Massimo Girardis

Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock A Randomized Clinical Trial

IMPORTANCE β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. OBJECTIVE To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P < .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P < .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P < .001). CONCLUSIONS AND RELEVANCE For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01231698.

Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial.

Importance Despite suggestions of potential harm from unnecessary oxygen therapy, critically ill patients spend substantial periods in a hyperoxemic state. A strategy of controlled arterial oxygenation is thus rational but has not been validated in clinical practice. Objective To assess whether a conservative protocol for oxygen supplementation could improve outcomes in patients admitted to intensive care units (ICUs). Design, Setting, and Patients Oxygen-ICU was a single-center, open-label, randomized clinical trial conducted from March 2010 to October 2012 that included all adults admitted with an expected length of stay of 72 hours or longer to the medical-surgical ICU of Modena University Hospital, Italy. The originally planned sample size was 660 patients, but the study was stopped early due to difficulties in enrollment after inclusion of 480 patients. Interventions Patients were randomly assigned to receive oxygen therapy to maintain Pao2 between 70 and 100 mm Hg or arterial oxyhemoglobin saturation (Spo2) between 94% and 98% (conservative group) or, according to standard ICU practice, to allow Pao2 values up to 150 mm Hg or Spo2 values between 97% and 100% (conventional control group). Main Outcomes and Measures The primary outcome was ICU mortality. Secondary outcomes included occurrence of new organ failure and infection 48 hours or more after ICU admission. Results A total of 434 patients (median age, 64 years; 188 [43.3%] women) received conventional (n = 218) or conservative (n = 216) oxygen therapy and were included in the modified intent-to-treat analysis. Daily time-weighted Pao2 averages during the ICU stay were significantly higher (P < .001) in the conventional group (median Pao2, 102 mm Hg [interquartile range, 88-116]) vs the conservative group (median Pao2, 87 mm Hg [interquartile range, 79-97]). Twenty-five patients in the conservative oxygen therapy group (11.6%) and 44 in the conventional oxygen therapy group (20.2%) died during their ICU stay (absolute risk reduction [ARR], 0.086 [95% CI, 0.017-0.150]; relative risk [RR], 0.57 [95% CI, 0.37-0.90]; P = .01). Occurrences were lower in the conservative oxygen therapy group for new shock episode (ARR, 0.068 [95% CI, 0.020-0.120]; RR, 0.35 [95% CI, 0.16-0.75]; P = .006) or liver failure (ARR, 0.046 [95% CI, 0.008-0.088]; RR, 0.29 [95% CI, 0.10-0.82]; P = .02) and new bloodstream infection (ARR, 0.05 [95% CI, 0.00-0.09]; RR, 0.50 [95% CI, 0.25-0.998; P = .049). Conclusions and Relevance Among critically ill patients with an ICU length of stay of 72 hours or longer, a conservative protocol for oxygen therapy vs conventional therapy resulted in lower ICU mortality. These preliminary findings were based on unplanned early termination of the trial, and a larger multicenter trial is needed to evaluate the potential benefit of this approach. Trial Registration clinicaltrials.gov Identifier: NCT01319643.

Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis

IntroductionThe safety of arterial hyperoxia is under increasing scrutiny. We performed a systematic review of the literature to determine whether any association exists between arterial hyperoxia and mortality in critically ill patient subsets.MethodsMedline, Thomson Reuters Web of Science and Scopus databases were searched from inception to June 2014. Observational or interventional studies evaluating the relationship between hyperoxia (defined as a supranormal arterial O2 tension) and mortality in adult intensive care unit (ICU) patients were included. Studies primarily involving patients with exacerbations of chronic pulmonary disease, acute lung injury and perioperative administration were excluded. Adjusted odds ratio (OR) of patients exposed versus those not exposed to hyperoxia were extracted, if available. Alternatively, unadjusted outcome data were recorded. Data on patients, study characteristics and the criteria used for defining hyperoxia exposure were also extracted. Random-effects models were used for quantitative synthesis of the data, with a primary outcome of hospital mortality.ResultsIn total 17 studies (16 observational, 1 prospective before-after) were identified in different patient categories: mechanically ventilated ICU (number of studies (k) = 4, number of participants (n) = 189,143), post-cardiac arrest (k = 6, n = 19,144), stroke (k = 2, n = 5,537), and traumatic brain injury (k = 5, n = 7,488). Different criteria were used to define hyperoxia in terms of PaO2 value (first, highest, worst, mean), time of assessment and predetermined cutoffs. Data from studies on ICU patients were not pooled because of extreme heterogeneity (inconsistency (I2) 96.73%). Hyperoxia was associated with increased mortality in post-cardiac arrest patients (OR = 1.42 (1.04 to 1.92) I2 67.73%) stroke (OR = 1.23 (1.06 to 1.43) I2 0%) and traumatic brain injury (OR = 1.41 (1.03 to 1.94) I2 64.54%). However, these results are limited by significant heterogeneity between studies.ConclusionsHyperoxia may be associated with increased mortality in patients with stroke, traumatic brain injury and those resuscitated from cardiac arrest. However, these results are limited by the high heterogeneity of the included studies.

Prevention of post-herpetic neuralgia: acyclovir and prednisolone versus epidural local anesthetic and methylprednisolone

Background: Treatment of herpes zoster (HZ) includes the use of acyclovir with or without steroids. An alternative therapy is the epidural administration of local anesthetics with or without steroids. This trial compared the efficacy of these two treatment regimens in the prevention of post‐herpetic neuralgia (PHN).

Characterization of Specific Immune Responses to Different Aspergillus Antigens during the Course of Invasive Aspergillosis in Hematologic Patients

Several studies in mouse model of invasive aspergillosis (IA) and in healthy donors have shown that different Aspergillus antigens may stimulate different adaptive immune responses. However, the occurrence of Aspergillus-specific T cells have not yet been reported in patients with the disease. In patients with IA, we have investigated during the infection: a) whether and how specific T-cell responses to different Aspergillus antigens occur and develop; b) which antigens elicit the highest frequencies of protective immune responses and, c) whether such protective T cells could be expanded ex-vivo. Forty hematologic patients have been studied, including 22 patients with IA and 18 controls. Specific T cells producing IL-10, IFN-γ, IL-4 and IL-17A have been characterized through enzyme linked immunospot and cytokine secretion assays on 88 peripheral blood (PB) samples, by using the following recombinant antigens: GEL1p, CRF1p, PEP1p, SOD1p, α1–3glucan, β1–3glucan, galactomannan. Specific T cells were expanded through short term culture. Aspergillus-specific T cells producing non-protective interleukin-10 (IL-10) and protective interferon-gamma (IFN-γ) have been detected to all the antigens only in IA patients. Lower numbers of specific T cells producing IL-4 and IL-17A have also been shown. Protective T cells targeted predominantly Aspergillus cell wall antigens, tended to increase during the IA course and to be associated with a better clinical outcome. Aspergillus-specific T cells could be successfully generated from the PB of 8 out of 8 patients with IA and included cytotoxic subsets able to lyse Aspergillus hyphae. Aspergillus specific T-cell responses contribute to the clearance of the pathogen in immunosuppressed patients with IA and Aspergillus cell wall antigens are those mainly targeted by protective immune responses. Cytotoxic specific T cells can be expanded from immunosuppressed patients even during the infection by using the above mentioned antigens. These findings may be exploited for immunotherapeutic purposes in patients with IA.

The effect of laparoscopic cholecystectomy on cardiovascular function and pulmonary gas exchange

Hemodynamic changes, pulmonary CO2 elimination (VECO2) and gas exchange were evaluated during laparoscopic cholecystectomy.An algorithm to calculate inspired ventilation (VI) needed to maintain constant PaCO2 was also developed. In 12 ASA physical status I patients undergoing laparoscopic cholecystectomy, heart rate (HR), mean arterial pressure (MAP), cardiac index (CI), and systemic vascular resistance index (SVRI) were measured by the analysis of a radial artery pressure profile before, during, and after CO2 insufflation. Alveolar-arterial oxygen pressure gradient (P(A-a)O2), physiological and alveolar ventilatory dead space fractions (VDphys/VT; VDalv/VT), and PaCO2 were measured as well. VECO2 was assessed every minute in the patients maintained in the head-up position. HR did not significantly change during pneumoperitoneum, whereas MAP showed a transient increase (24.9%; P < 0.05) after CO2 insufflation. CI remained stable during pneumoperitoneum, but increased (25.0%; P < 0.05) after deflation. As a consequence, SVRI transiently increased after CO2 insufflation and decreased by 15.8% (P < 0.05) 5 min after deflation. P(A-a)O (2) increased slightly (P < 0.05) with increased anesthesia time. VDphys/VT and VDalv/VT did not change after pneumoperitoneum onset, but VDalv/VT decreased after CO2 deflation (13.4%; P < 0.05). VECO2 increased (decreased) after a monoexponential time course during (after) CO2 insufflation in 8 of 12 patients. The mean time constants (t) of the monoexponential functions were 26.3 and 15.4 min during and after pneumoperitoneum. A monoexponential time course was shown also by PaCO2 during CO2 insufflation (tau = 27.8 min). Finally, the VI needed to maintain PaCO2 at a selected value could be calculated by the following algorithm: VI = [0.448 centered dot (1 - e-t/tau) + 2.52] centered dot (VA centered dot PaCO (2) centered dot 713)-1, where VA corresponds to alveolar ventilation and t must be chosen according to the pneumoperitoneum phase. We conclude that CO2 insufflation in the abdominal cavity does not induce significant changes in cardiopulmonary function in ASA physical status I patients. The algorithm proposed seems to be a useful tool for the anesthesiologists to maintain constant PaCO2 during all surgical procedures. (Anesth Analg 1996;83:134-40)

The Hemodynamic and Metabolic Effects of Tourniquet Application During Knee Surgery

We evaluated the effects of tourniquet application on the cardiovascular system and metabolism in 10 young men undergoing knee surgery with general anesthesia. The duration of inflation was from 75 to 108 min. Heart rate, mean arterial pressure, cardiac index (CI) by pulse contour method, and systemic vascular resistance were measured before, during, and after tourniquet inflation. pH, Pao2, Paco2, and lactate blood concentrations were also measured. &OV0312;o2 and &OV0312;co2 were assessed every minute from tracheal intubation up to 15 min after tourniquet deflation and &OV0312;o2 in excess of the basal value over the 15 min after deflation (&OV0312;o2exc) was calculated. Mean arterial pressure increased 26% (P < 0.05) during inflation and returned to basal values after deflation. CI did not change immediately after inflation; although, thereafter, it increased 18% (P < 0.05). Five minutes after deflation, CI further increased to a value 40% higher than the basal value. Therefore, systemic vascular resistance increased 20% suddenly after inflation (P < 0.05) and decreased 18% after deflation (P < 0.05). &OV0312;o2 and &OV0312;co2 remained stable during inflation and increased (P < 0.05) after deflation. &OV0312;o2exc depended on duration of tourniquet inflation time (Tisch) (P < 0.05). After deflation, Paco2 and lactate increased (P < 0.05) while Tisch increased. We conclude that tourniquet application induces modifications of the cardiovascular system and metabolism, which depend on tourniquet phase and on Tisch. Whether these modifications could be relevant in patients with poor physical conditions is not known. Implications The clinical effects of tourniquet application were evaluated in 10 young men undergoing knee surgery. Our data indicate that tourniquet application causes hemodynamic and metabolic changes which may become clinically relevant after a long period of tourniquet inflation, particularly in patients with concomitant cardiovascular diseases.

Perioperative Red Blood Cell Transfusion and Outcome in Stable Patients after Elective Major Vascular Surgery

OBJECTIVES Definitive evidence that red blood cell transfusion improves outcome after vascular surgery is lacking. The aims of the study were to determine, among stable consecutive patients who underwent elective major vascular surgery, (1) the association between postoperative transfusion and 30-day death, myocardial infarction, and both, and (2) and if this association differs according to the presence of postoperative anaemia (haemoglobin value less than 9.0 g/dL within 7 days after surgery). METHODS A retrospective observational study was conducted on 359 patients prospectively screened according to the ACC/AHA guidelines for preoperative risk in non-cardiac surgery. Main outcome was 30-day death; secondary outcomes 30-day myocardial infarction, and composite of 30-day myocardial infarction or death. RESULTS Of the patients included, 95 (26.5%) received at least one unit of red blood cells. Patients who received transfusion had a significantly increased hazard of 30-day death (hazard ratio [HR] 11.72, 95% confidence interval [CI] 3.92-35.10; p<0.0001), myocardial infarction (HR 3.3, 95% CI 1.7-6.1; p=0.0003), and both (HR 4.0 95% CI 2.2-7.3; p<0.0001). Such associations held even after adjusting for baseline characteristics, surgical risk, bleeding, and propensity to receive transfusion. There was a significant interaction between transfusion and postoperative anaemia (p=0.012). In patients without anaemia, transfusion was associated with higher risk of 30-day death (HR 19.20, 95% CI 3.99-92.45; p=0.007), myocardial infarction (HR 5.05, 95% CI 2.23-11.44; p=0.0001), and both. Conversely, in patients with anaemia this association was not significant. CONCLUSIONS In patients who underwent elective major vascular surgery, perioperative transfusion was associated with a significantly increased risk of 30-day events which was more attributable to patients with lesser degree of anaemia. Our data caution against the use of liberal transfusion in stable vascular surgery patients.

Effect of Performance Improvement Programs on Compliance with Sepsis Bundles and Mortality: A Systematic Review and Meta-Analysis of Observational Studies

Background Several reports suggest that implementation of the Surviving Sepsis Campaign (SSC) guidelines is associated with mortality reduction in sepsis. However, adherence to the guideline-based resuscitation and management sepsis bundles is still poor. Objective To perform a systematic review of studies evaluating the impact of performance improvement programs on compliance with Surviving Sepsis Campaign (SSC) guideline-based bundles and/or mortality. Data Sources Medline (PubMed), Scopus and Intercollegiate Studies Institute Web of Knowledge databases from 2004 (first publication of the SSC guidelines) to October 2014. Study Selection Studies on adult patients with sepsis, severe sepsis or septic shock that evaluated changes in compliance to individual/combined bundle targets and/or mortality following the implementation of performance improvement programs. Interventions may consist of educational programs, process changes or both. Data Extraction Data from the included studies were extracted independently by two authors. Unadjusted binary data were collected in order to calculate odds ratios (OR) for compliance to individual/combined bundle targets. Adjusted (if available) or unadjusted data of mortality were collected. Random-effects models were used for the data synthesis. Results Fifty observational studies were selected. Despite high inconsistency across studies, performance improvement programs were associated with increased compliance with the complete 6-hour bundle (OR = 4.12 [95% confidence interval 2.95-5.76], I2 = 87.72%, k = 25, N = 50,081) and the complete 24-hour bundle (OR = 2.57 [1.74-3.77], I2 = 85.22%, k = 11, N = 45,846) and with a reduction in mortality (OR = 0.66 [0.61-0.72], I2 = 87.93%, k = 48, N = 434,447). Funnel plots showed asymmetry. Conclusions Performance improvement programs are associated with increased adherence to resuscitation and management sepsis bundles and with reduced mortality in patients with sepsis, severe sepsis or septic shock.

World Society of Emergency Surgery (WSES) guidelines for management of skin and soft tissue infections

Skin and soft tissue infections (SSTIs) encompass a variety of pathological conditions ranging from simple superficial infections to severe necrotizing soft tissue infections. Necrotizing soft tissue infections (NSTIs) are potentially life-threatening infections of any layer of the soft tissue compartment associated with widespread necrosis and systemic toxicity. Successful management of NSTIs involves prompt recognition, timely surgical debridement or drainage, resuscitation and appropriate antibiotic therapy. A worldwide international panel of experts developed evidence-based guidelines for management of soft tissue infections. The multifaceted nature of these infections has led to a collaboration among surgeons, intensive care and infectious diseases specialists, who have shared these guidelines, implementing clinical practice recommendations.