Erica Adrario

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.

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.

Alteration of the sublingual microvascular glycocalyx in critically ill patients

Glycocalyx degradation may contribute to microvascular dysfunction and tissue hypoperfusion during systemic inflammation and sepsis. In this observational study we evaluated the alteration of the sublingual microvascular glycocalyx in 16 healthy volunteers and 50 critically ill patients. Sidestream Dark Field images of the sublingual microcirculation were automatically analyzed by dedicated software. The Perfused Boundary Region (PBR) was calculated as the dimensions of the permeable part of the glycocalyx allowing the penetration of circulating red blood cells, providing an index of glycocalyx damage. The PBR was increased in ICU patients compared to healthy controls (2.7 [2.59-2.88] vs. 2.46 [2.37-2.59]μm, p<0.0001) and tended to be higher in the 32 septic patients compared to non-septics (2.77 [2.62-2.93] vs. 2.67 [2.55-2.75]μm, p=0.05), suggesting more severe glycocalyx alterations. A PBR of 2.76 showed the best discriminative ability towards the presence of sepsis (sensitivity: 50%, specificity: 83%; area under the receiver operating characteristic curve: 0.67, 95% CI 0.52-0.82, p=0.05). A weak positive correlation was found between PBR and heart rate (r=0.3, p=0.03). In 17 septic patients, a correlation was found between PBR and number of rolling leukocytes in post-capillary venules (RL/venule) (r=0.55, p=0.02), confirming that glycocalyx shedding enhances leukocyte-endothelium interaction.

From macrohemodynamic to the microcirculation

ICU patients need a prompt normalization of macrohemodynamic parameters. Unfortunately, this optimization sometimes does not protect patients from organ failure development. Prevention or treatment of organ failure needs another target to be pursued: the microcirculatory restoration. Microcirculation is the ensemble of vessels of maximum 100 μm in diameter. Nowadays the Sidestream Dark Field (SDF) imaging technique allows its bedside investigation and a recent round-table conference established the criteria for its evaluation. First, microcirculatory derangements have been studied in sepsis: they are mainly characterized by a reduction of vessel density, an alteration of flow, and a heterogeneous distribution of perfusion. Endothelial malfunction and glycocalyx rupture were proved to be the main reasons for the observed microthrombi, capillary leakage, leukocyte rolling, and rouleaux phenomenon, even if further studies are necessary for a better explanation. Therapeutic approaches targeting microcirculation are under investigation. Microcirculatory alterations have been recently demonstrated in other diseases such as hypovolemia and cardiac failure but this issue still needs to be explored. The aim of this paper is to gather the already known information, focus the readers attention on the importance of microvascular physiopathology in critical illness, and prompt him to actively participate to achieve a more comprehensive understanding of the issue.

Microcirculatory effects of the transfusion of leukodepleted or non-leukodepleted red blood cells in patients with sepsis: a pilot study

IntroductionMicrovascular alterations impair tissue oxygenation during sepsis. A red blood cell (RBC) transfusion increases oxygen (O2) delivery but rarely improves tissue O2 uptake in patients with sepsis. Possible causes include RBC alterations due to prolonged storage or residual leukocyte-derived inflammatory mediators. The aim of this study was to compare the effects of two types of transfused RBCs on microcirculation in patients with sepsis.MethodsIn a prospective randomized trial, 20 patients with sepsis were divided into two separate groups and received either non-leukodepleted (n = 10) or leukodepleted (n = 10) RBC transfusions. Microvascular density and perfusion were assessed with sidestream dark field (SDF) imaging sublingually, before and 1 hour after transfusions. Thenar tissue O2 saturation (StO2) and tissue hemoglobin index (THI) were determined with near-infrared spectroscopy, and a vascular occlusion test was performed. The microcirculatory perfused boundary region was assessed in SDF images as an index of glycocalyx damage, and glycocalyx compounds (syndecan-1, hyaluronan, and heparan sulfate) were measured in the serum.ResultsNo differences were observed in microvascular parameters at baseline and after transfusion between the groups, except for the proportion of perfused vessels (PPV) and blood flow velocity, which were higher after transfusion in the leukodepleted group. Microvascular flow index in small vessels (MFI) and blood flow velocity exhibited different responses to transfusion between the two groups (P = 0.03 and P = 0.04, respectively), with a positive effect of leukodepleted RBCs. When within-group changes were examined, microcirculatory improvement was observed only in patients who received leukodepleted RBC transfusion as suggested by the increase in De Backer score (P = 0.02), perfused vessel density (P = 0.04), PPV (P = 0.01), and MFI (P = 0.04). Blood flow velocity decreased in the non-leukodepleted group (P = 0.03). THI and StO2 upslope increased in both groups. StO2 and StO2 downslope increased in patients who received non-leukodepleted RBC transfusions. Syndecan-1 increased after the transfusion of non-leukodepleted RBCs (P = 0.03).ConclusionsThis study does not show a clear superiority of leukodepleted over non-leukodepleted RBC transfusions on microvascular perfusion in patients with sepsis, although it suggests a more favorable effect of leukodepleted RBCs on microcirculatory convective flow. Further studies are needed to confirm these findings.Trial registrationClinicalTrials.gov, NCT01584999

Predictive value of interleukin 6 (IL-6), interleukin 8 (IL-8) and gastric intramucosal pH (pH-i) in major abdominal surgery.

Objective: To study plasma concentrations of interleukin 6 (IL-6) and interleukin 8 (IL-8) in patients with splanchnic hypoxia, as documented by gastric intramucosal measurements (pH-i), during major abdominal surgery and the relationship between IL-6 and IL-8 concentrations and postoperative complications as well as clinical outcome.Design: A prospective study.Patients: Twelve patients scheduled for major abdominal surgery with no evidence of coexisting infectious disease.Results: Six out of seven samples from patients with postoperative complications showed intraoperative pH-i levels lower than 7.32 and IL-6 levels higher than 300 pg/ml. Seven out of nine samples from patients without complications showed pH-i levels higher than 7.32 and IL-6 levels lower than 300 pg/ml. The difference in the pattern of distribution was statistically significant (p < 0.01). Only two out of seven samples of patients with postoperative complications showed intraoperative pH-i levels lower than 7.32 and IL-8 levels higher than 60 pg/ml. It was not possible to identify a clear distribution pattern of data points for IL-6 and IL-8 during the postoperative period.Conclusions: Intraoperative splanchnic ischemia, as documented by gastric intramucosal pH-i, is directly correlated to the increase of IL-6 plasma levels and to the incidence of postoperative complications, while IL-8 levels showed no correlation with surgical complications.

Plasma free hemoglobin and microcirculatory response to fresh or old blood transfusions in sepsis.

Background Free hemoglobin (fHb) may induce vasoconstriction by scavenging nitric oxide. It may increase in older blood units due to storage lesions. This study evaluated whether old red blood cell transfusion increases plasma fHb in sepsis and how the microvascular response may be affected. Methods This is a secondary analysis of a randomized study. Twenty adult septic patients received either fresh or old (<10 or >15 days storage, respectively) RBC transfusions. fHb was measured in RBC units and in the plasma before and 1 hour after transfusion. Simultaneously, the sublingual microcirculation was assessed with sidestream-dark field imaging. The perfused boundary region was calculated as an index of glycocalyx damage. Tissue oxygen saturation (StO2) and Hb index (THI) were measured with near-infrared spectroscopy and a vascular occlusion test was performed. Results Similar fHb levels were found in the supernatant of fresh and old RBC units. Despite this, plasma fHb increased in the old RBC group after transfusion (from 0.125 [0.098–0.219] mg/mL to 0.238 [0.163–0.369] mg/mL, p = 0.006). The sublingual microcirculation was unaltered in both groups, while THI increased. The change in plasma fHb was inversely correlated with the changes in total vessel density (r = -0.57 [95% confidence interval -0.82, -0.16], p = 0.008), De Backer score (r = -0.63 [95% confidence interval -0.84, -0.25], p = 0.003) and THI (r = -0.72 [95% confidence interval -0.88, -0.39], p = 0.0003). Conclusions Old RBC transfusion was associated with an increase in plasma fHb in septic patients. Increasing plasma fHb levels were associated with decreased microvascular density. Trial Registration ClinicalTrials.gov NCT01584999

Thermodilution vs pressure recording analytical method in hemodynamic stabilized patients

PURPOSE Many mini-invasive devices to monitor cardiac output (CO) have been introduced and, among them, the pressure recording analytical method (PRAM). The aim of this study was to assess the agreement of PRAM with the intermittent transpulmonary thermodilution and continuous pulmonary thermodilution in measuring CO in hemodynamically stabilized patients. MATERIALS AND METHODS This is a prospective clinical study in a mixed medical-surgical intensive care unit (ICU) and in a postcardiac surgical ICU. Forty-eight patients were enrolled: 32 patients to the medical-surgical ICU monitored with PiCCO (Pulsion Medical System AG, Munich, Germany) and 16 were cardiac patients monitored with Vigilance (Edwards Lifesciences, Irvine, CA). RESULTS A total of 112 measurements were made. Ninety-six comparisons of paired CO measurements were made in patients hospitalized in medical-surgical ICU; 16, in cardiac surgical patients. The mean Vigilance-CO was 4.49 ± 0.99 L/min (range, 2.80-5.90 L/min), and the mean PRAM-CO was 4.27 ± 0.88 L/min (range, 2.85-6.19 L/min). The correlation coefficient between Vigilance-CO and PRAM-CO was 0.83 (95% confidence interval, 0.57-0.94; P < .001). The bias was 0.22 ± 0.55 L/min with limits of agreement between 0.87 and 1.30 L/min. The percentage error was 25%. Mean TP-CO was 6.78 ± 2.04 L/min (range, 4.12-11.27 L/min), and the mean PRAM-CO was 6.11 ± 2.18 L/min (range, 2.82-10.90 L/min). The correlation coefficient between PiCCO-CO and PRAM-CO was 0.91 (95% confidence interval, 0.83-0.96; P < .0001). The bias was 0.67 ± 0.89 L/min with limits of agreement -1.07 and 2.41 L/min. The coefficient of variation for PiCCO was 4% ± 2%, and the coefficient of variation for PRAM was 10% ± 8%. The percentage error was 28%. CONCLUSIONS The PRAM system showed good agreement with pulmonary artery catheter and PiCCO in hemodynamically stabilized patients.

Fluid responsiveness in critically ill patients

The first therapeutic approach to patients affected by shock is fluids infusion. In particular, patients affected by sepsis usually require a great amount of fluids in the first phase of resuscitation. Fluids must be considered as other drugs with beneficial but also adverse effects especially in patients with a limited cardiac reserve. For this reason, it is helpful to know, if the patient will respond to fluids. Several studies have shown that hemodynamic parameters classically use to evaluate vascular volumes such as central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP), are not able to predict the response to fluids administration.[1] Volumetric parameters such as global end diastolic volume (GEDV) and left ventricular end diastolic volume (LVEDV), are better related to volume status but are not able to accurately predict fluid responsiveness.[2] Therefore, several dynamic parameters have been developed during the last years to assess fluid responsiveness. The easiest approach is a fluid challenge. It consists to give a small amount of fluid (250–500 ml of crystalloid in few minutes) and verify patient response in term of increase in cardiac output (CO).[3] However, also this small amount of fluid could be deleterious in patients with a limited cardiac reserve. In mechanically ventilated patients, the clinician can use cardiopulmonary interaction to predict patient response to the fluid.[4] Dynamic parameters such as pulse pressure variation, stroke volume variation, and systolic pressure variation are a better predictor of fluid responsiveness than static pressometric and volumetric parameters such as CVP, PAOP, GEDV, and LVEDV.[1] Furthermore, several mini-invasive monitoring systems are able to calculate CO and stroke volume continuously showing dynamic parameters.[5,6] However, these parameters have several limitations and cannot be used in every patient. In fact, a correct interpretation of dynamic parameters requires controlled ventilation with a tidal volume at least of 8 ml/kg, absence of arrhythmias, ventricular dysfunction, intra-abdominal hypertension, and a ratio between heart rate and respiratory rate 3 to 6. All these criteria are difficult to meet in the intensive care setting where we usually apply protective lung ventilation and patients are frequently in spontaneous ventilation. In these situations, an alternative approach could be the assessment of CO variation after a passive leg raising maneuver, responsible for a shift of small amount of blood from legs to the heart. Considering these approaches to hemodynamic evaluation, which could be the role for CVP? Do we still need to measure this parameter? The actual value of CVP is not related to volume status because it is determined by interaction between cardiac and pulmonary function. However, it is still very useful to determine if the patient has a problem in volume status and it has a greater significance, when a dynamic test is performed. With this perspective, the Guytons approach is needed to understand the importance of CVP.[7] If blood pressure is low, and CO is normal or elevated, low systemic vascular resistance is responsible for low blood pressure. If the CO is decreased, this can be due to a decrease in cardiac function or a decrease in the venous return. CVP helps to define whether a decrease in cardiac function or a decrease in return function is the primary problem. If the CVP is high, the problem is primarily decreased cardiac function. On the other hand, if the CVP is low, the primary problem is the venous return and providing more volume will probably solve the problem. CVP is also helpful to evaluate the effect of fluid challenge and to determine the amount of fluid need to perform this test. Sufficient fluid is given when the CVP will be raised by 2 mmHg or more. A concomitant increase in CO indicates that the patient is fluid responsive whereas an increase in CVP without an increase in CO shows that further fluids are not indicated. During spontaneous ventilation, CVP assessment during an inspiratory fall in pleural pressure is very helpful. According to Guytons approach, a decrease in pleural pressure makes the pressures in the heart more negative. When the heart functions on the ascending part of the cardiac function curve, this results in a fall in CVP and an increase in the gradient for venous return and, an increase in right heart output. Under this condition, a volume infusion should increase CO. However, when the heart is functioning on the flat part of the cardiac function curve, the fall in pleural pressure does not produce a change in CVP and therefore the gradient for venous return and consequently CO do not change. Finally, we know that response to fluids may be different if we consider macro-hemodynamic parameters or if we look at the micro-circulatory level. Macro- and micro-hemodynamic are not always coupled, and patients may improve hemodynamic parameters without a concomitant improvement of micro-vascular flow.[8,9] Because the capillary network is the site of oxygen delivery to tissue, every therapeutic intervention should aim to improve micro-vascular flow. The evaluation of sublingual micro-circulation is able to predict which patients are really fluid responsive.[10] In conclusion, the assessment of fluid responsiveness is very important in the management of critically ill patients. Dynamic parameters derived from heart-lungs interaction are very helpful in this setting, but the intensivist should not forget the important information that classical hemodynamic parameters such as CVP, can give us. The evaluation of sublingual micro-circulation may add useful information in decision making about the fluid administration. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Pain and discomfort management during central venous catheter insertion

The insertion of a central venous catheter (CVC) is one of the most frequently performed invasive procedures in anesthesia and critical care settings. It may be associated with considerable discomfort in the conscious patient, as it requires him/her to stay in Trendelenburg position, head-extended with the neck fully turned to the opposite side and perfectly still. Local anesthetics such as lidocaine are commonly used to reduce pain during the procedure. However, even after the establishment of an effective field block, subsequent steps such as anchoring of the catheter to the skin by suture or the eventual catheter tunneling are a source of pain and distress. The field infiltration with local anesthetics may be associated itself with significant pain. Pain is an unpleasant sensory and emotional experience arising from actual or potential tissue damage. Being a source of anxiety, it may negatively influence the patients perception of his/her illness and the treatment received. It is a duty of the physician to alleviate this unpleasant feeling by providing adequate analgesia and sedation. Ensuring the patients comfort is also important for increasing his/her cooperation and contributing to the ease of the procedure, thus decreasing the risk of insertion failure or catheter malpositioning.[1] The association of intravenous analgesics such as potent short acting opioids with local anesthetic agents is an effective therapeutic option during invasive percutaneous procedures, as it acts synergistically on peripheral pain fibers and central opiate receptors. However, the potential advantages of using intravenous opioids in the conscious patient must be weighed against their possible adverse effects, mainly cardiovascular events (hypotension and bradycardia) and respiratory depression. Ideally, the perfect analgesic strategy should provide adequate pain/discomfort relief while ensuring respiratory and cardiovascular stability and absence of side-effects for a prompt and safe recovery. In this issue of the Indian Journal of Critical Care Medicine, Samantaray et al. reported a prospective, randomized, double-blind, placebo-controlled trial that evaluated the efficacy of fentanyl along with local anesthetic field infiltration in controlling pain and discomfort associated with CVC positioning.[2] In this study, 44 conscious patients scheduled for planned CVC insertion randomly received a 10-ml preprocedural infusion of either fentanyl (2 μg/kg) or 0.9% saline in addition to local lidocaine infiltration. Verbal numeric rating scales were used to quantify pain and discomfort. Patients in the fentanyl group reported lower pain than the placebo group after local anesthetic injection, during the procedure and 10 min after the completion of the procedure. Lower discomfort was observed for fentanyl group only 10 min after the procedure. Patients in the fentanyl group tended to be more sedated, although the majority was responding to verbal command and to experience more episodes of bradycardia (4/26 vs. 1/25 in the placebo group) and desaturation (4/26 vs. 0/25). However, atropine was required in only one patient; in three patients a simple head tilt - chin lift maneuver was sufficient to maintain adequate oxygen saturation, while a nasopharyngeal stimulation was required in only one case. Bosch and Schiltmans[3] performed an observational study to evaluate the efficacy and adverse effects of intravenous stepwise sedation during CVC insertion in dialysis patients. In addition, they compared 2 time periods in which midazolam + fentanyl or midazolam alone were used. Overall, stepwise intravenous sedation ensured no or minor movements of the patient in 94% of the procedures, adequate amnesia in 86% and no or only a small amount of pain in 93%. The combination of midazolam and fentanyl did not significantly improve ease of the procedure, amnesia and pain experience compared to midazolam alone, but it relevantly increased incidence of oxygen desaturation. In a double-blind randomized controlled trial, Burlacu et al.[4] assessed the analgesic efficacy of three different rates of remifentanil infusion in 44 patients undergoing insertion or removal of long-term central venous access devices during monitored anesthesia care with propofol and local anesthetic field infiltration. Although equally effective for analgesia, the highest rate of remifentanil infusion (i.e., 0.075 μg/kg/min vs. 0.025 or 0.05 μg/kg/min) was associated with unnecessarily increased sedation scores; moreover, patients in the highest dose group more frequently required a reduction of the drug infusion rate, mainly because of respiratory depression. Taken together, these findings indicate that short-acting opioids alone or combined with other agents (e.g., propofol or midazolam) are effective in ensuring adequate pain and discomfort relief during CVC positioning with local anesthetic infiltration, but may be associated with a significant number of adverse effects, mainly respiratory depression. Even if simple head tilt - chin lift maneuvers were sufficient to reverse the opioid-induced oxygen desaturation in the most cases; larger trials are needed to provide a more robust evidence of their safety in the conscious spontaneously breathing patient. In the meantime, intravenous opioids must be administered only under close observation of the patient and monitoring of oxygen saturation, respiratory rate, heart rate and rhythm. Lastly, other drugs may be considered for pain and discomfort management during central line access. Dexmedetomidine was initially approved for clinical use as a sedative. Although it has analgesic effects and analgesic-sparing properties, its development in pain management has so far been limited. This selective short-acting α2-adrenergic agonist can act synergistically with opioid receptor agonists both systemically and locally. Its combination with local anesthetics may be a promising new use to enhance their effectiveness.[5] This could be explored in future studies, along with potential adverse effects.