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Limited data from resource-limited settings suggest that timely administration of antimicrobials in patients with sepsis and septic shock is beneficial and potentially feasible [ , , , , , ]. Access and availability of a wide range of antimicrobials in such settings may however vary [ 54 , 55 , 57 , 59 , 61 ]. The availability and turn-around time for laboratory testing, rapid infectious diagnostic, imaging, etc.

As such, the rapid assessment of infectious and non-infectious etiologies of illness will differ across settings, depending on what is feasible to achieve. Recent recommendations pertaining to the use of antimicrobials in patients with sepsis and septic shock in resource-limited settings are in line with the current recommendations [ ]. Procalcitonin is undetectable in healthy states, but rises rapidly in response to pro-inflammatory stimuli, especially bacterial infections [ ].

In theory, procalcitonin levels in combination with clinical evaluation may facilitate the diagnosis of serious bacterial infections and prompt early initiation of antimicrobials. We identified direct evidence from three RCTs that compared procalcitonin-guided protocols for antibiotic initiation vs usual care [ , , ].

Long-term mortality, readmission rates and hospital-free days were not reported in any of the trials, and no relevant studies on the costs associated with use of procalcitonin were found. In general, knowledge about the undesirable effects was lacking, and the quality of evidence was very low. Published guidelines for the management of community-acquired pneumonia recommend initiation of antimicrobials for patients with community-acquired pneumonia regardless of procalcitonin level [ ].

With no apparent benefit, unknown costs, and limited availability in some settings including low- and middle-income countries LMICs , the panel issued a weak recommendation against using procalcitonin to guide antimicrobial initiation in addition to clinical evaluation.

Patient-related risk factors for MRSA include prior history of MRSA infection or colonisation, recent IV antibiotics, history of recurrent skin infections or chronic wounds, presence of invasive devices, haemodialysis, recent hospital admissions and severity of illness [ , , , , , ]. Observational data on the impact of including MRSA coverage in empiric regimens vary.

Among undifferentiated patients with pneumonia or sepsis, broad-spectrum regimens including agents active against MRSA were associated with higher mortality, particularly among patients without MRSA [ , , , ]. Considering the increasing frequency of MDR bacteria in many parts of the world and associations between delays in active therapy and worse outcomes, the initial use of multidrug therapy is often required to ensure the empiric regimen includes at least one effective agent that is active against the offending organism [ 12 , 13 ].

In the empiric phase—before causative agent s and susceptibilities are known, the optimal choice of antibiotic therapy depends on the local prevalence of resistant organisms, patient risk factors for resistant organisms, and the severity of illness. This was borne out in a recent systematic review with meta-analysis of 10 RCTs, no differences in mortality or other patient-important outcomes between empiric mono- vs.

Results from the largest RCT included in the meta-analysis a comparison of sustained courses of moxifloxacin and meropenem vs meropenem alone in a low endemic resistance setting were consistent with the findings from the meta-analysis [ ]. Recommendations about the use of more than one gram-negative agent for empiric treatment over one gram-negative agent are challenging given clinical heterogeneity, including patient characteristics, source of infection, causative agents, and antibiotic resistance patterns.

Local information about the resistance patterns of the most common causative agents of sepsis is essential to choose the most appropriate empiric antibiotic therapy. The overall quality of evidence was very low, and the direct costs of antibiotics can increase with the routine use of multiple agents for treatment. This may specifically have an impact in resource-limited settings. In general, in patients at high risk for MDR organisms, we suggest using two gram negative agents for empiric treatment to increase the likelihood of adequate coverage, while in patients with a low risk for MDR organisms, we suggest using a single agents for empiric treatment, as there are no apparent benefits of using two agents and the a risk of antimicrobial-associated undesirable effects, including direct toxicity, Clostridioides difficile infection and development of antibiotic resistance [ ].

Empiric double coverage of gram-negative bacilli is most important in patients at high risk for resistant organisms with severe illness, particularly septic shock. Sepsis and septic shock due to fungi are most commonly observed in ICUs and are associated with poor outcomes [ , , , , ]. Some observational studies suggested that prompt initiation of appropriate empiric antifungal therapy may be associated with a reduction in mortality, however these studies do not prove a causal relationship between antifungal therapy and outcome, nor do they clarify the role of timing of treatment, and some other studies have failed to show this association [ , , , ].

In an updated meta-analysis of empiric antifungal therapy versus no antifungal therapy in adult critically ill patients, no difference in short-term mortality was observed. The overall quality of evidence was low, and treatment with empiric antifungals may be associated with increased costs. While patients with sepsis or septic shock may not in general benefit from empiric antifungals, some patients with particular risk factors for fungal infection may, for example patients with febrile neutropenia who fail to defervesce after 4—7 days of broad-spectrum antibacterial therapy are at increased risk of having fungal disease Table 2 [ , ].

The risk of Candida sepsis or septic shock for other immunosuppressed populations is highly disease- and therapy-specific. Importantly, the decision to start empiric antifungal therapy depends on the type and number of risk factors, along with the local epidemiology of fungal infections.

Accordingly, we suggest using empiric antifungal therapy in patients at high risk of fungal infection, while we suggest avoiding this if the risk is low. The choice of antifungal agent for empiric therapy depends on multiple issues including host factors, prior colonisation and infection, prior exposure to prophylactic or therapeutic antifungal therapy, comorbidities, and the toxicities and drug interactions of the therapeutic options.

Historically, influenza has been one of the more common viral causes of sepsis. However, it is unclear to what extent the primary viral infection as opposed to bacterial pneumonia co-infection is the cause of organ dysfunction in these patients [ , , , ]. The ongoing pandemic due to SARS-CoV-2 has resulted in the understanding of this condition changing very rapidly [ ]. While there appears to be no overall effect of neuraminidase inhibitors on mortality in patients with influenza-related pneumonia, there may be an effect when administered early in the course of the disease [ ].

For detailed information on specific antiviral therapy, including for influenza and SARS CoV-2, please refer to dedicated clinical practice guidelines [ , , ]. Immunocompromised patients are particularly vulnerable to viral infections, including patients with neutropenia, human immunodeficiency virus HIV infection, haematological malignancies and haematopoietic stem cell transplantation or solid organ transplants; in these patients herpes simplex virus, Epstein-Barr virus, cytomegalovirus, and respiratory viruses such as adenoviruses, can cause severe disease [ ].

Tropical and subtropical regions have endemic and epidemic outbreaks of zoonotic viral infections including those caused by Dengue, Ebola, Lassa, Marburg, Sin Nombre and Chikungunya virus. Many of these can manifest with clinical signs of sepsis, particularly in their early stages. Unfortunately, effective therapies are lacking for most of these viruses. The desirable effects of empiric antiviral therapy are unknown, and as for other antimicrobial agents there is a risk of undesirable effects [ ].

Data on cost effectiveness were not available. Due to the rapidly changing position related to antiviral therapies in critically ill patients presenting with several acute respiratory failure, this panel decided not to issue a recommendation on antiviral therapies and to refer the reader to more specific guidelines [ ].

Beta-lactam antibiotics may be subject to changes in important pharmacokinetic parameters in the setting of sepsis and septic shock resulting in sub-therapeutic concentrations [ , ]. Two meta-analyses reported similar results supporting reduced short-term mortality RR 0. No trials assessed the undesirable effects of continuous infusion, and the desirable effects were deemed important, while the overall quality of evidence was moderate.

Prolonged infusion is a feasible intervention if suitable IV access is present, and resources are available to ensure the beta-lactam is infused over the necessary duration. The latter may be an issue in some resource limited settings, including LMICs. Administration of a loading dose of antibiotic before prolonged infusion is essential to avoid delays to achieving effective beta-lactam concentrations [ ]. The reduction in short-term mortality from prolonged infusion of beta-lactams is significant with the intervention being feasible with negligible cost implications and no data suggesting inferior outcomes with prolonged infusion.

Accordingly, we suggest prolonged infusion of beta-lactams over conventional bolus infusion in patients with sepsis and septic shock if the necessary equipment is available. Further research is needed on long-term outcomes, on the effect on emergence of antimicrobial resistance, and on costs of prolonged versus bolus infusion of beta-lactams [ ]. Augmented renal clearance [ ], AKI [ ], hypoalbuminemia [ ], RRT [ , ], and extracorporeal membrane oxygenation [ , ] are examples of common scenarios that affect the concentrations of some antibiotics.

Some studies in critically ill patients have reported benefits in terms of clinical cure [ , , , , ]. Use of therapeutic drug monitoring has been described for all drugs, although it is not widely available for most. Appropriate source control is a key principle in the management of sepsis and septic shock [ 12 , 13 ]. Source control may include drainage of an abscess, debriding infected necrotic tissue, removal of a potentially infected device, or definitive control of a source of ongoing microbial contamination [ ].

Foci of infection readily amenable to source control include intra-abdominal abscesses, gastrointestinal perforation, ischaemic bowel or volvulus, cholangitis, cholecystitis, pyelonephritis associated with obstruction or abscess, necrotizing soft tissue infection, other deep space infection e.

Source control of infectious foci was associated with improved survival in recent observational and cluster randomised studies [ , , ]. Source control should be achieved as soon as possible following initial resuscitation [ , ]. While there are limited data to conclusively issue a recommendation regarding the timeframe in which source control should be obtained, smaller studies suggest that source control within 6—12 h is advantageous [ , , , , , , ].

Studies generally show reduced survival beyond that point. The failure to show benefit with source control implemented in less than 6 h may be a consequence of the limited number of patients and the heterogeneity of the intervention. Therefore, any required source control intervention in sepsis and septic shock should ideally be implemented as soon as medically and logistically practical after the diagnosis is made [ ].

Clinical experience suggests that without adequate source control, many severe presentations will not stabilise or improve despite rapid resuscitation and provision of appropriate antimicrobials. In view of this fact, prolonged efforts at medical stabilisation in lieu of source control for severely ill patients, particularly those with septic shock, are generally not advised [ ]. In general, the least invasive option that will effectively achieve source control should be pursued.

Open surgical intervention should be considered when other interventional approaches are inadequate or cannot be provided in a timely fashion. Surgical exploration may also be indicated when diagnostic uncertainty persists despite radiologic evaluation, when the probability of success with a percutaneous procedure is uncertain, or when the undesirable effects of a failed procedure are high.

Logistic factors unique to each institution, such as surgical or interventional staff availability, may also play a role in the decision. Future research is needed to investigate the optimal timing and method of source control in patients with sepsis and septic shock with a source of infection amenable to drainage. Removal of a potentially infected intravascular access device is considered a part of adequate source control [ ]. An intravascular device suspected to be a source of sepsis should be removed after establishing another site for vascular access and following successful initial resuscitation [ , ].

In the absence of septic shock or fungemia, some implanted tunnelled catheter infections may be treated effectively with prolonged antimicrobial therapy if removal of the catheter is not practical [ ]. However, catheter removal with adequate antimicrobial therapy is definitive and is the preferred treatment in most cases.

We identified one relevant RCT [ ] and two observational studies [ , ]. There was no evidence of a difference in mortality, however, the studies were hampered by significant limitations, including risk of confounding by indication the observational studies and imprecision the RCT , which is why the results should be interpreted cautiously. The quality of evidence was very low. Antimicrobial exposure is linked to the development of antimicrobial resistance and efforts to reduce both the number of antibiotics administered and their spectrum of therapy are therefore important strategies in patients with sepsis and septic shock [ ].

This is particularly relevant in empiric therapy where broad-spectrum therapy is recommended, as the causative pathogen has not yet been identified. Once both the pathogen s and susceptibilities are known, antimicrobial de-escalation—i. Given the adverse societal and individual risks to continued unnecessary antimicrobial therapy, thoughtful de-escalation of antimicrobials based on adequate clinical improvement is appropriate even if cultures are negative.

Early discontinuation of all antimicrobial therapy if infection is ruled out is advisable [ ]. Antimicrobial de-escalation should ideally be done as soon as possible, and rapid diagnostic techniques may facilitate this. We identified direct evidence from 13 studies patients [ ], including 1 RCT [ ]. In our meta-analysis, we observed improved short-term mortality in patients who were de-escalated RR 0.

Long-term mortality was evaluated in one study only and did not demonstrate a difference RR 0. Most studies were observational, and there are concerns that de-escalation is used primarily in patients who are getting better, which is why the reported improved short-term mortality should be interpreted with caution [ , ]. De-escalation is in generally safe, may offer cost savings when unnecessary antibiotics are discontinued, and reduced risk of antimicrobial resistance and reduced toxicity and side-effects may be important [ ].

Based on the overall very low quality of evidence, RCTs are warranted along with more studies on antimicrobial resistance. Restricting antimicrobial therapy to the shortest course associated with better outcomes is an important part of antimicrobial stewardship [ , , , , ]. The optimal duration of antimicrobial therapy for a given patient with sepsis or septic shock depends on many factors, including host, microbe, drug, and anatomical site Table 2 [ 99 , ]. There are data from RCTs in specific conditions such as pneumonia [ , , , ], urinary tract infections [ ], bacteremia [ , ], and intraabdominal infections [ ].

In many of the trials, the shorter course was just as effective as the longer course but associated with fewer adverse consequences. Very few trials, however, focussed exclusively on critically ill patients with sepsis or septic shock, and the overall quality of evidence was very low. Given the lack of definitive and generalizable data regarding the optimal duration of therapy for patients who are critically ill, it is not surprising that there is considerably practice variation [ , ].

Specialist consultation appears to be associated with improved patient outcomes for a variety of infectious syndromes [ , , , , , ]. This has generally been ascribed to improvements in microbial appropriateness of the empiric antimicrobial regimen provided. However, it is also possible that reducing the duration of unnecessary therapy may account for at least part of the benefit.

Thus, for adults with an initial diagnosis of sepsis or septic shock and adequate source control, we suggest a shorter course of antibiotics, as this is less costly, has fewer undesirable effects without impacting adversely on outcomes see Table 4. Shorter durations of antimicrobial therapy are in general recommended; however, critically ill patients often receive antimicrobials for more days than necessary [ , , ]. While typically clinical evaluation alone is used to decide duration, biomarkers could offer additional information.

C Reactive Protein is often used in this regard. Procalcitonin has been studied most extensively both in critically ill and non-critically ill patients, both for initiation and discontinuation of therapy [ ]. A meta-analysis suggested improved mortality in patients who were managed using procalcitonin versus control RR 0.

Antibiotic exposure was consistently lower in patients who were managed with procalcitonin and clinical evaluation, however, in many trials the total duration of therapy was still 7 days or longer in the intervention group. Also, the algorithms for antimicrobial therapy, frequency of procalcitonin monitoring and the thresholds or percentage change in procalcitonin concentration for discontinuation differed across the trials.

Therefore, the overall quality of evidence was judged to be low. The undesirable effects of using procalcitonin along with clinical evaluation to decide when to discontinue antimicrobials are considered minimal, and do not outweigh the potential benefits [ ]. Limited data on the cost-effectiveness are available, although a single centre study reported decreased hospital costs associated with PCT-guided antibiotic in medical ICU patient with undifferentiated sepsis [ ].

Procalcitonin testing may not be available in all countries and healthcare settings, including LMICs. Based on apparent benefit and no obvious undesirable effects, we suggest using procalcitonin along with clinical evaluation to decide when to discontinue antimicrobials in adults with an initial diagnosis of sepsis or septic shock and adequate source control, if the optimal duration of therapy is unclear and if procalcitonin is available.

Fluid therapy is a key part of the resuscitation of sepsis and septic shock. Crystalloids have the advantage of being inexpensive and widely available. The absence of clear benefit following the administration of colloids compared to crystalloid solutions supports the use of crystalloid solutions in the resuscitation of patients with sepsis and septic shock [ ]. The optimal fluid remains a subject of debate. For decades, the administration of normal saline solution 0.

Subsequently, a network meta-analysis of 14 RCTs of patients with sepsis showed in an indirect comparison that balanced crystalloids were associated with decreased mortality, compared to saline [ ]. There have been a number of recent RCTs assessing the question of which crystalloid may be most beneficial in patients with sepsis.

In the SPLIT multicentre, double-blinded clinical trial, the comparison between balanced solutions and normal saline yielded no differences in mortality or AKI [ ]. The primary outcome, a composite outcome including mortality, new RRT or persistent renal dysfunction major adverse kidney event within 30 days, MAKE30 , was similar between groups Subsequently, the SMART trial was published in , a single-centre, multiple-crossover study including 15, patients who received balanced solutions or normal saline, alternating on a monthly basis [ ].

In the pre-specified subgroup of patients admitted with sepsis in all participating ICUs, day mortality was lower in those receiving balanced solutions, compared to normal saline OR 0. Likewise, in a secondary analysis including only the 1, patients admitted to medical ICUs with a diagnosis of sepsis, balanced solutions were associated with reduced day hospital mortality OR 0.

The SMART trial was a single-centre study without individual patient randomisation and no blinded assignment of the intervention, it exposed participants to moderate amount of fluid volume, identification of sepsis subgroups was based on ICD codes, and it used a composite outcome which may not be as relevant as a patient-centered outcome [ ]. However, the use of balanced solutions in sepsis may be associated with improved outcomes compared with chloride-rich solutions. No cost-effectiveness studies compared balanced and unbalanced crystalloid solutions.

Therefore, we considered the desirable and undesirable consequences to favour balanced solutions, but as the quality of the evidence is low, we issued a weak recommendation. Two ongoing large RCTs will provide additional data and inform future guideline updates [ , ]. Although albumin is theoretically more likely to maintain oncotic pressure than crystalloids [ ], it is more costly and there is no clear benefit with its routine use.

Since the publication of the guidelines [ 12 ] two single-centre trials and two meta-analyses have been published on this topic [ , , , ]. A Cochrane review including RCTs with 12, patients comparing albumin versus crystalloids found no difference in day RR 0. This meta-analysis included patients with critical illness, and while the main solution included in the analysis was albumin, some studies in other analyses included fresh frozen plasma.

The largest clinical trial in sepsis, the ALBIOS trial comparing a combination of albumin and crystalloids to crystalloids alone in patients with sepsis or septic shock did not demonstrate a difference in day RR 1. A meta-analysis of studies including septic patients did not show a significant difference in mortality RR 0. In addition, the risk of new organ failures RR 1. Although albumin use resulted in a larger treatment effect in the septic shock subgroup RR 0. The lack of proven benefit and higher cost of albumin compared to crystalloids contributed to our strong recommendation for the use of crystalloids as first-line fluid for resuscitation in sepsis and septic shock.

The suggestion to consider albumin in patients who received large volumes of crystalloids is informed by evidence showing higher blood pressure at early and later time points [ ], higher static filling pressures [ ], and lower net fluid balance [ ] with albumin. Limited data precludes a cutoff value for crystalloid infusion above which albumin might be considered as part of resuscitation. No new data were identified. A network meta-analysis of patients with sepsis or septic shock also demonstrated a higher risk of death OR 1.

Therefore, the recommendation against the use of HES in resuscitation of patients with sepsis or septic shock did not change [ , ]. Gelatin is a synthetic colloid used as a resuscitation fluid; there is a lack of powered well-designed studies supporting its administration in sepsis and septic shock. Included studies are generally small and include mostly post-operative, non-critically ill patients. In an indirect comparison, a 4-node network meta-analysis conducted in patients with sepsis, showed no clear effect on mortality when compared to crystalloids OR 1.

Adverse effects of gelatin have been reviewed in a network meta-analysis, which demonstrated higher risk of RRT with gelatin use compared to normal saline OR 1. Overall, the quality of evidence was moderate, due to imprecision and indirectness. In a systematic review of RCTs including patients with hypovolemia, gelatin use increased the risk of anaphylaxis RR 3.

Furthermore, gelatins may affect haemostasis and the effect on blood transfusions was unclear RR 1. Therefore, in the face of inconclusive effect on mortality, increased adverse effects, and higher costs, the panel issued a weak recommendation against the use of gelatin for acute resuscitation. More high-quality studies are needed to inform future guideline updates. At lower dosages, dopamine causes vasodilation via dopamine-1 receptor activity in the renal, splanchnic, cerebral, and coronary beds.

Norepinephrine is more potent than dopamine as a vasoconstrictor. In a systematic review and meta-analysis of 11 RCTs, norepinephrine resulted in a lower mortality RR 0. Potential adverse effects of epinephrine include arrhythmias and impaired splanchnic circulation [ ].

A randomised blinded study comparing epinephrine with norepinephrine in patients with shock showed no difference in day mortality HR 0. The panel issued a strong recommendation for norepinephrine as the first-line agent over other vasopressors Fig. Vasopressin is an endogenous peptide hormone produced in the hypothalamus and stored and released by the posterior pituitary gland. Its mechanism for vasoconstrictive activity is multifactorial and includes binding of V 1 receptors on vascular smooth muscle resulting in increased arterial blood pressure.

Studies show that vasopressin concentration is elevated in early septic shock but decreases to normal range in the majority of patients between 24 and 48 h as shock continues [ , ]. The significance of this finding is unknown. Unlike most vasopressors, vasopressin is not titrated to response, but it is usually administered at a fixed dose of 0. In clinical trials, vasopressin was used up to 0. Higher doses of vasopressin have been associated with cardiac, digital, and splanchnic ischaemia [ ].

There was no significant difference between the vasopressin and norepinephrine groups in day mortality [ Although there was no difference with respect to kidney injury RR 0. As for combination therapy, the main study the VASST trial comparing norepinephrine alone to norepinephrine plus vasopressin 0. Both VANISH and VASST demonstrated a catecholamine-sparing effect of vasopressin; as such, the early use of vasopressin in combination with norepinephrine may help reduce the adrenergic burden associated with traditional vasoactive agents [ ].

In our systematic review of 10 RCTs, vasopressin with norepinephrine reduced mortality as compared to norepinephrine alone RR 0. There was no difference in the risks of digital ischaemia RR 1. The threshold for adding vasopressin varied among studies and remains unclear. Starting vasopressin when norepinephrine dose is in the range of 0. Another meta-analysis of RCTs on distributive shock showed a lower risk of atrial fibrillation with the combination of vasopressin and norepinephrine compared to norepinephrine alone [ ].

However, a recent individual patient data meta-analysis of patients with septic shock from 4 RCTs showed that vasopressin alone or in combination with norepinephrine led to higher risk of digital ischaemia risk difference [RD] 1.

The evidence regarding the optimal therapeutic strategy for shock requiring high dose vasopressors is scant [ ]. Epinephrine has been suggested as second or third-line vasopressor for patients with septic shock. Thus, the use of another drug such as epinephrine that targets the same receptors may be of limited utility and vasopressin could be more adequate in this scenario.

In an indirect comparison, a network meta-analysis did not find any significant difference between epinephrine and vasopressin in terms of mortality RR 0. Epinephrine might be useful in refractory septic shock patients with myocardial dysfunction.

Thus, we considered the desirable and undesirable consequences of these vasopressors and issued a strong recommendation to use norepinephrine as a first line agent instead of dopamine, vasopressin, epinephrine and selepressin and angiotensin II in patients with septic shock as a first-line agent, and a weak recommendation over selepressin and angiotensin II. Although some evidence suggests that vasopressin might be superior to norepinephrine in terms of clinical outcomes, the panel took into consideration its higher costs and lower availability and have issued a strong recommendation to use norepinephrine as first line agent instead of vasopressin.

We also consider the potential benefit and undesirable consequences of using the combination of norepinephrine and vasopressin and issue a weak recommendation for adding vasopressin instead of escalating the dose of norepinephrine.

Further evidence is needed to properly address the role of combination therapy of vasopressors in septic shock. The panel also recognised that availability of, and experience with, norepinephrine may vary. As part of the global campaign for universal healthcare, the World Health Organisation WHO essential medicines and health products programme works to increase global access to essential, high-quality, safe, effective, and affordable medical products.

If norepinephrine is unavailable, either dopamine or epinephrine can be used with special attention given to the risk of arrhythmias. Selepressin is a highly selective V1 agonist, inducing vasoconstriction via stimulation of vascular smooth muscle. It does not share the typical V1b and V2 receptor effects of vasopressin increased pro-coagulant factors, salt, and water retention, nitric oxide, and corticosteroid release and has, therefore, been postulated as a potentially attractive non-catecholamine vasopressor alternative to norepinephrine.

Selepressin has been studied in two randomised trials in septic shock. The first, a double-blind, randomised, placebo-controlled phase IIa trial, compared three ascending doses of selepressin 1. Selepressin at a dose of 2. The study was stopped for futility after enrolment of patients, with no significant differences between any of the key endpoints [ventilator- and vasopressor-free days, The meta-analysis of the two studies did not show significant difference in mortality [selepressin: As selepressin failed to demonstrate clinical superiority over norepinephrine, we considered the desirable and undesirable consequences to be in favour of norepinephrine and issued a weak recommendation against the use of selepressin as a first-line therapy.

Furthermore, it is not currently commercially available. Angiotensin II is a naturally occurring hormone with marked vasoconstrictor effects, triggered through stimulation of the renin-angiotensin system. A synthetic human preparation has recently become available for clinical use and has been studied in two clinical trials.

The primary endpoint, an increase of MAP of at least 10 mmHg or to at least 75 mmHg, was achieved in of patients in the angiotensin II group and in 37 of patients in the placebo group A meta-analysis found no difference in mortality rates between angiotensin II and norepinephrine There was no clear increase in adverse events with the use of angiotensin II.

As the available evidence is of very low quality, and clinical experience in sepsis and, therefore, demonstration of safety remains limited, the panel considered that angiotensin should not be used as a first-line agent, but having demonstrated physiological effectiveness, it may have a role as an adjunctive vasopressor therapy.

Terlipressin is more specific for the V1 receptors and it has been studied in 9 clinical trials of patients with sepsis, with or without cirrhosis, involving patients in total. Our meta-analysis showed no difference in mortality terlipressin: The primary outcome was death from any cause at 28 days. There were three cases of mesenteric ischaemia in the terlipressin group versus one in the norepinephrine group.

Therefore, the panel considered that the undesirable consequences are higher with the use of terlipressin and issued a weak recommendation against its use in patients with septic shock. Sepsis-induced myocardial dysfunction is recognised as a major contributor to the haemodynamic instability and is associated with worse outcomes of patients with septic shock [ ].

Inotropic therapy can be used in patients with persistent hypoperfusion after adequate fluid resuscitation, and in patients with myocardial dysfunction, based on suspected or measured low CO and elevated cardiac filling pressures. Dobutamine and epinephrine are the most commonly used inotropes. Physiologic studies demonstrate that dobutamine increases CO and oxygen transport, increases splanchnic perfusion and tissue oxygenation, improves intramucosal acidosis and hyperlactatemia [ ].

However, these effects may not be predictable [ ]. Dobutamine infusion may produce severe vasodilation and result in lower MAP. In addition, the inotropic response may be blunted in sepsis with a preserved chronotropic effect causing tachycardia without an increase in stroke volume SV [ ].

No RCTs compared dobutamine to placebo in this population. Indirect comparison from network meta-analysis showed that dobutamine with norepinephrine had no clear impact on mortality when compared to no inotropic agents OR 0. None of the trials directly compared dobutamine combined with norepinephrine to norepinephrine alone. In an observational study of patients with septic shock, the use of an inotropic agent dobutamine, levosimendan, epinephrine, or milrinone was independently associated with increased day mortality OR 2.

However, the analysis adjusted only to baseline characteristics, without accounting for time-varying confounders including the patient condition at the time of initiating inotropes which may explain the association with mortality. The panel considered the network meta-analysis as a higher quality than observational studies and issued a suggestion to use inotropes only in selected situations.

No evidence supports the superiority of dobutamine over epinephrine. Epinephrine is commonly available especially in low-resource settings [ ]. In an indirect comparison of dobutamine versus epinephrine, a network meta-analysis showed no clear effect on mortality OR 1. Therefore, we considered the desirable and undesirable consequences to be comparable for both drugs and issued a weak recommendation to use either one for patients with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate fluid status and MAP.

Both should be discontinued in the absence of improvement in hypoperfusion or in the presence of adverse events. Further evidence derived from high quality RCTs is needed to properly address the role of inotropes in sepsis. Levosimendan is a calcium-sensitizing drug with inotropic and vasodilatory properties. It has been evaluated in septic shock [ ]. A meta-analysis of seven RCTs comparing levosimendan with dobutamine showed that levosimendan was not superior to dobutamine in adults with sepsis in terms of mortality OR 0.

Thus, the panel issued a weak recommendation against the use of levosimendan based on the lack of benefit, in addition to the safety profile, cost and the limited availability of the drug. Estimation of blood pressure using a non-invasive cuff tends to be inaccurate and the discrepancy more pronounced in shock states [ , , , , ].

Insertion of an arterial catheter permits safe, reliable and continuous measurement of arterial pressure and allows real time analysis so that therapeutic decisions can be based on immediate and accurate blood pressure information [ ]. Ultrasound guidance may increase the first attempt success rate and decrease the complication rate [ , ].

A systematic review showed higher risk of infections when femoral arterial catheters were used compared to radial artery catheters RR 1. In the previous version of these guidelines, a weak recommendation was issued for using invasive monitoring of arterial blood pressure over non-invasive monitoring [ 12 ]. Since then, no new relevant evidence became available.

Large, randomised trials that compare arterial blood pressure monitoring versus non-invasive methods are still lacking. In view of the low complication rate and likely higher accuracy of blood pressure measurement, the benefits of arterial catheters probably outweigh the risks. However, the potentially limited resources in some countries and the lack of high-quality studies need to be considered.

Therefore, the panel issued a weak recommendation in favour of arterial catheter placement. Arterial catheters should be removed as soon as continuous haemodynamic monitoring is no longer required to minimise the risk of complications. The prompt initiation of vasopressors to restore blood pressure is an integral component of the management of septic shock. Vasopressors have been traditionally administered via a central venous access due to concerns of extravasation, local tissue ischaemia and injury if administered peripherally.

However, the process of securing central venous access can be time consuming and requires specialised equipment and training that may not be available in under resourced settings even in high income countries, leading to a delayed initiation of vasopressors [ ]. Large randomised trials that compare central and peripheral catheters for initial infusion of vasopressor are lacking. The incidence of major catheter-related complications was higher in those randomised to peripheral venous lines with no significant difference in the incidence of minor catheter-related complication.

The most common peripheral venous line complication was difficulty in placement. Almost half of the patients assigned to the peripheral access group did not need a central line throughout their ICU stay. Other authors also showed that central lines could be avoided by peripheral line insertion [ ]. The administration of vasopressors through peripheral IV catheters is generally safe.

A recent systematic review showed that extravasation occurred in 3. Most of the studies reported no need for active treatment of the extravasation, and a systematic review concluded that most patients who experience extravasation events have no long-term sequelae [ ]. The occurrence of local tissue injury may be more likely with prolonged administration of vasopressors. The time to initiation of vasopressors may be shorter if peripheral access is used. Delay in vasopressor initiation and achieving MAP of 65 is associated with increased mortality [ , ].

Given the low complication rate of peripheral vasopressors and the possibility of restoring blood pressure faster, the benefits of initiating vasopressors for a short period of time in a vein proximal to the antecubital fossa probably outweigh the risks.

Therefore, we issued a weak recommendation in favour of the rapid initiation of vasopressors peripherally. If the infusion of vasopressors is still needed after a short period of time, as soon as practical and if resources are available, they should be infused through a central venous access to minimise the risk of complications. The lack of availability and expertise in placement of central venous catheters in different settings is an important consideration [ 55 ].

Though data are generally sparse on the latter, a study of mostly senior resident doctors in Nigeria concluded that knowledge of central venous catheter placement was limited [ ]. Though the panel suggests peripheral administration of norepinephrine as a temporizing measure until a central venous catheter can be placed, its longer-term central administration may not be possible in some settings.

Larger prospective studies are needed to provide better evidence on the adequacy and safety of peripheral lines in this scenario. The current literature does not provide clear guidance about the best fluid strategy following the initial resuscitation bolus of fluids. The four largest clinical trials in sepsis resuscitation used moderate to large amounts of fluids in the first 72 h.

However, recent evidence suggests that IV fluids used to restore organ perfusion may damage vascular integrity and lead to organ dysfunction [ ]. Data from observational studies have shown an association of high-volume fluid resuscitation and increased mortality, but these studies are likely affected by unmeasured variables i.

The current evidence evaluating a restrictive IV fluid strategy in the management of septic patients varies with respect to the inclusion criteria, the definition of restrictive and liberal fluid strategies, the criteria guiding the administration of additional IV fluids e. Moreover, the primary outcomes were mostly related to IV fluid volumes administered during the study period and given the small sample sizes, they were not powered to identify differences in patient-centered outcomes.

Given the quality of the evidence and the variability among existing studies, the panel issued no recommendation for either restrictive or liberal fluid management in the first 24 h of resuscitation after the initial fluid bolus in patients with sepsis and septic shock.

However, it is important to emphasise this discussion does not affect the recommendation for the initial IV fluid bolus and that the administration of IV fluids after the initial fluid bolus should be guided by perfusion parameters and not only by a response in haemodynamic variables. Patients who are undergoing mechanical ventilation in the ICU often receive a high fraction of inspired oxygen and have a high arterial oxygen tension. The conservative use of oxygen may reduce oxygen exposure and diminish lung and systemic oxidative injury.

In the participant ICU-ROX trial [ ], conservative oxygen therapy did not significantly affect the primary outcome, which was the number of ventilator-free days, compared with liberal oxygen therapy for ventilated adults in ICU. Mortality at 90 and days did not differ. These findings are at variance with the results of a previous single-centre trial, which was stopped early after an unplanned interim analysis. In that trial, conservative oxygen therapy in the ICU was associated with a markedly lower rate of death than usual oxygen therapy [ ].

In a recent systematic review and meta-analysis of multiple clinical syndromes, investigators found that a conservative oxygen strategy was associated with a lower rate of death in acutely ill adults than a liberal oxygen strategy [ ]. However, in a post hoc analysis of the ICU-ROX trial including adults with sepsis, point estimates for the treatment effect of conservative oxygen therapy on day mortality raise the possibility of clinically important harm [ ].

The LOCO-2 study was terminated early by the data safety and monitoring board and reported no difference in day survival in ARDS patients managed with a conservative oxygenation strategy [ ]. There are several ongoing trials of conservative oxygen targets that will inform clinical practice in the future. At this point in time, there is insufficient evidence to make an evidence-based recommendation.

Acute hypoxemic respiratory failure can result from causes of sepsis such as pneumonia or non-pulmonary infections resulting in ARDS. Patients presenting with hypoxia without hypercapnia are treated with high concentrations of inhaled oxygen which may be delivered conventionally with interfaces including nasal prongs, facemask with reservoir or Venturi mask. Advanced interventions for patients with severe hypoxia requiring escalation of support include non-invasive ventilation NIV or high flow oxygen.

Both therapies avoid the complications of intubation and invasive mechanical ventilation and promote patient interaction. In addition to improving gas exchange, NIV may help to reduce work of breathing in select patients. However, NIV use can be associated with development of complications including increased risk of gastric insufflation and aspiration, facial skin breakdown, excessively high tidal volumes as well as patient discomfort related to inability to eat or effectively phonate during therapy.

High flow nasal cannula HFNC is a non-invasive, high concentration oxygen delivery interface that confers warming and humidification of secretions, high flow rates to better match patient demand, washout of nasopharyngeal dead space, and modest positive airway pressure effect. Complications with HFNC are possible; however, they are usually self-limited and do not require discontinuing therapy.

When comparing the strategies of NIV versus HFNC for acute hypoxemic respiratory failure despite conventional oxygen , a single, large randomised trial has been conducted for direct comparison [ ]. However, the NIV technique was not standardised and the experience of the centers varied. Although the quality of evidence is low, the benefits of a trial of HFNC for the sepsis patient with non-hypercapnic progressive hypoxia over NIV seems justified.

Patients requiring HFNC for acute hypoxemic respiratory failure are at high risk of requiring intubation; therefore, such trials must be accompanied by careful surveillance for ventilatory failure. When directly compared to invasive positive pressure ventilation, NIV may be able to achieve similar physiologic benefits including improved gas exchange and reduced work of breathing in select patients, while avoiding complications associated with intubation, invasive ventilation, and accompanying sedation.

In contrast, NIV can cause mask-related discomfort, unrecognised patient-ventilator asynchrony due to leaks, and gastric insufflation. The main risk of NIV for the indication of acute respiratory failure is the potential for delaying needed intubation and increasing the risk of an interval aspiration events.

Studies have suggested that NIV failure is an independent risk factor for mortality specifically in this population, although careful patient selection may reduce this risk [ , ]. Patients with sepsis-induced hypoxemic respiratory failure may or may not have a competing chronic respiratory disease ex. Since the last guideline distribution, only one additional study was added for analysis [ ].

Due to small number of patients studied, low quality of evidence, uncertainty regarding whether clinicians can identify hypoxic patients in respiratory failure in whom NIV might be beneficial, and observational data that suggest the potential for harm with NIV in this setting, no clear recommendation can be made. If NIV is used for patients with sepsis-associated hypoxic respiratory failure, we suggest monitoring for an early reduction in work of breathing and close monitoring of tidal volumes [ ].

This recommendation is the same as that of the previous guidelines. Several multicentre RCTs have been performed in patients with established ARDS to evaluate the effects of limiting inspiratory pressure through moderation of tidal volume [ , , , ]. These studies showed differing results, which may have been caused by differences in airway pressures in the treatment and control groups [ , , ].

Several meta-analyses suggest decreased mortality in patients with a pressure- and volume-limited strategy for established ARDS [ , ]. Patients with profound metabolic acidosis, high minute ventilation, or short stature may require additional manipulation of tidal volumes.

The plateau pressure is only truly valuable if the patient is passive during the inspiratory hold. A recent patient-level mediation analysis suggested that a tidal volume that results in a driving pressure plateau pressure minus set PEEP below 12—15 cm H 2 O may be advantageous in patients without spontaneous breathing efforts [ ].

Prospective validation of tidal volume titration by driving pressure is needed before this approach can be recommended. The clinician should keep in mind that very low tidal volumes may result in significant patient-ventilatory dyssynchrony and patient discomfort. Volume- and pressure-limited ventilation may lead to hypercapnia even with these maximum-tolerated set respiratory rates; this appears to be tolerated and safe in the absence of contraindications e.

No single mode of ventilation pressure control, volume control has consistently been shown to be advantageous when compared with any other that respects the same principles of lung protection. This recommendation is unchanged from the previous guidelines, as no new trials evaluating plateau pressure have been published since then. These three RCTS compared a strategy of low tidal volume and limited plateau pressure with a strategy using higher tidal volume and plateau pressure; pooled data suggest reduced mortality RR 0.

A recent systematic review which included five RCTs also identified a strong relationship between plateau pressure and mortality [ ]. The recommendation is also supported by observational data. LUNGSAFE, a large international observational study, which reported that plateau pressure correlated with mortality; however, the relationship between the two was not evident when plateau pressure was below 20 cm H 2 O [ ]. A secondary analysis of five observational studies identified a plateau pressure cut-off value of 29 cm H 2 O, above which an ordinal increment was accompanied by an increment of risk of death [ ].

We therefore recommend that the upper limit goal for plateau pressure should be less than 30 cm H 2 O. The recommendation is unchanged from Two RCTs [ , ] were published since the Guidelines [ 12 , 13 ], but we did not include these trials in the meta-analyses because both studies applied recruitment maneuvers to titrate PEEP levels.

Our conclusions did not change in a sensitivity analysis which includes these two trials. The optimal method of selecting a higher PEEP level is not clear. One option is to titrate PEEP according to bedside measurements of thoracopulmonary compliance with the objective of obtaining the best compliance or lowest driving pressure, reflecting a favourable balance of lung recruitment and overdistension [ ].

Esophageal pressure guided PEEP titration has been evaluated in two trials [ , ]. While the pilot study suggested benefit [ ], the subsequent patient multicentre RCT that compared PEEP titration guided by esophageal P ES measurement versus empirical high PEEP-FiO 2 titration, showed no significant difference in a composite outcome of death and days free from mechanical ventilation through day 28 [ ].

There is not as strong an evidence base, however, for the patients presenting with acute respiratory failure requiring mechanical ventilation who do not fulfil the criteria for ARDS. A systematic review and meta-analysis found a reduction in the risk of a composite endpoint of ARDS or pneumonia during the hospital stay in the low tidal volume ventilation group compared to the high tidal volume ventilation group RR 0.

There are limited data on ventilation strategies for patients with sepsis-induced respiratory failure who do not meet criteria for ARDS. However, sepsis is an independent risk factor for the development of ARDS, and delays in diagnosing ARDS may result in delayed use of low tidal volumes. We therefore suggest that low tidal volume ventilation be used in all patients with sepsis who are receiving mechanical ventilation in order to avoid underuse or delayed use of this intervention. Furthermore, the use of low tidal volume ventilation avoids the risk of promoting ventilator induced lung injury in septic patients in whom the diagnosis of ARDS has been missed.

Many strategies exist for treating refractory hypoxemia in patients with severe ARDS [ ]. Temporarily raising transpulmonary pressure may facilitate opening atelectatic alveoli to permit gas exchange [ ], but could also over distend aerated lung units leading to ventilator-induced lung injury and transient hypotension.

When the incremental PEEP recruitment studies are analysed separately from studies utilizing traditional recruitment maneuvers, recruitment with incremental PEEP is associated with increased day mortality RR 1. Adobe Photoshop is designed specifically for digital images, although it has also been used to modify printing plates and posters.

It was released in and is available for the Windows, Macintosh and Linux platforms. The first version of Photoshop was designed to implement features based on the Macintosh graphical user interface GUI and hence it did not include the Windows UI. It was later converted to Windows as Photoshop Classic. Adobe Photoshop comes with tutorials and other content that can help you learn how to use the program to complete basic tasks like adding text, editing images, making adjustments like color correction, sharpening and noise reduction, and so on.

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Adobe Photoshop is used by many people in marketing and advertising, video editing, photography, web design and art. Requirements Photoshop needs to be installed on your computer; you can download it free from the Adobe website. The version of Photoshop that you have installed on your computer must be compatible with your operating system. The minimum afe. HomeAway is the world leader in vacation rentals with over 1 million listings. We offer the largest selection of properties for any travel occasion and every budget.

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Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection [ 1 ].

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Skaly horosvaz cztorrent What is Adobe Photoshop? When advanced haemodynamic monitoring is not available, alternative measures of organ perfusion may be used to evaluate the effectiveness and safety of volume administration. Palliative care meetings failed to show benefit in decreasing anxiety and depression in surrogate decision makers in the intervention group but did increase post-traumatic stress disorder PTSD symptoms. Delay in vasopressor initiation and achieving MAP of 65 is associated with increased mortality []. Dt utilities digital rescue torrent the empiric phase—before causative agent s and susceptibilities are known, the optimal choice of antibiotic therapy depends on the local prevalence of resistant organisms, patient risk factors for resistant organisms, and the severity of illness. Click one trial, all intervention participants were treated at one centre, which may have inflated the effect size because the centre specialised in ECMO management [ check this out. Substantial uncertainty as to any beneficial effect exists and the frequency of undesirable effects is reported in few trials.
Dt utilities digital rescue torrent The failure to show benefit with source control implemented go here less than 6 h may be a consequence of the limited number of patients and the heterogeneity of the intervention. Since this situation is not always apparent, continued reassessment of the patient should dt utilities digital rescue torrent the chances of infected patients receiving antimicrobial therapy and non-infected patients avoiding therapy that is not indicated. However, NIV use can be associated with development of complications including increased risk of gastric insufflation and aspiration, facial skin breakdown, excessively high tidal volumes as well as patient discomfort related to inability to eat or effectively phonate during therapy. A meta-analysis of studies including septic patients did not show a significant difference in mortality RR 0. No differential effect was observed between patients with vs without sepsis. In general, knowledge about the undesirable effects was lacking, and the quality of evidence was very low. No RCTs compared dobutamine to placebo in this population.
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