Using corticosteroids in intensive care.
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Adult↗
Biomedical subjects
Didier Keh
Publications and source records attributed to Didier Keh.
Prognostic value of an early soluble L-selectin (sCD62L) assay for risk assessment in blunt multiple trauma: a metaanalysis.
BACKGROUND: After severe trauma, decreased plasma concentrations of the soluble adhesion molecule L-selectin (sCD62L) have been linked to an increased incidence of lung failure and multiorgan dysfunction syndrome (MODS). Individual studies have had conflicting results, however. We examined multiple studies in an attempt to determine whether early sCD62L concentrations are predictive of major complications after severe trauma. METHODS: We performed a systematic review of six electronic databases and a manual search for clinical studies comparing outcomes of multiply injured patients (Injury Severity Score > or =16) depending on their early sCD62L blood concentrations. Because of various outcome definitions, acute lung injury (ALI) and adult respiratory distress syndrome (ARDS) were studied as a composite endpoint. Weighted mean differences (WMDs) in sCD62L concentrations were calculated between individuals with and without complications by fixed- and random-effects models. RESULTS: Altogether, 3370 citations were identified. Seven prospective studies including 350 patients were eligible for data synthesis. Published data showed the discriminatory features of sCD62L but did not allow for calculation of measures of test accuracy. Three of four studies showed lower early sCD62L concentrations among individuals progressing to ALI and ARDS (WMD = -229 microg/L; 95% confidence interval, -476 to 18 microg/L). No differences in sCD62L concentrations were noted among patients with or without later MODS. Nonsurvivors had significantly lower early sCD62L plasma concentrations (WMD = 121 microg/L; 95% confidence interval, 63-179 microg/L), but little information was available on potential confounders in this group. CONCLUSIONS: Early decreased soluble L-selectin concentrations after multiple trauma may signal an increased likelihood of lung injury and ARDS. The findings of this metaanalysis warrant a large cohort study to develop selectin-based models targeting the risk of inflammatory complications.
Humans↗
Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis.
OBJECTIVE: To assess the effects of corticosteroids on mortality in patients with severe sepsis and septic shock. DATA SOURCES: Randomised and quasi-randomised trials of corticosteroids versus placebo (or supportive treatment alone) retrieved from the Cochrane infectious diseases group's trials register, the Cochrane central register of controlled trials, Medline, Embase, and LILACS. REVIEW METHOD: Two pairs of reviewers agreed on eligibility of trials. One reviewer entered data on to the computer and four reviewers checked them. We obtained some missing data from authors of trials and assessed methodological quality of trials. RESULTS: 16/23 trials (n = 2063) were selected. Corticosteroids did not change 28 day mortality (15 trials, n = 2022; relative risk 0.92, 95% confidence interval 0.75 to 1.14) or hospital mortality (13 trials, n = 1418; 0.89, 0.71 to 1.11). There was significant heterogeneity. Subgroup analysis on long courses (> or = 5 days) with low dose (< or = 300 mg hydrocortisone or equivalent) corticosteroids showed no more heterogeneity. The relative risk for mortality was 0.80 at 28 days (five trials, n = 465; 0.67 to 0.95) and 0.83 at hospital discharge (five trials, n = 465, 0.71 to 0.97). Use of corticosteroids reduced mortality in intensive care units (four trials, n = 425, 0.83, 0.70 to 0.97), increased shock reversal at 7 days (four trials, n = 425; 1.60, 1.27 to 2.03) and 28 days (four trials, n = 425, 1.26, 1.04 to 1.52) without inducing side effects. CONCLUSIONS: For all trials, regardless of duration of treatment and dose, use of corticosteroids did not significantly affect mortality. With long courses of low doses of corticosteroids, however, mortality at 28 days and hospital morality was reduced.
Adrenal Cortex Hormones↗
Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock.
OBJECTIVE: To develop management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis. DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. The modified Delphi methodology used for grading recommendations built upon a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along 5 levels to create recommendation grades from A-E, with A being the highest grade. Pediatric considerations were provided to contrast adult and pediatric management. PARTICIPANTS: Participants included 44 critical care and infectious disease experts representing 11 international organizations. RESULTS: A total of 46 recommendations plus pediatric management considerations. CONCLUSIONS: Evidence-based recommendations can be made regarding many aspects of the acute management of sepsis and septic shock that will hopefully translate into improved outcomes for the critically ill patient. The impact of these guidelines will be formally tested and guidelines updated annually, and even more rapidly when some important new knowledge becomes available.
Adult↗
Corticosteroid therapy in patients with severe sepsis and septic shock.
Corticosteroids have been considered for decades for the treatment of severe sepsis and septic shock, based on their pivotal role in the stress response and their hemodynamic and antiinflammatory effects. Whereas short-term therapy with high doses of corticosteroids (up to 42 g hydrocortisone equivalent for 1-2 days) has been ineffective or potentially harmful, prolonged therapy with lower doses (200-300 mg hydrocortisone for 5-7 days or longer) in septic shock has recently revealed beneficial effects in several randomized, controlled trials. Assuming relative adrenal insufficiency (RAI) and peripheral cortisol resistance, treatment with low-dose hydrocortisone improved shock reversal, reduced inflammation, and improved outcome. Shock reversal and reduction of mortality were more effective in patients with RAI, and most significant in patients with severe shock. Diagnosis of RAI with corticotropin tests in septic shock, however, is highly dependent on cut-off values and definition of RAI. Thus, it is not clear yet which patients benefit most from low-dose hydrocortisone and if treatment should be restricted to patients with RAI. In addition the role of fludrocortisone is uncertain. Nevertheless, based on current data, low-dose hydrocortisone therapy should definitely be considered in vasopressor-dependent septic shock. This review will address some critical points.
Journal Article↗
Sepsis in 2003: are we still in the middle of nowhere?
PURPOSE OF REVIEW: Although enthusiasm of intensivists has been raised during the last 2-3 years due to several successful clinical trials, severe sepsis and septic shock still have an increasing incidence with more or less unchanged mortality. Within the last 12 months, the progress in sepsis research covering definitions, epidemiology, pathophysiology, diagnosis, standard and adjunctive therapy, as well as experimental approaches is encouraging. In this review, state-of-the-art publications of 2003 are presented to elucidate the possible impact on clinical routine. RECENT FINDINGS: The rationale for using a new definition based on the PIRO system has been widely acknowledged, although it is not yet applicable in clinical practice. This includes genomic information for stratifying subgroups of patients, and a broader field of laboratory diagnostics due to clinical studies and basic research on the cellular mechanisms of inflammation and organ dysfunction. Early diagnosis is important for a fast implementation of specific therapies, and it has been confirmed that the time until the start of therapy has an impact on patient outcome. Thorough data analysis of successful trials with activated protein C has revealed encouraging details on long-term outcome and subgroup effects. Together with new findings on low-dose hydrocortisone, this stresses the relevance of adjunctive therapy in severe sepsis and septic shock. SUMMARY: Scientific progress in areas of sepsis has been continuing throughout 2003, although the challenges are still enormous. The identification of more specific markers and new therapeutic approaches will hopefully improve the diagnosis, monitoring of therapy, and outcome in the septic patient.
Journal Article↗
Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock.
OBJECTIVE: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis. DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. METHODS: We used a modified Delphi methodology for grading recommendations, built on a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade. Pediatric considerations were provided to contrast adult and pediatric management. RESULTS: Key recommendations, listed by category and not by hierarchy, include early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition; appropriate diagnostic studies to ascertain causative organisms before starting antibiotics; early administration of broad-spectrum antibiotic therapy; reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate; a usual 7-10 days of antibiotic therapy guided by clinical response; source control with attention to the method that balances risks and benefits; equivalence of crystalloid and colloid resuscitation; aggressive fluid challenge to restore mean circulating filling pressure; vasopressor preference for norepinephrine and dopamine; cautious use of vasopressin pending further studies; avoiding low-dose dopamine administration for renal protection; consideration of dobutamine inotropic therapy in some clinical situations; avoidance of supranormal oxygen delivery as a goal of therapy; stress-dose steroid therapy for septic shock; use of recombinant activated protein C in patients with severe sepsis and high risk for death; with resolution of tissue hypoperfusion and in the absence of coronary artery disease or acute hemorrhage, targeting a hemoglobin of 7-9 g/dL; appropriate use of fresh frozen plasma and platelets; a low tidal volume and limitation of inspiratory plateau pressure strategy for acute lung injury and acute respiratory distress syndrome; application of a minimal amount of positive end-expiratory pressure in acute lung injury/acute respiratory distress syndrome; a semirecumbent bed position unless contraindicated; protocols for weaning and sedation/analgesia, using either intermittent bolus sedation or continuous infusion sedation with daily interruptions/lightening; avoidance of neuromuscular blockers, if at all possible; maintenance of blood glucose <150 mg/dL after initial stabilization; equivalence of continuous veno-veno hemofiltration and intermittent hemodialysis; lack of utility of bicarbonate use for pH > or =7.15; use of deep vein thrombosis/stress ulcer prophylaxis; and consideration of limitation of support where appropriate. Pediatric considerations included a more likely need for intubation due to low functional residual capacity; more difficult intravenous access; fluid resuscitation based on weight with 40-60 mL/kg or higher needed; decreased cardiac output and increased systemic vascular resistance as the most common hemodynamic profile; greater use of physical examination therapeutic end points; unsettled issue of high-dose steroids for therapy of septic shock; and greater risk of hypoglycemia with aggressive glucose control. CONCLUSION: Evidence-based recommendations can be made regarding many aspects of the acute management of sepsis and septic shock that are hoped to translate into improved outcomes for the critically ill patient. The impact of these guidelines will be formally tested and guidelines updated annually and even more rapidly as some important new knowledge becomes as available.
Adult↗
Use of corticosteroid therapy in patients with sepsis and septic shock: an evidence-based review.
OBJECTIVE: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for the use of corticosteroid therapy in patients with sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis. DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. METHODS: The modified Delphi methodology used for grading recommendations built upon a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade. Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al. on p. S591. CONCLUSIONS: Low doses of corticosteroids are recommended in patients with septic shock. In the absence of vasopressor requirement, corticosteroids should not be used to treat sepsis. High-dose corticosteroids are not recommended in severe sepsis. The use of adrenal function tests to guide decisions on corticosteroid therapy, the weaning of steroids at the end of the treatment period, the decision to discontinue steroids earlier with resolution of shock, and the addition of oral fludrocortisone are considered optional approaches.
Adrenal Cortex Hormones↗
Recent progress in sepsis epidemiology--have we learned enough?
The encouraging results of recent clinical trials on therapy of severe sepsis and septic shock are paralleled by ongoing studies on the epidemiology of sepsis and infection in intensive care unit patients all over the world. The development of network-based systems for assessing morbidity and mortality in intensive care unit patients has contributed to a significant improvement in quality of care. Data from the SOAP (Sepsis Occurrence in the Acutely Ill Patient) study demonstrate that the treatment of septic patients varies widely, and that even those strategies that have been evaluated are not yet implemented in routine practice. Hence, activities on surveillance and education still merit further attention.
Adult↗
Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study.
Inhaled nitric oxide (NO) improves systemic oxygenation (PaO2/FIO2) in adult patients with acute respiratory distress syndrome (ARDS). However, individual response varies, and previous trials demonstrated no outcome benefit. This prospective, randomized study in 40 ARDS patients analyzed dose-response (DR) characteristics during long-term inhaled NO. Patients were randomized for conventional therapy (control) or continuous treatment with 10 parts per million (ppm) inhaled NO until weaning was initiated. We measured DR curves of PaO2/FIO2 versus the inhaled NO dose at regular intervals. Before treatment (Day 0), peak improvement in PaO2/FIO2 was achieved at 10 ppm for both control and NO-treated patients. After 4 days, the DR curve of the NO-treated patients was left shifted with a peak response at 1 ppm. At higher doses (10 and 100 ppm), oxygenation deteriorated, and the response to inhaled NO disappeared in several patients. This effect was not observed in the control group. There was no effect of inhaled NO on duration of mechanical ventilation or stay at the intensive care unit. In conclusion, long-term inhaled NO with constant doses of 10 ppm leads to enhanced sensitivity after several days and does do not allow reduction of ventilation parameters. Hence, previous trials on therapy with inhaled NO in ARDS should be carefully interpreted, as they used constant NO concentrations, which may have become overdoses leading to deterioration of oxygenation after several days.
Acute Disease↗
Inactivation of platelet glycoprotein IIb/IIIa receptor by nitric oxide donor 3-morpholino-sydnonimine.
Nitric oxide (NO) is known to modulate platelet adhesion and aggregation, which are both mediated by fibrinogen receptor glycoprotein (GP)IIb/IIIa. To investigate effects of NO on GPIIb/IIIa activation and inactivation, platelets were exposed to NO donor 3-morpholino-sydnonimine (SIN-1) before and after stimulation with different agonists: thromboxane analog U-46619, epinephrine, adenosine diphosphate, human a-thrombin, and phorbol-12-myristate-13-acetate (0.02 micromol/l). (1) Flow cytometry analysis of SIN-1-pre-incubated samples using PAC-1 monoclonal antibody revealed an inhibition of receptor activation by 80.9 +/- 1.2, 71.3 +/- 1.8, 56 +/- 4.9, 87 +/- 3.4, and 56 +/- 5% (mean +/- SEM, relative to baseline). (2) Administration of SIN-1 after stimulation reversed receptor activation by 55 +/- 5.2, 56 +/- 2.0, 53 +/- 5.4, 42 +/- 4.3, and 44 +/- 5%, respectively. With 0.1 micromol/l phorbol-12-myristate-13-acetate, GPIIb/IIIa activation was irreversible. (3) SIN-1 effects could completely be blocked by equimolar addition of guanylyl cyclase inhibitor 1H(1,2,4)oxadiazolo(4,3-alpha)quinoxalin-1-on. (4) Spontaneous receptor closure after activation with human alpha-thrombin and adenosine diphosphate was not due to platelet-derived NO; SIN-1, however accelerated spontaneous receptor inactivation. (5) SIN-1-inactivated receptors still responded to stimulation. In conclusion, SIN-1 or NO modulates GPIIb/IIIa conformational change in vitro via guanosine 3',5'-monophosphate-dependent pathways. Whereas spontaneous receptor inactivation may be enhanced by exogenous NO, platelet-derived NO is not involved in receptor inactivation.
Blood Platelets↗
Clinical equipoise remains for issues of adrenocorticotropic hormone administration, cortisol testing, and therapeutic use of hydrocortisone.
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Adrenal Insufficiency↗
Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study.
Within the last few years, increasing evidence of relative adrenal insufficiency in septic shock evoked a reassessment of hydrocortisone therapy. To evaluate the effects of hydrocortisone on the balance between proinflammatory and antiinflammation, 40 patients with septic shock were randomized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a loading dose and 10 mg per hour until Day 3 (n = 20) or placebo (n = 20), followed by the opposite medication until Day 6. Hydrocortisone infusion induced an increase of mean arterial pressure, systemic vascular resistance, and a decline of heart rate, cardiac index, and norepinephrine requirement. A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support. The inflammatory response (interleukin-6 and interleukin-8), endothelial (soluble E-selectin) and neutrophil activation (expression of CD11b, CD64), and antiinflammatory response (soluble tumor necrosis factor receptors I and II and interleukin-10) were attenuated. In peripheral blood monocytes, human leukocyte antigen-DR expression was only slightly depressed, whereas in vitro phagocytosis and the monocyte-activating cytokine interleukin-12 increased. Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects. In conclusion, hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression.
Adult↗