Leonardo Gottin

Baroreflex and oscillation of heart period at 0.1 Hz studied by α‐blockade and cross‐spectral analysis in healthy humans

1 Parameters derived from frequency‐domain analysis of heart period and blood pressure variability are gaining increasing importance in clinical practice. However, the underlying physiological mechanisms in human subjects are not fully understood. Here we address the question as to whether the low frequency variability (∼0.1 Hz) of the heart period may depend on a baroreflex‐mediated response to blood pressure oscillations, induced by the α‐sympathetic drive on the peripheral resistance. 2 Heart period (ECG), finger arterial pressure (Finapres) and respiratory airflow were recorded in eight healthy volunteers in the supine position with metronome respiration at 0.25 Hz. We inhibited the vascular response to the sympathetic vasomotor activity with a peripheral α‐blocker (urapidil) and maintained mean blood pressure at control levels with angiotensin II. 3 We performed spectral and cross‐spectral analysis of heart period (RR) and systolic pressure to quantify the power of low‐ and high‐frequency oscillations, phase shift, coherence and transfer function gain. 4 In control conditions, spectral analysis yielded typical results. In the low‐frequency range, cross‐spectral analysis showed high coherence (> 0.5) and a negative phase shift (‐65.1 ± 18 deg) between RR and systolic pressure, which indicates a 1‐2 s lag in heart period changes in relation to pressure. In the high‐frequency region, the phase shift was close to zero, indicating simultaneous fluctuations of RR and systolic pressure. During urapidil + angiotensin II infusion the low‐frequency oscillations of both blood pressure and heart period were abolished in five cases. In the remaining three cases they were substantially reduced and lost their typical cross‐spectral characteristics. 5 We conclude that in supine rest conditions, the oscillation of RR at low frequency is almost entirely accounted for by a baroreflex mechanism, since it is not produced in the absence of a 0.1 Hz pressure oscillation. 6 The results provide physiological support for the use of non‐invasive estimates of the closed‐loop baroreflex gain from cross‐spectral analysis of blood pressure and heart period variability in the 0.1 Hz range.

Randomized Evidence for Reduction of Perioperative Mortality

OBJECTIVE With more than 220 million major surgical procedures performed annually, perioperative interventions leading to even minor mortality reductions would save thousands of lives per year. This international consensus conference aimed to identify all nonsurgical interventions that increase or reduce perioperative mortality as suggested by randomized evidence. DESIGN AND SETTING A web-based international consensus conference. PARTICIPANTS More than 1,000 physicians from 77 countries participated in this web-based consensus conference. INTERVENTIONS Systematic literature searches (MEDLINE/PubMed, June 8, 2011) were used to identify the papers with a statistically significant effect on mortality together with contacts with experts. Interventions were considered eligible for evaluation if they (1) were published in peer-reviewed journals, (2) dealt with a nonsurgical intervention (drug/technique/strategy) in adult patients undergoing surgery, and (3) provided a statistically significant mortality increase or reduction as suggested by a randomized trial or meta-analysis of randomized trials. MEASUREMENTS AND MAIN RESULTS Fourteen interventions that might change perioperative mortality in adult surgery were identified. Interventions that might reduce mortality include chlorhexidine oral rinse, clonidine, insulin, intra-aortic balloon pump, leukodepletion, levosimendan, neuraxial anesthesia, noninvasive respiratory support, hemodynamic optimization, oxygen, selective decontamination of the digestive tract, and volatile anesthetics. In contrast, aprotinin and extended-release metoprolol might increase mortality. CONCLUSIONS Future research and health care funding should be directed toward studying and evaluating these interventions.

Mortality reduction in cardiac anesthesia and intensive care: results of the first International Consensus Conference

There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first International Consensus Conference on this topic. The consensus was a continuous international internet‐based process with a final meeting on 28 June 2010 in Milan at the Vita‐Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons, and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting, and ranking. Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic β‐blockade, early aspirin therapy, the use of pre‐operative intra‐aortic balloon counterpulsation, and referral to high‐volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated. This International Consensus Conference has identified the non‐surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra‐aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic β‐blockade, early aspirin therapy, and referral to high‐volume centers. The use of aprotinin and aged red blood cells may result in increased mortality.

Ondansetron versus metoclopramide in the treatment of postoperative nausea and vomiting

In this prospective, randomized, double-blind study, we compared the efficacy and safety of ondansetron and metoclopramide in the treatment of postoperative nausea and vomiting (PONV). One hundred seventyfive patients with PONV during recovery from anesthesia for gynecological laparoscopy were treated intravenously with either ondansetron 4 mg (58 patients), metoclopramide 10 mg (57 patients), or placebo (60 patients). Early antiemetic efficacy (abolition of vomiting within 10 min and of nausea within 30 min from the administration of the study drugs with no further vomiting or nausea episodes during the first hour) was obtained in 54 of 58 patients (93.1%) in the ondansetron group, in 38 of 57 patients (66.7%) in the metoclopramide group, and in 21 of 60 patients (35%) in the placebo group (P < 0.001). This difference was still significant when controlling for age, body weight, history of motion sickness, previous PONV episodes, duration of anesthesia, and intraoperative fentanyl consumption using a logistic model. Early antiemetic efficacy was inversely related to the amount of fentanyl administered during anesthesia, regardless of treatment. According to the Kaplan-Meier method, the probability of remaining PONV-free for 48 h after a successful treatment was 0.59 (95% confidence interval 0.45-0.71) in the ondansetron group, 0.45 (0.29-0.60) in the metoclopramide group, and 0.33 (0.15-0.53) in the placebo group (P = 0.003). In conclusion, ondansetron 4 mg is more effective than metoclopramide 10 mg and placebo in the treatment of established PONV. (Anesth Analg 1997;85:395-9)

Reducing Mortality in Acute Kidney Injury Patients: Systematic Review and International Web-Based Survey

OBJECTIVE To identify all interventions that increase or reduce mortality in patients with acute kidney injury (AKI) and to establish the agreement between stated beliefs and actual practice in this setting. DESIGN AND SETTING Systematic literature review and international web-based survey. PARTICIPANTS More than 300 physicians from 62 countries. INTERVENTIONS Several databases, including MEDLINE/PubMed, were searched with no time limits (updated February 14, 2012) to identify all the drugs/techniques/strategies that fulfilled all the following criteria: (a) published in a peer-reviewed journal, (b) dealing with critically ill adult patients with or at risk for acute kidney injury, and (c) reporting a statistically significant reduction or increase in mortality. MEASUREMENTS AND MAIN RESULTS Of the 18 identified interventions, 15 reduced mortality and 3 increased mortality. Perioperative hemodynamic optimization, albumin in cirrhotic patients, terlipressin for hepatorenal syndrome type 1, human immunoglobulin, peri-angiography hemofiltration, fenoldopam, plasma exchange in multiple-myeloma-associated AKI, increased intensity of renal replacement therapy (RRT), CVVH in severely burned patients, vasopressin in septic shock, furosemide by continuous infusion, citrate in continuous RRT, N-acetylcysteine, continuous and early RRT might reduce mortality in critically ill patients with or at risk for AKI; positive fluid balance, hydroxyethyl starch and loop diuretics might increase mortality in critically ill patients with or at risk for AKI. Web-based opinion differed from consensus opinion for 30% of interventions and self-reported practice for 3 interventions. CONCLUSION The authors identified all interventions with at least 1 study suggesting a significant effect on mortality in patients with or at risk of AKI and found that there is discordance between participant stated beliefs and actual practice regarding these topics.

Procalcitonin levels in surgical patients at risk of candidemia

OBJECTIVE Although the majority of cases of sepsis in intensive care unit (ICU) patients are due to bacterial infection, fungal infections are common and their early identification is important so that appropriate treatment can be started. Biomarkers have been used to aid diagnosis of bacterial infections, but their role in fungal infections is less defined. In this study we assessed the value of procalcitonin (PCT) levels for the diagnosis of candidemia or bacteremia in septic patients. METHODS We prospectively recorded PCT levels in 48 critically ill surgical patients with signs of sepsis and at high risk for fungal infection, and compared levels in patients with candidemia and bacteremia. RESULTS Bacterial species were isolated from blood cultures in 16 patients, Candida species in 17, and mixed bacterial and Candida species in 2 patients. PCT levels were less elevated in patients with candidemia (median 0.71 [IQR 0.5-1.1]) than in those with bacteremia (12.9 [2.6-81.2]). A PCT value less than 2 ng/ml enabled bacteremia to be ruled out with a negative predictive value of 94%, and had a similar positive predictive value for candidemia. CONCLUSIONS Our data indicate that a low PCT value in a critically ill septic patient is more likely to be related to candidemia than to bacteremia.

Soluble urokinase-type plasminogen activator receptor as a prognostic biomarker in critically ill patients.

PURPOSE The aim of this study was to assess the role of blood soluble urokinase-type plasminogen activator receptor (suPAR) levels in the diagnosis and prognostication of sepsis in critically ill patients. METHODS Serum suPAR levels were measured prospectively in adult intensive care unit (ICU) patients on admission and then daily until ICU discharge (maximum of 14 days) using an enzyme-linked immunosorbent assay kit. Normal levels were established in 31 healthy controls. RESULTS We included 258 patients (161 men); median admission Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 17 (9-23) and 6 (3-9), respectively. The mortality rate was 13.6%. Sepsis was diagnosed on admission in 94 patients (36%), of whom 23 had severe sepsis and 49 had septic shock. On admission, septic patients had higher suPAR levels than did nonseptic patients (8.9 [5.9-12.7] vs 3.7 [2.7-5.4] ng/mL), but the predictive value of suPAR for diagnosing sepsis was weaker than that of C-reactive protein. During the week after ICU admission, serum suPAR concentrations correlated with Sequential Organ Failure Assessment scores over time. High suPAR levels on admission were a strong independent predictor for ICU and 28-day mortality. In the global population, a suPAR level higher than 6.15 ng/mL had 66% sensitivity and 64% specificity for prediction of ICU mortality, with a receiver operating characteristic area under the curve of 0.726 (95% confidence interval, 0.645-0.808). CONCLUSIONS In ICU patients, serum suPAR concentrations have limited use for identifying sepsis, but their time course correlated with the degree of organ dysfunction, and they have prognostic value in septic and nonseptic populations.

Normobaric hyperoxia alters the microcirculation in healthy volunteers

The use of high concentrations of inhaled oxygen has been associated with adverse effects but recent data suggest a potential therapeutic role of normobaric hyperoxia (NH) in sepsis and cerebral ischemia. Hyperoxia may induce vasoconstriction and alter endothelial function, so we evaluated its effects on the microcirculation in 40 healthy adult volunteers using side-stream dark field (SDF) video-microscopy on the sublingual area and near-infrared spectroscopy (NIRS) on the thenar eminence. In a first group of volunteers (n=18), measurements were taken every 30 min: at baseline in air, during NH (close to 100% oxygen via a non-rebreathing mask) and during recovery in air. In a second group (n=22), NIRS measurements were taken in NH or ambient air on two separate days to prevent any potential influence of repeated NIRS measurements. NH significantly decreased the proportion of perfused vessels (PPV) from 92% to 66%, perfused vessel density (PVD) from 11.0 to 7.3 vessels/mm, perfused small vessel density (PSVD) from 9.0 to 5.8 vessels/mm and microvascular flow index (MFI) from 2.8 to 2.0, and increased PPV heterogeneity from 7.5% to 30.4%. Thirty minutes after return to air, PPV, PVD, PSVD and MFI remained partially altered. During NH, NIRS descending slope and NIRS muscle oxygen consumption (VO2) decreased from 8.5 to 7.9%/s and 127 to 103 units, respectively, in the first group and from 10.7 to 9.4%/s and 150 to 115 units in the second group. NH, therefore, alters the microcirculation in healthy subjects, decreasing capillary perfusion and VO2 and increasing the heterogeneity of the perfusion.

Circulating neutrophils of septic patients constitutively express IL-10R1 and are promptly responsive to IL-10

Previous studies have demonstrated that neutrophils isolated from the blood of healthy donors do not respond to IL-10 in terms of either activation of signal transducer and activator of transcription-3 (STAT3) tyrosine phosphorylation or induction of suppressor of cytokine signalling (SOCS)-3 protein, unlike autologous mononuclear cells. This was explained by the fact that circulating neutrophils of healthy donors express only IL-10R2, but not IL-10R1, the latter IL-10R chain being essential for mediating IL-10 responsiveness. In this study, we report that peripheral blood neutrophils of septic patients constitutively display, besides IL-10R2, also abundant levels of surface IL-10R1. Consequently, septic neutrophils are promptly responsive to IL-10 in vitro, as revealed by a direct IL-10-mediated induction of STAT3 tyrosine phosphorylation and SOCS-3 gene transcription, mRNA and protein expression. Consistent with the presence of a fully functional IL-10R, modulation of LPS-induced CXCL8, CCL4, tumour necrosis factor-alpha and IL-1ra gene expression was also rapidly induced by IL-10 in septic, but not normal, neutrophils. Collectively, these data uncover that neutrophils of septic patients are predisposed to be promptly responsive to IL-10, presumably to help limiting their pro-inflammatory state. They also fully validate our previous observations, herein in the context of a human disease, that responsiveness of human neutrophils to IL-10 is strictly dependent upon the modulation of IL-10R1 expression.

A prospective evaluation of the Infection Probability Score (IPS) in the intensive care unit

OBJECTIVES Identification of infection remains a major challenge, particularly in acutely ill patients. The Infection Probability Score (IPS) was developed to help rule out infection in acutely ill patients. In the present study, we determined the IPS in acutely ill, intensive care unit (ICU) patients to assess its use in the diagnosis and treatment of infection. METHODS In this prospective, observational study, we enrolled 107 consecutive patients who were admitted to the ICU without antibiotic therapy. Patients were allocated to four groups according to the probability of infection determined from clinical and microbiological data and their IPS values were then evaluated daily throughout the ICU stay. RESULTS The IPS was higher in patients with the highest clinical probability of infection and decreased significantly in these patients after 5 days of effective antimicrobial therapy. The IPS remained below the cut-off value in non-infected patients. Patients in whom inadequate antimicrobial therapy was administered had a greater mortality than the other patients. CONCLUSIONS The IPS had a good predictive value for diagnosis of infection. In addition, dynamic evaluation of this score may help to assess the response to therapy.