Rocco Romano

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.

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.

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

Changes in cerebrospinal fluid magnesium levels in patients undergoing spinal anaesthesia for hip arthroplasty: does intravenous infusion of magnesium sulphate make any difference? A prospective, randomized, controlled study

BACKGROUND Most investigators have attributed the reduced postoperative pain or anaesthetic drug requirements in patients receiving i.v. magnesium sulphate (MgSO(4)) infusion during spinal or general anaesthesia to central N-methyl-d-aspartate (NMDA) receptor magnesium (Mg) activity. In this study, we investigated how cerebrospinal fluid (CSF) Mg concentrations change after spinal anaesthesia, and whether peripherally infusing MgSO(4) influences central Mg levels. METHODS Forty-five patients undergoing continuous spinal anaesthesia for hip arthroplasty were randomly assigned to receive either i.v. MgSO(4) at a dose of 50 mg kg(-1) diluted in 100 ml 0.9% saline solution followed by 15 mg kg(-1) h(-1) for 6 h or saline at the same volume [mean (sd) 64 (10) ml]. The changes in CSF and serum total and ionized Mg concentrations were assessed at six time points before and after spinal anaesthesia. Secondary outcome variables included serum and CSF electrolytes and proteins. RESULTS Thirty-five patients completed the study. We found that spinal anaesthesia reduced total and ionized Mg concentrations in CSF by about 10%. Increasing serum Mg concentration over 80% of the baseline value left CSF Mg levels unchanged. CONCLUSIONS Spinal anaesthesia unexpectedly reduced CSF total and ionized Mg concentrations in patients undergoing hip arthroplasty, although the mechanism is unclear. The dose used for peripheral MgSO(4) infusion in this study had no influence on central Mg concentrations in neurologically healthy patients undergoing spinal anaesthesia. If CSF Mg concentration is a reliable marker of Mg brain bioavailability, peripherally infused MgSO(4) during spinal anaesthesia is unlikely to influence central NMDA receptor activity.

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.