood salvage: 20 years of experience. Rizzoli Study Group on Orthopaedic Anesthesia.

BACKGROUND: Through a prospective study, we evaluated the efficacy of an integrated autotransfusion regimen comprised of predeposit-hemodiluition and intra and post-operative blood salvage in major orthopaedic surgery. METHODS: We examined the records of 2303 consecutive patients (1524 females and 779 males, mean age 62.7, standard deviation 11 years (range 16-90 yrs), pre-operative haemoglobin (Hb) concentration 13.5 (SD 1.4) (range 6.7-19.3) g/dl undergong total hip arthroplasty (THA 1582 patients), THA after the removal of internal fixation devices (RFD+THA, 25 patients), total knee arthroplasty (TKA, 347 patients), revision surgery of the hip (HR, cup+stem revision, 248 patients; cup revision 64 patients; stem revision 23 patients) and total knee revision (TKR 14 patients). We estimated that the number of predonations (MSBOS - maximum surgery blood order schedule) was 2 units for THA, TKA and TKR, and 3 units for partial or total hip revision and for total hip arthroplasty with fixation removal. RESULTS: It was possible to obtain the MSBOS in 2070 patients (89.8%). Homologous red blood cell (HRBC) transfusion were carried out in 184 patients (8%). We found that the need to use HRBC was significantly associated with failure to meet the number of MSBOS, female sex, lower pre-operative Hb concentration, use of calcium heparin for antithrombosis prophylaxis, more extensive surgery, a higher ASA rating and co-existing diseases such as coronary artery disease. CONCLUSIONS: Cooperation among anaesthesis, transfusionists and surgeons in the application of an integrated autotransfusion regimen enabled us to treat 92% of our patients with only autotransfusion.

Plasma predeposit: the role of productive plasmapheresis.

At the Rizzoli Orthopaedic Institute, as part of our autotransfusion program, we have recently had the possibility to introduce plasma predeposit by means of productive plasmapheresis in patients undergoing major orthopaedic surgery, in which bleeding more than 50-60% of circulating blood mass was expected and so a greater quantity of plasma compared to red blood cells was considered necessary. Red cells and fresh frozen plasma predeposits and perioperative blood recovery was sufficient to cover transfusional needs. In our opinion, plasma predepositing by plasmapheresis is indicated in patients with anaemia, cardiopathy and/or vasculopathy, minute constitution.

Effects of predeposit and intentional perioperative haemodilution on blood saving program in major orthopaedic surgery.

In this study we evaluated the effects of predeposit and intentional perioperative haemodilution on a blood saving program in major orthopaedic surgery. We demonstrated that autologous blood phlebotomy and maintenance of optimal levels of perioperative haemodilution by delaying blood transfusion, even autologous, are efficient techniques in reducing homologous, red blood cell (HRBC) transfusion. Patients who received autologous red blood cell (ARBC) or HRBC more than one day after surgery, while having Hb values <8 g/dl, are less at risk of needing the first or additional HRBCs. In conclusion, predeposit and intentional haemodilution obtained by delaying blood transfusions, even autotransfusional, is a correct way of conducting a blood saving program (BSP) in major orthopaedic surgery. These techniques are clinically effective in avoiding or reducing HRBC transfusion.

Anaesthesia and autologous transfusion.

The anaesthesiologist plays a central role in co-ordinating the combined application of the various blood saving techniques. In fact, to carry out transfusion therapy correctly, the anaesthesiologist must plan the right number of units of predeposit blood during the first examination, estimate the salvage of intra and post operative blood loss and spread the infusion of the units over the first three days in order to keep the patient in a state of haemodilution. From January 1992 to June 1994 in the department of anaesthesia and the intensive care unit, 980 patients were treated for total joint replacement: 714 total hips (7 after removal of plates and screws) 145 revisions, and 121 total knee prostheses. Basal Hb was 13.4 +/- 1.4 g/dl (range 6.7-17.9 g/dl). Homologous transfusions were carried out in 6.3% of these patients. The need to use homologous transfusions was negatively influenced by female sex, coronary heart disease (p = 0.005), length of surgery and type of antithromboembolic prophylaxis (indobufen has a significantly low incidence-p = 0.0001--compared to calcium heparin or low molecular weight heparin).

Intensive predeposit-hemodilution autologous blood donation and IOBS increase in erythropoietic levels in patients undergoing hip arthroplasty.

Erythropoietin (EPO) plasma levels were monitored during the perioperative period in 61 consecutive patients (22 males - 39 females), aged 62.5 +/- 9.5 years, scheduled for hip arthroplasty. All patients underwent intraoperative blood salvage (IOBS) and were subdivided into three different groups according to their hemoglobin levels (Hb) 24 hours postoperatively (group A: Hb < 8 g/dl; group B: Hb between 8-9 g/dl; group C: HB > or = 9 g/dl). Seventy-two hours after surgery EPO levels were significantly different in group A (135 +/- 68) compared to group C (54.3 +/- 32), with a positive correlation (p < 0.01) between Hb and EPO levels. On the basis of these results we suggest that a programmed autologous red blood cell collection aimed at obtaining the lowest hemoglobin values during the first 24 hours after surgery, may be of clinical utility in preventing homologous blood needs.

Autotransfusion: 15 years experience at Rizzoli Orthopaedic Institute.

The program of blood saving, result of 15 years of experience, includes predeposit (1977) hemodilution (1979) intra (1984) and postoperative (1985) salvage, careful intra and postoperative bleeding control, use of homologous transfusion only in case of intolerated anaemia even for 7-8g/dl Hb values. The use of autologous compared to homologous transfusion passed from 19% in 1984 to 62% in 1992. In 1992 in the surgical division of the 1st Anaesthesia and Intensive Care unit, 414 patients underwent prosthetic hip and knee surgery, 8% of these patients were homologously transfused.

Reducing perioperative blood loss in patients undergoing total hip arthroplasty.

In this prospective, randomised, double-blind study, we investigated the effect of epidural anaesthesia and an antifibrinolytic agent, Aprotinin (500,000 KIU in bolus before surgery and 500,000 KIU h(-1) in drip form during surgery), on intra and postoperative blood loss and transfusion requirements in total hip arthroplasty. Sixty patients were allocated randomly to four groups (A: epidural + general anesthesia + Aprotinin, B: epidural + general anesthesia + placebo (equal volume), C: general anaesthesia + Aprotinin, D: general anaesthesia + placebo). Postoperative analgesia: epidural analgesia in groups A and B, systemic analgesia with opiates in groups C and D. Blood loss during surgery was monitored and salvaged with the Compact-A Dideco, and postoperative blood loss with the BT 797 Recovery Dideco for the first 24 hours. Perioperative blood loss, frequency and quantity of transfusions were significantly higher in group D (p<0.0001). Total blood loss was reduced by 31.3% by epidural anaesthesia, 20.4% by Aprotinin and 51.4% using a combination of the two techniques.

Salvage and reinfusion of chyle in closed chest injury.

The aim of this study was to describe a system of salvaging and reinfusing chyle which accumulated in the right pleural cavity of a patient after a thoracic duct lesion caused by a closed chest injury associated with amyelic fracture of the dorsal spine D10-D11. The chyle was collected in a reservoir (BT 844 Dideco), transferred by an electronic pump (BT 797 recovery Dideco) to a storage bag, microfiltered and then reinfused to the patient A solution was needed to prevent the patient with severe chylothorax, from having immunological and metabolic imbalance. The long period of conservative treatment with our system was imposed by the onset of acute post-traumatic myocardic infarction which delayed surgery. From experience gained, we can say that using total parenteral nutrition, chyle can not only be salvaged but also reinfused, respecting the strict rules of hygiene.

Asymptomatic carotid disorder and hemodilution: a perioperative study in major orthopaedic surgery.

The aim of this study was to assess the pattern of adaptation to severe Haemodilution in pts with normal or stenotic carotid vessels. We enrolled 180 consecutive pts undergoing total hip replacement: 138 pts had echo-Doppler documented normal carotid arteries, 10 pts had kinking and 32 pts had monolateral or bilateral stenosis of internal carotid arteries (lesions, class of stenosis 1-49%). Haemoglobin values on the 4th day after surgery was 8.7 +/- 1.2 g/dl with no statistically significant differences in pts (patients) with carotid disorders versus normal pts. No pt showed clinical signs of cerebral ischemia or brain damage in the postoperative period. These results are consistent with experimental and clinical data showing that normovolaemic anaemia is well tolerated without disabling symptoms in pts with mild or moderate stenosis of carotid arteries.

Proximal deep vein thrombosis: the use of the echoDoppler for diagnosis and therapeutic indications.

Our objective was to assess the impact of echo-Doppler technique on the diagnosis of Deep Vein Thrombosis (DVT) in major orthopedic surgery (80% of DVT diagnosed are asymptomatic). We therefore analyzed 200 consecutive pts submitted to elective surgery for total hip replacement. The postoperative echo-Doppler study indicated DVT in 13 pts: these pts underwent a postoperative lower limb phlebography. Echo-Doppler and phlebography had concordant results in 11 of 13 echo assessed proximal DVT. These observations suggest that Duplex scanning is a good method to diagnose and to guide therapy for proximal DVT in orthopaedic clinic.

Autotransfusion with intra- and postoperative blood recovery in prosthetic hip surgery. A study conducted on 1368 cementless prostheses.

With regard to increasing reservations as to homologous transfusions and the objective risks that they involve, since 1984 we have been using an autotransfusion technique in total hip arthroplasty constituting blood predeposit for hemodilution, and intra- and postoperative blood recovery. When this method was used postoperative complications were not very significant even when patients were high-risk (cardiopathic); furthermore, the use of homologous transfusions was required in 2.2% of the patients in 1994 as compared to 90% in 1985. The use of our orthopaedic protocol allows for rapid recovery of movement in the patient thus reducing time bed-ridden and related risks (DVT and/or PTE); the transfusion protocol allows for a return to normal of hemodynamic conditions a few days after surgery. Finally, the reduced incidence of complications caused by homologous transfusions (hepatitis, AIDS...) constitutes a financial saving for the government.

Methods of blood saving in revision surgery of the hip.

The blood saving protocol, which is the product of 15 years of experience, has gradually been improved, until the current form has been achieved, which includes predeposit, acute intentional isovolemic hemodilution, controlled hypotension, intraoperative blood recovery, postoperative monitoring and blood recovery, external compressive elastic dressing. The acceptance of values for hemoglobin which may even be < 8 g/dl during the late postoperative period, as long as this is well-tolerated by patients, has allowed us to drastically reduce the use of homologous transfusions. Over the last 2 years, out of 59 autotransfused patients submitted to revision surgery of the hip, only 9 (equal to 15%) required homologous transfusion. An analysis of the data shows that the use of homologous blood is associated with the presence of ischemic cardiopathy (p < 0.001) and with a predeposit which is less than 4 units of blood (packed red blood cell+fresh frozen plasma) (p = 0.05).