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When it comes to commonly used painkillers, there are so many different types and categories that it can be quite tricky to get a clear overview. But did you actually realise? All commonly used painkillers work by the same way: Inhibition of Cyclooxygenase - or short COX! This isn’t just true for the well-known non-steroidal anti-inflammatory drugs (NSAIDs), but also for medications like metamizole and paracetamol. So, the term “NSAIDs” is actually outdated and misleading — COX-inhibitors would be a much more accurate way to describe them as a common group of medications! The term “non-steroidal analgesics” also suggests that steroids are analgesics — which is not correct either! Cyclooxygenase inhibitors (COX inhibitors) are medications that reduce inflammation, alleviate pain, and lower fever. They are widely used in conditions such as arthritis, injuries, infections, and other inflammatory diseases. The way these drugs influence COX though is different and therefore is their mode of action.
There are 3 kinds of COX inhibitors: Non-Selective COX inhibitors: (e.g. ibuprofen and naproxen) inhibit both COX 1 and COX2. They are effective but can irritate the gastrointestinal tract. Selective COX-2 inhibitors: (e.g. etoricoxib, celecoxib) primarily inhibit COX-2 and are designed to avoid stomach-related side effects. Central COX inhibitors: Other agents like paracetamol and metamizole act through central COX inhibition and are safer for many patients but lack anti-inflammatory properties.  All COX inhibitors offer pain and fever reduction. However, anti-inflammatory effects are only seen with COX-2 inhibition. Platelet inhibition, important for cardiovascular protection, is achieved through COX-1 inhibition (e.g., aspirin). The selective inhibition of COX-2 alone is sufficient to achieve maximum analgesic and anti-inflammatory effects. Recognising the fact that COX-2 inhibition is sufficient for therapeutic effects, while COX-1 inhibition causes many side effects, led to the development of selective COX-2 inhibitors - so called Coxibs. Although COX-2 selectivity is beneficial, concurrent COX-1 inhibition (e.g., with aspirin) may reduce cardiovascular risk. Selectivity is based on a small structural difference between COX-1 and COX-2 (isoleucine vs. valine at position 523). All Coxibs inhibit COX-2 in the central nervous system as well. Benefits of Coxibs:
Even with all their advantages, COX-2 inhibitors (Coxibs) haven’t completely taken over the NSAID world—and there are some good reasons: Coxibs are a valuable option—especially for patients at high GI risk—but they haven’t replaced non-selective NSAIDs because of: Let's have a closer look at the most common COX-inhibitors used. DiclofenacDiclofenac is a fast-acting, potent non-selective COX inhibitor with slight COX-2 preference (non-selective) and serves as a reference drug for comparing other COX inhibitors. It achieves maximum analgesia through COX-2 inhibition, penetrates inflamed tissue and the CNS well, and has enhanced tissue targeting due to its acidic pKa and plasma protein binding. However, its clinical use is limited by variable absorption, a short half-life (2–4 h), and gastrointestinal and hepatic side effects. High dosing (e.g., 2×75 mg/day) is common but may cause unnecessary adverse effects, including GI erosion and rare severe hepatotoxicity. In general, erosions of the gastric mucosa can be expected after just a few days of use. Protective measures such as proton pump inhibitors or misoprostol cannot prevent direct damage to the mucosal lining. Hepatotoxicity or nephrotoxicity caused by diclofenac is independent of gastric protection. IbuprofenIbuprofen, an arylpropionic acid derivative and preferential COX-1 inhibitor (non-selective), is generally well tolerated, especially at low doses (200–400 mg). At standard daily doses (600–1200 mg), it causes fewer GI side effects than high-dose diclofenac, but at high doses (3×800 mg), its side effect profile (GI and cardiovascular risks) is similar to diclofenac or etoricoxib.
IndometacinIndometacin is a potent COX-1 inhibitor (non-selective) with good penetration into inflamed tissue and the nervous system. It is mainly used for ankylosing spondylitis, acute gout attacks, and prevention of heterotopic ossification. In obstetrics, it is used to close a patent ductus arteriosus in newborns. Its use is limited by frequent GI and central nervous system side effects, such as headache and dizziness. KetoloracKetorolac, a preferential COX-1 inhibitor (non-selective) is often used as eye drops, but in many countries, it is an important intravenous alternative to morphine for treating postoperative pain. It relieves pain up to six hours and is generally well tolerated. There is an association though with a risk of GI-bleeding and renal failure. By the way: It is an isomer of ibuprofen and structurally related to indometacin. NaproxenNaproxen, also a preferential COX-1 inhibitor (non-selective), is widely used in the U.S. but less so in Europe. Due to its long half-life (12–15 hours) and strong COX-1 affinity, it significantly inhibits platelet aggregation, increasing the risk of gastrointestinal bleeding and interactions with anticoagulants. However, this effect also contributes to its lower cardiovascular risk compared to other COX inhibitors. Acetylsalicylic Acid - AspirinAspirin holds a unique position among COX inhibitors. Developed by Felix Hoffmann, the acetylation of salicylic acid improved its tolerability and broadened its effects. At low doses (50–100 mg/day), aspirin irreversibly inhibits COX-1in platelets, preventing aggregation and offering cardioprotection. This effect persists for several days due to the lack of nucleus in platelets. At higher doses (2–3 g/day), aspirin also inhibits COX-2, producing anti-inflammatory and analgesic effects, but significantly increases gastrointestinal side effects due to its acidic nature (pKa 3.0). Notably, aspirin also inhibits NFκB, iNOS, and COX-2 expression—effects that go beyond enzymatic COX inhibition. Pharmacokinetically, the irreversible COX inhibition means aspirin’s duration of action is not tied to plasma levels. The half-life of salicylic acid increases with dose due to enzyme saturation. Indications:
325 mg tablets, common in the U.S., are considered unnecessarily high for cardiovascular prevention. ParacetamolParacetamol (acetaminophen) is widely used as a first-choice analgesic and antipyretic for mild to moderate pain, especially in children, pregnant women, and the elderly, due to its low side-effect profile. Did you know: The IV form (Perfalgan®)offers the most effective analgesia! Despite recurring concerns about safety, especially in high doses or misuse, paracetamol remains one of the safest options when used correctly--no COX inhibitor matches its safety at equal analgesic doses. Mechanism of Action:
Paracetamol has NO Anti-inflammatory Effect! Though it inhibits COX-2, paracetamol has no anti-inflammatory effect. This is because it can’t reduce the high peroxide levels in inflammatory cells needed to block PGH2 synthesis effectively. MetamizoleMetamizole (also known as dipyrone) is a potent analgesic, antipyretic, and spasmolytic drug used for severe pain, including tumor pain, high fever, and biliary or urinary colic. It's a prodrug and rapidly converted to 4-MAA, a reversible, non-selective COX-1/COX-2 inhibitor with central nervous activity. Its COX inhibition is comparable to diclofenac or ibuprofen and likely explains its strong analgesic effect. However, it does not reduce inflammation, and unlike other COX inhibitors. Metamizole:
This lack of typical COX-inhibitor side effects may be due to biochemical antagonism of anti-inflammatory pathways. At high doses, metamizole opens potassium channels and reduces calcium influx in smooth muscles, relieving colic pain but also contributing to blood pressure drops. Despite its clinical usefulness, long-term safety data is limited, especially regarding rare but serious side effects like agranulocytosis. Conclusion
Want to get more insight into this topic, read this excellent article on COX-inhibitors (Original in German): 
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 The treatment and management options of COVID-19 patient are rapidly evolving. The amount of research published daily is endless so that keeping an overview seems almost impossible. This short review of current publications is intended to overview current treatment options and its evidence. We will look at: - How do you Identify and Triage Patients at Risk for Severe Disease? - What about High Flow Nasal Cannulas (HFNC) and Non-Invasive Ventilation (NIV)? - Should we Prone Position the Spontaneously Breathing Patient? - When to Use Corticosteroids? - Should we Use Remdesivir? - What about Convalescent Plasma? - How do we Manage Thromboprophylaxis? How do you Identify and Triage Patients at Risk for Severe Disease? In an ideal world, we would be able to assess newly admitted patients with COVID-19 to predict the risk of getting critically ill in the course of the disease. Apart from a proper clinical assessment, JAMA published the COVID-GRAM Risk Score to address this problem. They used a cohort of 1590 patients to develop this score and validated this with a cohort of 710 patients. From 72 potential predictors, ten variables were independent predictive factors and were included in the risk score.  The practicability in a clinical setting is not clear yet, and as any predictive score, there are several limitations when it comes to assessing a single patient instead of a cohort. The COVID-GRAM Score Calculator can be accessed via the following link: http://118.126.104.170/  Early identification of COVID-19 patients at risk for severe disease would be helpful for management. Every clinic/ ICU should have a triage and risk assessment tool at hand.
For triage, we use the following simple criteria: 
As a predictive assessment tool for severe disease the COVID-GRAM Calculator can be used:
What about High Flow Nasal Cannulas (HFNC) and Non-Invasive Ventilation (NIV)? Especially at the beginning during the first wave of the pandemic, the use of HFNC and NIV was often avoided due to aerosolisation fear. Many ICU's tended to intubate their patients with respiratory failure relatively early. The lack of ventilators in some areas and reports that invasive ventilation is associated with high mortality (Zhou F, Lancet 2020; 395:1054) led to a constant change in management. KEEP IN MIND: Randomised-controlled studies for the treatment of COVID-19 patients with HFNC and NIV lack until now! Aerosolisation remains a big concern for health care workers (Niedermann MS; Am J Respir Crit Care Med 2020; 201:1019, Wu Z; JAMA 2020, February 24) and the amount of leakage flows is highly variable (Winck JC; Pulmonology 2020, April 20). Experience during the year 2020 showed, that most critical care providers have moved to use NIV and HFNC more frequently than initially. Proper personal protection equipment is essential and minimises risk for health care providers. Some evidence supports this approach (Avdeev SN, Am J Em Med AJEM Volume 39, p 154-157). NIV and HFNC is feasible in patients with COVID-19 and acute hypoxemic respiratory failure, even outside the ICU Helmet-NIV, leakage-free masks (non-vented masks) and double hose systems with virus-proof filters seem to be advantageous in this respect (Pfeiffer M; Pneumologie 2020, April 22). It is recommended that patients under HFNC should wear a surgical face mask over their cannulas Helmet NIV might advantageous compared to Mask NIV, though evidence is limited. (Patel BK et al. JAMA 2016. PMID: 27179847, single center study, trial stopped early, larger randomized-controlled studies awaited). KEEP IN MIND: Generally, there is only minimal evidence regarding the therapeutic benefit of these measures compared to their risks for the environment due to aerosolisation. Whether HFNC and NIV itself might produce self-inflicted lung injury (SILI) to some extend is not fully understood! Following patients should be considered for intubation and invasive ventilation - Severe hypoxemia (PaO2/FiO2 <150mmHg or respiratory rate >30/min) - Persistent or worsening respiratory failure (i.e. O2 sat <88%, RR > 36/min) - Neurologic deterioration - Intolerance of face mask or helmet - Airway bleeding - Copious respiratory secretions Should we Prone Position the Spontaneously Breathing Patient?Since the publication of Guerin C et al. (N Engl J Med 2013; 368:2159) prone positioning of patients with moderate to severe ARDS has become standard procedure in ICU's around the world. It is, therefore, evident that this treatment modality seems appropriate for COVID-19-induced lung injury, too. Trying to avoid intubations, clinicians rose the question, whether a prone position in the spontaneous breathing patient could avoid the need for invasive ventilation or even improve outcome. Ding L et al. (Crit Care 2020; 24:289) published a small multicenter study including 20 patients, whereas in 11 patients intubation could be avoided by prone positioning patients under NIV or HFNC. Telias et al. published an JAMA editorial (JAMA. 2020;323(22):2265-2267). He states that the prone position can improve oxygenation and can potentially result in less injurious ventilation. Unfortunately, this does not necessarily equate to lung protection and a better outcome. While improved oxygenation might prevent clinicians from intubating a patient, delayed intubation might worsen the patient's outcome. Regarding some evidence showing improved oxygenation during prone position, there are reasons to give it a try (Caputo ND et al. Acad Emerg Med Published online April 22, 2020). In the hypoxemic patient with no relevant respiratory distress awake prone positioning is a valid option - Use nasal cannulas or HFNC first - If comfortable enough, ask the patient to self-prone - Encourage the patient to remain in the prone position as long as well tolerated - Patients need close nursing and appropriate monitoring - Select prone positioning mattresses might be of help When to Use CorticosteroidsPatients with COVID-19 often show a biphasic course of the disease. The first phase is characterised by profound virus replication which decreases significantly after 5-7 days. After 7-10 days, a second phase develops in which an excessive or dysfunctional immune response can appear. This can lead to ARDS and multi-organ failure, which might be tackled by immunomodulating therapy. The largest, pragmatic randomised control trial we have at this stage is RECOVERY, performed in 176 hospitals around the UK and including more than 6400 patients (RECOVERY Collaborative group, N Engl J Med, July 17, 2020). COVID-19 patients that required oxygen or mechanical ventilation and presented with symptoms for at least seven days showed a significant reduction in 28-day mortality when treated with 6 mg Dexamethason OD for up to 10 days. Patients in the early viremic phase or patients that not required any oxygen performed worse with Dexamethasone. A broader insight into this topic brings a meta-analysis from JAMA in September 2020, including seven studies: DEXA-COVID19, CoDEX, RECOVERY, CAPE COVID, COVID STEROID, REMAP-CAP and Steroids-SARI. They ended up looking at 1703 patients and found a significant reduction in 28-day mortality when treated with steroids compared to placebo. Patients with COVID 19 that require oxygen, HFNC, NIV, mechanical ventilation or ECMO should be treated with steroids In patients not requiring oxygen, there is a trend towards harm when giving steroids - In these situations, steroids are NOT indicated Should we Use Remdesivir?Brief: Evidence in regards to the treatment with remdesivir is scattered and inconclusive. In the largest randomised control triad available so far is ACTT-1 looking at about 1600 patients (Beigel JH et al. N Engl J Med 2020; 383:1813-1826). In a few words, remdesivir showed a trend towards a 4-5 day shorter time to recovery, but not if symptoms existed for more than nine days. There was no significant influence on mortality, except maybe for patients requiring oxygen but not any help in ventilation. If at all, remdesivir might provide some advantage in a very selected patient group, but even this remains debatable. For this reason, many consider remdesivir the 'Tamiflu for COVID-19'. Two other papers remain to be mentioned briefly: Wang et al. (The Lancet; April 29) presented results from a relatively small study which was terminated early and showed no statistically significant clinical benefits of remdesivir - except for a trend towards a shorter duration of illness. Goldmann JD et al. presented the so-called '5 versus 10 days study', a phase 3 multicentre study with 397 patients. The primary outcome was their clinical status on day 14, secondary outcome patients with adverse events. Interestingly a 5-day course of remdesivir resulted in a better clinical outcome that a 10-day course. Again, It did not show any benefit compared to placebo. Remdesivir - The "Tamiflu for COVID-19" There is insufficient evidence to recommend the use of Remdesivir strongly. It is expensive, and if used, maybe there is only a short time window reasonable to act. Should We Use ECMO?During the early phase of the pandemic, first reports raised some concern that ECMO in COVID-19 patients might be associated with very high mortality (Henry BM et al. J Crit Care; 58:27). In the meanwhile, though we have new results from a more extensive cohort study looking at data from the Extracorporeal Life Support Organisation (ELSO, Barbaro RP et al. Lancet Volume 396, ISSUE 10257) The investigators looked at 1035 COVID-19 patients from 36 countries that were treated with ECMO (mean age 49 years, 74% male). 70% of all patients had relevant co-morbidities. The median time of ECMO support was 14 days. The incidence of in-hospital mortality 90 days after the initiation of ECMO was 37·4%. Mortality was 39% in patients with a final disposition of death or hospital discharge. These results are comparable with earlier mult-centre studies with patients suffering from non-COVID-19 ARDS (Combes A et al. N Engl J Med 2018; 378:1965). A retrospective cohort study from France looking at 83 patients treated with ECMO showed a probability to die after 60 days of 31%. Mortality at the time of the last follow-up was 36% (Schmidt et al. Lancet Respir Med 2020; 8:1121-1131). Various Societies recommend the use of ECMO in COVID-19 patients with treatment-refractory lung failure (Surviving Sepsis Campaign, ESICM, SCCCM and ELSO, WHO) Regarding the ongoing pandemic and limited resources, uniform indication and selection criteria for ECMO use should be available What about Convalescent Plasma?After a negative small randomised control trial (Li L et al. JAMA. 2020;324(5):460-470), a controversial Emergency Use Authorisation was granted by the FDA on 23.8.20 due to an observational study with a favourable effect on mortality with a high specific IgG content and onset less than days after symptom onset (Joyner MJ et al. MedRxiv; https://doi.org/10.1101/2020.08.12.20169359 - non peer-reviewed). At this stage the use of covalescent plasma can not be recommended How do we Manage Thromboprophylaxis?COVID 19 undoubtedly causes an inflammatory state that seems to trigger thrombotic activation in the venous and the arterial circulation. Thromboembolic complications are common, but the evidence is not robust on whether prophylactic or therapeutic doses should be used. Patients often have a significant elevation of D-dimers, an acute phase reactant representing the severity of disease rather than the dosage of thromboprophylaxis. One observational study looking at 1716 patients found no improved outcomes among in-hospital patients with COVID-19 when treated with therapeutic anticoagulation compared to prophylactic dosing. Moreover, patients who were started on anticoagulation for COVID-19 without evidence of thrombosis, new VTE, or new atrial fibrillation had worse outcomes compared to patients who were on prophylactic anticoagulation (Patel NG et al. Thrombosis Update; Volume 2, 2021, 100027) A case-based review of current literature and the COVID-19 specific coagulopathy end with the same finding that all in-hospital patients should receive prophylactic thromboprophylaxis. Whether a higher dose of prophylactic anticoagulation may be more effective is currently unknown (Chen EC et al. Oncologist. 2020 Oct; 25(10): e1500–e1508.). A small and retrospective study with 152 patients showed a lower risk of death and a lower cumulative incidence of thromboembolic events in patients with respiratory failure when a high-dose thromboprophylaxis was used. (Jonmarker S et al. Critical Care volume 24, Article number: 653 (2020)). Evidence supports the use of prophylactic thromboprophylaxis in patients with COVID-19 Whether a higher dose of anticoagulation might be more effective is currently unknown This single slide turn you into an expert in the nomenclature of monoclonal antibodies, but also helps to understand quickly what sort of medication your patient is treated with. Share and Care!  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  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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| Pocket Cards Toxine und Antidots |
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.
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