Mind the GAPS Study - Compression Stockings are Useless for Most Elective Surgery Patients!14/9/2020  Cricoid pressure prevents aspirations, preoperative antibiotics avoid infections, and compression stockings protect against deep vein thrombosis. Many medical measures aim to reduce morbidity and mortality among patients, but unfortunately, the benefit of these measures is often not, or insufficiently, proven. Under certain circumstances, they may lead to additional problems or even cause harm (e.g. cricoid pressure Read Here). Time has definitely come to take a closer look at compression stockings for surgical patients. Apart from the fact that they look terrible, they are just as uncomfortable to wear and even carry certain risks in patients with peripheral vascular disease, for example. The effectiveness of compression stockings in modern practice has been questioned, but robust evidence has been lacking. This seems to change, as the long-awaited GAPS-Trial has been published and now provides further evidence on what concern patients undergoing elective surgery.  Among this population, adding compression stockings to pharmaco-thromboprophylaxis was non-superior compared to pharmaco-thromboprophylaxis alone (primary outcome). There was also no difference in the quality of life outcomes found (secondary outcome).  There is now some robust evidence to omit compression stockings in surgical patients that receive pharmacological thromboprophylaxis. Shalhou J. et al. BMJ 2020;369:m1309
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 The W.H.O. has repeatedly warned that antibiotic resistance is one of the biggest threats to global health today. Among all measures we can take to try and reduce this problem, merely avoiding unnecessary treatments is maybe one of the most effective. It is therefore pleasing that another piece of good evidence has been published, supporting the avoidance of antibiotics in the event of non-complicated diverticulitis (defined as non-perforated diverticulitis with a Hinchey 1a grade in computed tomography). The investigators performed a randomized, placebo-controlled, double-blind trial in which they compared 180 patients with non-complicated diverticulitis to receive either cefuroxime, metronidazole, and amoxicillin/clavulanic acid or placebo. They found No significant difference in the median time of hospital stay (primary outcome). Also, there were no significant differences between groups in adverse events, readmission to the hospital within one week, and readmission to the hospital within 30 days.  These findings complement other studies indicating that observational treatment without antibiotics can be considered appropriate in patients with uncomplicated diverticulitis.  The lastest updated surviving sepsis guidelines for COVID-19 patient recommends a high-peep strategy in the intubated, mechanically ventilated patient. As most of these patients present with moderate to severe ARDS, PEEP is used to keep lung areas open and therefor to improve oxygenation. This seems to be especially true in the classical case of ARDS, where the lung become 'wet' and 'heavy' which results in widespread atelectasis of the dependent parts of the lungs, often further complicated by pleural effusions. Classical CT appearance in the acute phase of ARDS is an opacification with an antero-posterior density gradient. Dense consolidation in the most dependent regions merges into a background of widespread ground-glass attenuation and the normal or hyperexpanded lung in the non-dependent areas (Howling SJ et al. Clin Radiol 1998;53(2):105-109). The theory behind these changes is that the increased weight of overlying lung causes compression-atelectasis posteriorly. The fact that prone positioning these patients quickly redistributes these gradients supports this theory (Desai SR et al. Anaesthesiology 1991;74(1):15-23).  Classical ARDS finding in pneumococcal pneumonia Chest CT's in patients with COVID-19 often show ground-glass opacification with or without consolidations. These are changes often seen in viral pneumonia. Several case series suggest, that CT abnormalities seem to be mostly bilateral and tend to have a peripheral distribution, often involving the lower lobes. In contrast to the classical ARDS pleural thickening, pleural effusion and lymphadenopathy seem to be a less common finding (Shi H et al. Lancet Infect Dis 2020).  ARDS in COVID-19 patient The leading problem in COVID-19 patients with ARDS is hypoxemia, while hypercapnia does not seem to be a significant problem. Sometimes profound hypoxemia does not seem to correlate with patient symptoms at all. In regards to the images above, atelectasis might not be the predominant reason for V/Q mismatches in these patients. Observations of mechanically ventilated patients in our unit and other hospitals in Switzerland have shown, that higher PEEP levels (15cmH2O and higher) often result in significantly reduced compliance values complicating ventilation and favouring the development of pulmonary over-inflation. This observation might support the theory that patients with COVID do not represent the traditional manner of ARDS with distinctive atelectasis. Another observation that supports this theory is that COVID-19 patients often do not respond as clearly to Prone Positioning as classical ARDS patients do. More probably, V/Q mismatch seems so happen on a more microscopical level in COVID-Patients. Lung compliance is often normal on these patients and, therefore, applying high PEEP-levels does NOT add any benefit at all. Maybe the principle of less is more also applies to COVID-19 patients we treat (Gattinoni L et al. Intensive Care Medicine; 46, pages780–782(2020)) Looking at the New Surviving Sepsis Campain COVID-19 Guidelines: Given these considerations, the strategy with High PEEP-levels in general should be questioned in principle.  The European Society of Intensive Care Medicine ESICM and the Society of Critical Care Medicine SCCM have been very efficient in providing us health care workers with a guideline manuscript giving recommendations on the treatment of COVID-19 patients in a critical care setting. It is imperative to keep in mind that research is moving forward very quickly in these times and changes to these recommendations are likely to occur. A collection of many reliable OPEN ACCESS platforms on SARS-CoV-2 can be found on www.foam.education. Infection ControlWhen performing aerosol-generating procedures on patients with COVID-19 in the ICU, fitted respirator masks (N95 respirators, FFP2) should be used (in combination with full Personal Protective Equipement PPE) Aerosol-generating procedures on ICU patients with COVID-19 should be performed in a negative pressure room During usual care for non-ventilated and non-aerosol-generating procedures on mechanically ventilated (closed circuit) patients surgical masks are adequate For endotracheal intubation video-guided laryngoscopy should be used, if available In intubated and mechanically ventilated patients, endotracheal aspirates should be used for diagnostic testing Supportive CareIn COVID-19 patients with shock, dynamic parameters like skin temperature, capillary refilling time, and/or serum lactate measurement should be used in order to assess fluid responsiveness For the acute resuscitation of adults with COVID-19, a conservative over a liberal fluid strategy is recommended For the acute resuscitation of adults cristalloids should be used - avoid colloids! Buffered/balanced crystalloids should be used over unbalanced crystalloids Do NOT use hydroxyethyl starches! Do NOT use gelatins! Do NOT use dextrans! Avoid the routine use of albumin for initial resuscitation! In shock use norepinephrine/ noradrenaline as the first-line vasoactive agent The use of dopamine is NOT recommended Add vasopressin, if target MAP cannot be reached Titrate vasoactive agents to target a MAP of 60-65 mmHg, rather than higher MAP targets For patients in shock and with evidence of cardiac dysfunction and persistent hypoperfusion despite fluid resuscitation and norepinephrine, adding dobutamine should be used For persistent shock despite all these measures, low-dose corticosteroids should be tried Ventilatory SupportKeep peripheral saturation SpO2 above 90% with supplemental oxygen
There is NO need for supplemental oxygen with SpO2 above 96% In acute hypoxemic respiratory failure despite conventional oxygen therapy, high-flow nasal cannulas (HFNC or High-Flow) should be used next High-Flow should be used over non-invasive ventilation (NIV) If High-Flow is not available and there is no urgent need for endotracheal intubation, NIV with close monitoring can be tried In the event of worsening respiratory status, early endotracheal intubation should be performed In mechanically ventilated patients, low-tidal volume ventilation should be used: 4 to 8 ml/kg In mechanically ventilated patients with ARDS targeting plateau pressures (Pplat) of < 30 cm H2O should be aimed for In patients with moderate to severe ARDS, a high-PEEP strategy should be used (PEEP >10cmH2O). Patients have to be monitored for potential barotrauma NOTE by Crit.Cloud: The strategy for high PEEP levels in general is currently discussed controversially. Observations in our own unit showed, that high PEEP levels tend to impaire compliance and therefor the quality of ventilation. Read also: "Less is More" in mechanical ventilatio, Gattinoni L. et al. Intensive Care Med (2020) 46:780-782 Patients with ARDS should receive a conservative/restrictive fluid strategy In moderate to severe ARDS, prone positioning for 12-16 hours is recommended To facilitate lung protective ventilation in moderate to severe ARDS, intermittent boluses of neuromuscular blocking agents (NMBA) should be used first In the event of persistent ventilator dyssynchrony, the need for ongoing deep sedation, prone ventilation, or persistently high plateau pressures, a continuous NMBA infusion for up to 48 hours should be used next Do NOT use inhaled nitric oxide in COVID-19 patients with ARDS routinely In severe ARDS and hypoxemia despite optimising ventilation and other rescue strategies, a trial of inhaled pulmonary vasodilator as a rescue therapy can be considered; if no rapid improvement in oxygenation is observed, the treatment should be tapered off If hypoxemia persists despite optimising ventilation, recruitment manoeuvres should be applied If recruitment manoeuvres are used, DO NOT use staircase (incremental PEEP) recruitment manoeuvres If all these measures fail, the patient should be considered for venovenous ECMO COVID-19 TherapyIn mechanically ventilated patients WITHOUT ARDS, systemic corticosteroids should NOT be used routinely In contrast, mechanically ventilated patients WITH ARDS, the use of systemic corticosteroids is recommended Mechanically ventilated patients with respiratory failure should be treated with empiric antimicrobials/antibacterial agents Critically ill patients with fever should be treated with paracetamol (acetominophen) for temperature control In critically ill patients standard intravenous immunoglobulins (IVIG) should NOT be used routinely Also, the routine use of convalescent plasma is NOT recommended The routine use of lopinavir/ritonavir (Kaletra®) is NOT recommended Currently, there is insufficient evidence to issue a recommendation on the use of other antiviral agents in critically ill adults with COVID-19 Currently, there is insufficient evidence to issue a recommendation on the use of recombinant interferons (rIFNs); chloroquine or hydroxychloroquine; tocilizumab (humanised immunoglobulin)    The Aerosol-Danger of SARS-Cov-2The outbreak of the SARS Coronavirus-2 (SARS-CoV-2) in China 2019 has within a short time spread around the globe and is just about to hit central Europe. Although about 80% of all confirmed cases develop a mild febrile illness, around 17% develop severe Corona viral disease (COVID-19) with findings of acute respiratory distress syndrome (ARDS), of which about 4% will require mechanical ventilation. Since this virus, which was previously unknown to humans, spread rapidly around the globe, a large number of patients requiring intensive medical care now arise within a very short time. The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme ACE2, which is most abundant in type II alveolar cells of the lungs. This results in mainly type 1 respiratory failure, which often requires urgent tracheal intubation and mechanical ventilation. Due to viral shedding in the patient's lungs, COVID-19 spread mainly via droplets. Events like coughing, high flow nasal oxygen (High-Flow), intubation and more can cause aerosol generation, allowing these airborne particles to travel even further distances. Performing endotracheal intubation in these patients is, therefore, a high-risk procedure, and it is required to adhere to certain principles to avoid infection of health care providers. The Safe Airway Societies of Australia and New Zealand have published a consensus statement that describes the problem very well and provides practical tips based on the currently available evidence. 1. Non Invasive Ventilation (NIV) and High Flow Nasal Oxygen (High-Flow)Current evidence suggests that the failure rate of NIV in COVID-19 patients seems to be similarly high as observed among Influenza A patients. Failure in these patients resulted in higher mortality. In general, NIV is recommended to be avoided or at least used very cautiously! The utility of High-Flow in viral pandemics in unknown. There is some evidence suggesting a decreased need for tracheal intubation compared to conventional oxygen therapy. High Flow Nasal Oxygen is worth a try, although it has to be assumed, that this is aerosol-generating. High-Flow should only be used in (negative pressure) airborne isolation rooms, and staff should wear full personal protective equipment (PPE) including N95/P2 masks. NIV and High-Flow are NOT recommended for patients with severe respiratory failure or when it seems clear that invasive ventilation is inevitable!  Full Personal Protective Equipment PPE
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Patients who have survived critical illness are at increased risk for long term morbidity and mortality. Maybe we tend to forget this fact, as we lose sight of these patients when they leave our unit. But this is especially true for ICU patients aged 65 and older!
There have been clues that influenza vaccination might reduce morbidity after surviving critical illness and Christiansen et al. have looked exactly into this topic.
The investigators examined whether an influenza vaccination (flu shot) affects the 1-year risk of myocardial infarction, stroke, heart failure, pneumonia, and death among ICU survivors aged 65 and older.
There have been clues that influenza vaccination might reduce morbidity after surviving critical illness and Christiansen et al. have looked exactly into this topic.
The investigators examined whether an influenza vaccination (flu shot) affects the 1-year risk of myocardial infarction, stroke, heart failure, pneumonia, and death among ICU survivors aged 65 and older.
The investigators
Performed a nationwide population-based cohort study
They used the Danish Intensive Care Database
To evaluate a total 89'818 ICU survivors from 2005 until 2015
It is noteworthy that
Influenza vaccinated patients (these were 39% of all) were older, had more chronic diseases and used more prescription medications!
Their findings show that
1. Influenza vaccinated patients showed an 8% decreased risk of death and a 16% reduced risk of hospitalisation for stroke within one year
2. Cardiac surgery patients were the subgroup that profited most
3. Unfortunately, no significant association was found for the risk of hospitalisation for myocardial infarction, heart failure or pneumonia.
Performed a nationwide population-based cohort study
They used the Danish Intensive Care Database
To evaluate a total 89'818 ICU survivors from 2005 until 2015
It is noteworthy that
Influenza vaccinated patients (these were 39% of all) were older, had more chronic diseases and used more prescription medications!
Their findings show that
1. Influenza vaccinated patients showed an 8% decreased risk of death and a 16% reduced risk of hospitalisation for stroke within one year
2. Cardiac surgery patients were the subgroup that profited most
3. Unfortunately, no significant association was found for the risk of hospitalisation for myocardial infarction, heart failure or pneumonia.
The flu shot saves lives! This is another strong hint, that the influenza vaccination is clearly of benefit to all adults aged 65 and older. This is especially true for ICU survivors!
Christiansen at al. Intensive Care Med 2019 Jul;45(7):957-967.
Also worth mentioning:
Not only influenza A but also Influenza B infection can pose a risk for severe secondary infection in previously healthy and younger persons.
Aebi et al. BMC Infect Dis 2010 Oct 27;10:308.
When the FDA approved dexmedetomidine (DEX) in 1999, intensive care medicine had a novel and highly promising drug at its disposal. Compared to clonidine, dexmedetomidine is an 8 times more selective, central alpha 2 agonist, which binds to all 3 subtypes of the receptor. The properties of this substance were auspicious, among them: sedation, analgesia, neuroprotective effects and a lack of respiratory depression.
- Sedation decreases sympathetic activity, aggression and leads to a non-REM-like state, which of all sedatives comes closest to natural sleep. Cognitive functions are maintained, and patients usually remain arousable.
- Dexmedetomidine has a particular analgesic effect via modulation in the region of the posterior horn of the spinal cord. This has shown to reduce the use of opiates.
- By reducing cerebral catecholamines, dexmedetomidine exerts a neuroprotective effect.
- Interestingly, sedation with dexmedetomidine is not associated with significant respiratory depression.
These properties pointed to a wide range of applications in the intensive care unit:
- Sedation in patients with non-invasive ventilation
- Weaning of invasively ventilated patients
- Agitated delirium
- Treatment of various withdrawal syndromes
- Fiberoptic awake intubation in theatre conditions
Dexmedetomidine comes with its side effects, though. Most commonly bradycardia and hypotension are observed, making second and third-degree heart block a contraindication. Also, nausea and a dry mouth might be seen.
Interestingly, prolonged use might be associated with some extent of discontinuation syndrome similar to clonidine. This involves hypertension, tachycardia, nervousness etc.
- Sedation decreases sympathetic activity, aggression and leads to a non-REM-like state, which of all sedatives comes closest to natural sleep. Cognitive functions are maintained, and patients usually remain arousable.
- Dexmedetomidine has a particular analgesic effect via modulation in the region of the posterior horn of the spinal cord. This has shown to reduce the use of opiates.
- By reducing cerebral catecholamines, dexmedetomidine exerts a neuroprotective effect.
- Interestingly, sedation with dexmedetomidine is not associated with significant respiratory depression.
These properties pointed to a wide range of applications in the intensive care unit:
- Sedation in patients with non-invasive ventilation
- Weaning of invasively ventilated patients
- Agitated delirium
- Treatment of various withdrawal syndromes
- Fiberoptic awake intubation in theatre conditions
Dexmedetomidine comes with its side effects, though. Most commonly bradycardia and hypotension are observed, making second and third-degree heart block a contraindication. Also, nausea and a dry mouth might be seen.
Interestingly, prolonged use might be associated with some extent of discontinuation syndrome similar to clonidine. This involves hypertension, tachycardia, nervousness etc.
What Evidence Do We Have So Far?
Current data indicate that dexmedetomidine, compared to benzodiazepines:
- Might reduce the duration of sedation in mechanically ventilated patients, JAMA. 2007 Dec 12;298(22):2644-53.
- Might improve performance in patients with sepsis in regards to delirium, coma-free days and maybe even survival, Crit Care. 2010;14(2):R38. PMC2887145.
- Seems to reduce delirium in ICU and the need for mechanical ventilation in critically ill patients, JAMA. 2009 Feb 4;301(5):489-99.
- Seems to allow earlier extubation in mechanically ventilated patients and makes them more alert to communicate pain, and
- Compared to propofol, dexmedetomidine was comparable in terms of duration of mechanical ventilation, length of stay in ICU and hospital and also the incidence of hypotension and bradycardia. JAMA. 2012 Mar 21;307(11):1151-60.
- Some further evidence indicates that dexmedetomidine might be helpful in the treatment of mechanically ventilated patients with agitated delirium, resulting in more ventilator-free days. JAMA. 2016 Apr 12;315(14):1460-8.
According to all this, the question arises, whether we should use dexmedetomidine early in ventilated, critically ill patients.
- Might reduce the duration of sedation in mechanically ventilated patients, JAMA. 2007 Dec 12;298(22):2644-53.
- Might improve performance in patients with sepsis in regards to delirium, coma-free days and maybe even survival, Crit Care. 2010;14(2):R38. PMC2887145.
- Seems to reduce delirium in ICU and the need for mechanical ventilation in critically ill patients, JAMA. 2009 Feb 4;301(5):489-99.
- Seems to allow earlier extubation in mechanically ventilated patients and makes them more alert to communicate pain, and
- Compared to propofol, dexmedetomidine was comparable in terms of duration of mechanical ventilation, length of stay in ICU and hospital and also the incidence of hypotension and bradycardia. JAMA. 2012 Mar 21;307(11):1151-60.
- Some further evidence indicates that dexmedetomidine might be helpful in the treatment of mechanically ventilated patients with agitated delirium, resulting in more ventilator-free days. JAMA. 2016 Apr 12;315(14):1460-8.
According to all this, the question arises, whether we should use dexmedetomidine early in ventilated, critically ill patients.
The SPICE III Trial |  |
Precisely this question was now addressed by Shehabi et al., published in the NEJM
They performed an
International (8 countries, 74 ICU's), randomised controlled, unblinded trial
In which they evaluated
4000 ICU patients that were expected to need mechanical ventilation for at least 48 hours and required sedation for safety or comfort
They compared
Patients sedated with propofol, midazolam or other agents as prescribed by the treating physician with patients receiving dexmedetomidine as a continuous infusion
(if DEX alone was insufficient, other agents could be added! In fact, 64% of patients also received propofol, 3% midazolam and 7% received both)
They found
1. No difference in 90-day mortality (primary outcome) and
2. No difference in death after 180 days, institutional dependency at 180 days, mean cognitive decline and assessment of the quality of life. Also no difference in median days free from coma to day 28 and median ventilator-free days at day 28 (all secondary outcomes)
3. Dexmedetomidine was though associated with significantly more events of bradycardia, hypotension (no further info on the use of vasopressors) and asystoles (14 vs 2; 7 required mechanical resuscitation measures)
- DEX is an attractive sedative in certain situations (alcohol withdrawal, other forms of delirium, weaning process etc.), BUT
- DEX doesn't seem to provide any advantage in the sedation of mechanically ventilated patients in the ICU and
- Might be problematic due to adverse cardiovascular effects, especially in this group of patients
Shehabe et al. N Engl J Med 2019; 380:2506-2517
Did you Know?
Apparently, intranasal dexmedetomidine seems used successfully for sedation in adults and children. J Clin Neurophysiol. 2019 May 16.
Acute decompensated heart failure comes in many ways as remains a challenge for optimal treatment since various conditions can cause it, e.g. advanced chronic heart failure, cardiogenic- and septic-shock, cardiac- and non-cardiac surgery, etc. Among many other interventions, the infusion of positive inotropes is often used on one side and vasodilators on the other side to stabilize the situation and improve cardiac function. Despite all these measures, the re-admission rate and mortality remain a significant problem among these patients.
While Levosimendan is still under investigation in the U.S., it is used worldwide for the short-term treatment of acutely decompensated severe chronic heart failure, especially when other treatment options have failed. Some recommend the usage of this drug in a different setting like sepsis-related heart failure or coronary heart disease.
How does Levosimendan work?
Levosimendan has some remarkable properties, which are mainly caused by three mechanisms:
1. Enhancement of the calcium sensitivity of the myofilament by binding to troponin C.
2. Opening of adenosine triphosphate-sensitive potassium (KATP) channels in vasculature smooth muscle.
3. Opening of mitochondrial KATP channels.
These mechanisms result in a positive inotropy of the heart, an increase in stroke volume (SV) and therefore, cardiac output (CO). Besides, it's vasodilatory properties seems beneficial for coronary perfusion and reduce pulmonary capillary wedge pressure (PCWP).
All these effects do not appear to induce an unfavourable energy balance in the myocardial cell, and also the oxygen demand is not increased.
ScienceDirect.com
So what's the Evidence?
The Small Bits and Pieces
First publications back in the 90ies and early 2000s were indicative for the properties of levosimendan. Three studies were randomized and double-blinded but very low in patient numbers and therefore not powered enough to provide substantial evidence. Their statements were also not concerning patient outcome or mortality, but its results confirmed that levosimendan enhances cardiac output without oxygen wasting, is well tolerated and leads to favorable hemodynamic effects.
Lilleberg et al. Eur Heart J. 1998;19:660–668.
Ukkonen et al. Clin Pharmacol Ther. 2000;68:522–531.
Nieminen et al. J Am Coll Cardiol. 2000;36:1903–1912.
In 2003 Kivikko et al. published further data from another small trial indication that its beneficial effects (decreases in left and right heart filling pressures and in SVR, as well as increases in stroke volume and cardiac index) are maintained for at least 24 hours after discontinuation of a 24-hour infusion. At this point, it is worth mentioning that the author published these findings as a current employee of Orion Pharma, which manufactures levosimendan.
Kivikko et al. Circulation. 2003;107:81–86.
Further data indicated that its effect might be sustained for up to at least a week, although also this study included only 22 patients!
8. Lilleberg et al. Eur J Heart Fail. 2007;9:75–82.
A Lancet publication in 2002 by Follath et al. presented a multicentre, randomized, double-blind trial in which they compared the effect of levosimendan to dobutamine in patients that were admitted to a hospital with low-output heart failure and were judged to require hemodynamic monitoring and treatment with an intravenous inotropic agent. In these 203 patients, levosimendan had a consistently better effect than dobutamine on the individual hemodynamic variables at the end of the 24 h treatment period (cardiac output and pulmonary capillary wedge pressure). The change in clinical symptoms like fatigue and dyspnoea were not significantly different, though.
Interestingly, for the first time, the levosimendan group showed lower mortality than in the dobutamine group for up to 180 days. However, it's important to mention its absence of placebo control and its rather small sample size.
Follath et al. Lancet. 2002;360:196–202.
The Big Lumps
The SURVIVE Study
In the SURVIVE study Mebazaa et al. compared the efficacy and safety of intravenous levosimendan or dobutamine in patients hospitalized with acute decompensated heart failure who required inotropic support.
They performed a
randomized, double-blind trial at 75 centers in 9 countries
in which they evaluated
1327 patients hospitalized with acute decompensated heart failure who required inotropic support
They found that
the addition of levosimendan to standard therapy resulted in fewer deaths compared with dobutamine, especially in the first few weeks after treatment
but
Levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes
randomized, double-blind trial at 75 centers in 9 countries
in which they evaluated
1327 patients hospitalized with acute decompensated heart failure who required inotropic support
They found that
the addition of levosimendan to standard therapy resulted in fewer deaths compared with dobutamine, especially in the first few weeks after treatment
but
Levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes
The REVIVE Studies - Heart Failure
In the Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy studies (REVIVE I and REVIVE II) the efficacy of levosimendan on symptoms of heart failure during five days after starting a 24h trial drug infusion was assessed.
Each patient's clinical course over 5 days was determined by a composite of the patient's self-assessment of symptoms together with a physician's assessment of the occurrence of clinical deterioration.
The primary endpoint of the study was a new clinical composite endpoint (improvement, unchanged or worse - including death) derived from studies in chronic heart failure and first evaluated in 100 ADHF patients in the REVIVE I pilot study.
In REVIVE II the investigators performed one of the
first large, prospective, randomized, double-blind, controlled trials
in which they evaluated
600 patients admitted at 103 sites in the United States, Australia, and Israel
with
worsening heart failure and dyspnea at rest despite treatment with intravenous diuretics, and left ventricular ejection fraction of < 35% measured within the last year
whereas
patients were randomized to either receive levosimendan for 24h or standard treatment alone
They found that after 5 days
- more patients receiving levosimendan experienced improvement compared with those who were on placebo (19.4% vs 14.6%, respectively, a 33% relative increase; P = .015)
- fewer patients receiving levosimendan worsened compared with patients who were on placebo (19.4% vs 27.2%, respectively), a 29% relative decrease, and
- fewer patients receiving levosimendan required rescue therapy (15.1%) vs placebo (26.2%), a 42% relative decrease.
Among other secondary endpoints, levosimendan improved
B-type natriuretic peptide (BNP) levels, length of hospital stay and dyspnoea at 6 hours
But
mortality at 90 days did not differ significantly between treatment arms (a secondary endpoint) and
the most common treatment-emergent cardiovascular adverse events were more frequent with levosimendan, including hypotension (50% vs 36%), ventricular tachycardia (25% vs 17%), and atrial fibrillation (8% vs 2%).
first large, prospective, randomized, double-blind, controlled trials
in which they evaluated
600 patients admitted at 103 sites in the United States, Australia, and Israel
with
worsening heart failure and dyspnea at rest despite treatment with intravenous diuretics, and left ventricular ejection fraction of < 35% measured within the last year
whereas
patients were randomized to either receive levosimendan for 24h or standard treatment alone
They found that after 5 days
- more patients receiving levosimendan experienced improvement compared with those who were on placebo (19.4% vs 14.6%, respectively, a 33% relative increase; P = .015)
- fewer patients receiving levosimendan worsened compared with patients who were on placebo (19.4% vs 27.2%, respectively), a 29% relative decrease, and
- fewer patients receiving levosimendan required rescue therapy (15.1%) vs placebo (26.2%), a 42% relative decrease.
Among other secondary endpoints, levosimendan improved
B-type natriuretic peptide (BNP) levels, length of hospital stay and dyspnoea at 6 hours
But
mortality at 90 days did not differ significantly between treatment arms (a secondary endpoint) and
the most common treatment-emergent cardiovascular adverse events were more frequent with levosimendan, including hypotension (50% vs 36%), ventricular tachycardia (25% vs 17%), and atrial fibrillation (8% vs 2%).
The LeoPARDS-Trial - Sepsis
In this study investigators wanted to know whether in adult patients who have sepsis the application of levosimendan reduces the incidence and severity of acute organ dysfunction compared with placebo.
In this study investigators wanted to know whether in adult patients who have sepsis the application of levosimendan reduces the incidence and severity of acute organ dysfunction compared with placebo.
They performed a
Randomised, double-blind, placebo-controlled multi-centre trial in 34 general ICUs in the UK
in which they evaluated
516 patients with suspected or confirmed infection and 2 or more SIRS criteria who were dependent on vasopressors for at least four hours to maintain their blood pressure.
They compared
the intravenous infusion of levosimendan or placebo for 24 hours in addition to standard care
and found:
- No significant difference in the daily Sequential Organ Failure Assessment (SOFA) score up to day 28 (primary outcome)
- No statistical difference on death at 28 days, at ICU discharge and hospital discharge (secondary outcome)
- And: The use of levosimendan was associated with more hemodynamic instability, lower mean arterial pressures, therefore more need for noradrenalin at 24h and significantly more supraventricular tachyarrhythmias (all secondary outcomes).
Randomised, double-blind, placebo-controlled multi-centre trial in 34 general ICUs in the UK
in which they evaluated
516 patients with suspected or confirmed infection and 2 or more SIRS criteria who were dependent on vasopressors for at least four hours to maintain their blood pressure.
They compared
the intravenous infusion of levosimendan or placebo for 24 hours in addition to standard care
and found:
- No significant difference in the daily Sequential Organ Failure Assessment (SOFA) score up to day 28 (primary outcome)
- No statistical difference on death at 28 days, at ICU discharge and hospital discharge (secondary outcome)
- And: The use of levosimendan was associated with more hemodynamic instability, lower mean arterial pressures, therefore more need for noradrenalin at 24h and significantly more supraventricular tachyarrhythmias (all secondary outcomes).
The CHEETAH Trial - Cardiac Surgery
The question in CHEETAH was if levosimendan compared to placebo reduces mortality in patients undergoing cardiac surgery with left ventricular dysfunktion.
This time Landoni et al. performed a
Multi-centre, randomised, placebo-controlledand parallel group designed trial
in which they evaluated
506 patients scheduled for cardiac surgery with peri-operative cardiovascular dysfunction
defined as
pre-operative left ventricular ejection fraction (LVEF) < 25%, pre-operative intra-aortic balloon pump (IABP), intra- or post-operative (within 24 hours) IABP or significant inotropic requirement
They compared
Levosimendan infusion continued for up to 48 hours (or until ICU discharge) or placebo
and found
No difference in mortality at thirty 30 days (primary outcome)
And no difference in survival over time, renal replacement therapy, the median duration of mechanical ventilation, the median hospital stay and interruptions due to adverse events (all secondary outcomes).
Any Other Clues?
In contrast to these clinically somewhat discouraging results Shang et al. have published a meta-analysis in 2017 of randomized controlled trials looking at the usage of levosimendan in patients with heart failure, cardiogenic shock and acute coronary syndrome.
They ended up looking at a total of nine studies, most of them low in patient numbers and comparing levosimendan to either placebo or other drugs (dobutamine and enoximone).
In contrast to these clinically somewhat discouraging results Shang et al. have published a meta-analysis in 2017 of randomized controlled trials looking at the usage of levosimendan in patients with heart failure, cardiogenic shock and acute coronary syndrome.
They ended up looking at a total of nine studies, most of them low in patient numbers and comparing levosimendan to either placebo or other drugs (dobutamine and enoximone).
According to these data the authors conclude that levosimendan is associated with reduced total mortality, decreased incidence of worsening HF, and improved hemodynamic outcomes and does not increase the risk of adverse events except for hypotension in patients with HF (including CS) complicating ACS. Thus, levosimendan should be recommended for routine clinical application in these patients.
Am J Cardiovasc Drugs 2017 Dec;17(6):453-463.
According to current evidence
- Levosimendan has interesting mechanisms of action and successfully seems to enhance cardiac output without additional oxygen wasting. This includes decreased right and left ventricular filling pressures, decreased SVR, as well as increases in stroke volume and cardiac index. Also, PCWP is decreased.
- In terms of various patient groups, patients with acute heart failure or acute on chronic heart failure appear to benefit in terms of clinical symptoms, if at all.
- Unfortunately, there is no convincing clinical evidence that levosimendan has any benefit in long term outcomes in terms of mortality.
- And, levosimendan seems to be associated with some potential treatment-emergent cardiovascular adverse events like hypotension, supraventricular and ventricular arrhythmia.
Acute myocardial infarction - It's pain radiating to the right arm we have to worry about!
15/3/2019
It was only back in in 1987 when William Heberdeen (not to confound with William Heberdeen, a London doctor who described the Heberdeen nodes back in the 18th century) published the first description of ischemic chest pain. It was the birth of the classical image of strangling chest pain that occasionally radiates to the left arm, associated with exertion and relieved by rest.
A recent publication in the BMJ shows, that positive troponin levels are found frequently in patients with non-cardiac problems. This finding underlines the importance of good history taking, including the assessment of chest pain (CP) characteristics.
A recent publication in the BMJ shows, that positive troponin levels are found frequently in patients with non-cardiac problems. This finding underlines the importance of good history taking, including the assessment of chest pain (CP) characteristics.
Circulation. 2018;138:e618–e651. (Click image for link to article)
The TRAPID-AMI Study
McCord J et al. have taken a closer look at chest pain and associated symptoms and their association with the diagnosis of acute myocardial infarction. They also analysed these symptoms in relation to the size of the AMI.
They performed an
international, multicenter diagnostic study
in which they evaluated
1282 patients admitted for possible AMI to emergency departments in Europe, the US and Australia
The outcome was
the correlation of symptoms with the diagnosis of AMI and its relation to myocardial infarction size
They found that
1. only 4 symptoms were independently predictive of AMI
- Radiation to the right arm/ shoulder (OR 3.0, CI 1.8-5.0)
- Chest pressure (OR 2.5, CI 1.3-4.6)
- CP worsened by physical activity (OR 1.7, CI 1.2-2.5)
- Radiation to left arm/ shoulder (OR 1.7, CI 1.1-2.4)
2. Patients with more than 1 of the 4 symptoms were more likely to have AMI
- For patients who had all 4 symptoms, 55% had a diagnosis of AMI
3. Patients with larger AMI's were more likely to have
- pulling CP
- pain in the right upper chest (right supramammillary area)
- and right arm/shoulder radiation
They performed an
international, multicenter diagnostic study
in which they evaluated
1282 patients admitted for possible AMI to emergency departments in Europe, the US and Australia
The outcome was
the correlation of symptoms with the diagnosis of AMI and its relation to myocardial infarction size
They found that
1. only 4 symptoms were independently predictive of AMI
- Radiation to the right arm/ shoulder (OR 3.0, CI 1.8-5.0)
- Chest pressure (OR 2.5, CI 1.3-4.6)
- CP worsened by physical activity (OR 1.7, CI 1.2-2.5)
- Radiation to left arm/ shoulder (OR 1.7, CI 1.1-2.4)
2. Patients with more than 1 of the 4 symptoms were more likely to have AMI
- For patients who had all 4 symptoms, 55% had a diagnosis of AMI
3. Patients with larger AMI's were more likely to have
- pulling CP
- pain in the right upper chest (right supramammillary area)
- and right arm/shoulder radiation
- It's time to get rid of the classical image of CP radiating only into the left arm. While this might still be the predominant complaint at presentation, it's the right sided shoulder/ arm pain we should keep a close eye on!
- Chest pain radiating to the right shoulder/ arm is more predicitive of myocardial infarction than left sided chest pain
- And remember: a positive Troponin alone does not fullfill the diagnostic criteria of AMI!
Crit Pathw Cardiol. 2019 Mar;18(1):10-15.
Top Ten Websites in Critical Care Medicine Education
The Journal of Intensive Care Medicine has recently published a review of websites providing educational content that is part of the Free Open Access Meducation (FOAMed) movement. The authors have searched the web for critical care medicine education websites and have identified 97 sites they consider relevant for critical care.
These websites were then reviewed and evaluated using the Critical Care Medical Education Website Quality Evaluation Tool (CCMEWQET). They were then split up into three tertiles according to their score.
Congratulations to the Top Ten websites that indeed provide excellent educational information freely accessible.
Oh, and by the way we might mention that our small site Crit.Cloud has been considered among 96 other as relavant in this field and has ended up in the middle tertile with its ranking. 🙃
A big thank you to the authors of this paper for their excellent work and for providing us with an updated list of websites worth taking a closer look! We are delighted to follow their wish by sharing the table of these websites.
Wolbrink TA et al. J Intensive Care Med. 2018 Jan;34(1):3-16
Full List of all Website Reviewed (Click on a table enlarge)
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