The headlines in the news 2017 were remarkable indeed: "Doctor believes he has found the cure for sepsis..." or "Doctor says improvised 'cure' for sepsis has had remarkable results".
Dr. Paul Marik described his observation in an interview in 2017, where he mentions several cases of sepsis that have almost miraculously responded to the application of vitamin c (watch here: Interview on WAVY TV). He even continues, that since then they see "the same thing over and over again". This implicated that these results were reproducible. He finally stated that the current data at that stage were "impressive" and that there was enough basic science to show that it works.
Vitamin C has many interesting properties that theoretically could be on benefit in sepsis. (read here: Crit☁ post on Vitamin C). Its application was already proposed for the treatment of other diseases like the common cold of Influenza. Despite some moderate positive influence observed, these results could not be reproduced in trials.
While the news picked up on this story as a miracle drug, Paul Marik et al. published their results of a before-and-after single-centre, retrospective cohort study in Chest 2017. In this paper, they compared 47 patients with sepsis that received the metabolic cocktail (Vitamin C 1.5g 6-hourly, hydrocortisone 50mg 6-hourly and thiamine 200mg 12-hourly) to 47 patients which did not - notably in a non-double-blinded, non-randomized fashion. Their results showed overall hospital mortality of 8.5% with the 'cocktail' and 40.4% without its application.
This publication was reason enough to launch a small war of faith about sense and nonsense of this cocktail for sepsis.
The VITAMINS Trial - First Failure
Since 2017 a tiny bunch of studies were published, many of them with significant limitations like a small number of patients, often not randomized-controlled and with conflicting results.
Nabil Habib T, Ahmed I (2017) Early Adjuvant Intravenous Vitamin C Treatment in Septic Shock may Resolve the Vasopressor Dependence. Int J Microbiol Adv Immunol. 05(1), 77-81.
Shin et al. J Clin Med. 2019 Jan; 8(1): 102.
Fowler et al. JAMA. 2019 Oct 1;322(13):1261-1270.
Fujii et al. have just now published the first more substantial and rigorous trial taking a closer look at the influence on vitamin c in sepsis.
They performed an
international, multicenter, randomized-controlled open label trial
In which they enrolled 211 patients with septic shock admitted to an ICU.
Treatment with Vitamin C 1.5g 6-hourly IV, hydrocortisone 50mg 6-hourly IV and thiamin 200mg 12-hourly IV
Hydrocortisone 50mg 6-hourly IV only.
No difference in time alive and time free of vasopressors (primary endpoint) and
No difference 28 days or 90 days mortality (secondary endpoint)
This first study on a larger scale, unfortunately, disappoints. More trials are on the way and might give a clearer picture of this topic to come to a final decision eventually.
For the moment it is appropriate to state:
Just as a reminder: Guidelines recommend against the routine use of glucocorticoids in patients with sepsis. However, corticosteroid therapy is appropriate in patients with septic shock that is refractory to adequate fluid resuscitation and vasopressor administration.
Fujii et al. JAMA. Published online January 17, 2020. doi:10.1001/jama.2019.22176
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.
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.
The European Society for Clinical Microbiology and Infectious Diseases has now released new guidelines on the diagnosis and treatment of biofilm infections. Written for clinical microbiologists and infectious disease specialists this paper is a MUST READ for anyone involved in treating critically ill patients.
These guidelines outline the nature and properties of biofilms and and their implications on mostly chronic infections caused. As biofilms are very common in critically ill patients it is important to know what specific problems you might encounter, how to proceed and perform a proper diagnosis and what are the essential bits and pieces in the prevention and treatment of biofilm infections.
The article is OPEN ACCESS: Clin Microbiol Infect. 2015 Jan 14. pii: S1198-743X(14)00090-1.
Almost exactly one year ago the Cochrane Library published an intervention review on the prevention and treatment of influenza with neuraminidase inhibitors in adults and children. The reason for this review was the fact that many countries stockpile these drugs and the WHO classified them as an essential medicine.
Jefferson et al. used the data of 46 trials with oseltamivir or zanamivir for this review. They basically conclude that:
- Both drugs shorten the duration of symptoms of influenza-like symptoms by less than a day
- Oseltamivir did not affect the number of hospitalizations
- Prophylaxis trials showed a reduced risk of symptomatic influenza in individuals and households, but no definite conclusion can be made
- Oseltamivir use was associated though with nausea, vomiting, headaches, renal and psychiatric events
...and finally write: 'The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence'. This review certainly undermined the importance of oseltamivir for many of us.
The Cochrane review though did not look at outcomes like mortality, but the Lancet Respiratory Medicine did! Stella G at al. have now published a large systematic review which included 29'234 patients from 78 studies during the period from 2009 to 2014. Their findings come rather surprisingly:
- Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk
- Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk
- The reduction in mortality risk was observed when treatment was started up to 5 days of symptoms onset
There still seem to be some good reasons to use oseltamivir in critically ill patients with suspected or proven influenza... up to 5 days of symptoms onset!
Jefferson T et al. The Cochrane Collaboration, Published Online: 10 APR 2014
The Cochrane Collaboration News Release 10 April 2014
Muthuri, Stella G et al. The Lancet Respiratory Medicine , Volume 2 , Issue 5 , 395 - 404
Microbiologically confirmed ventilator-associated pneumonia (VAP) or ventilator-associated conditions (VAC, e.g. worsening oxygenation) in intubated patients remains a major concern in ICU's. VAP is defined as a hospital-acquired pneumonia which develops within 48-72 hours after endotracheal intubation.
To prevent this complication ICU's uniformly have adapted the VAP-bundle, a bunch of measures aiming to prevent ventilator-associated pneumonia. Unfortunately the evidence of the VAP-bundle is not as robust as one might think it is. Here's the evidence of some elements of the VAP bundle:
- Elevation of the head to bed 45° (low evidence)
- Daily sedation interruptions (the impact on reducing VAP has not been shown so far)
- Daily oral chlorhexidine rinses (low evidence)
... it's most likely the combination of measures that is of benefit to the patient... hopefully! But hold on, there is another intervention that finally brings quite some evidence with it!
Active suctioning of the subglottic area, where nasal-oral secretions gather and create a rich culture medium for all sorts of micro-organisms, also aims to reduce the incidence of VAP. In contrast to the classical VAP-bundle the evidence here is strongly in favour for these devices!
In 2005 four registrars in cardiothoracic surgery looked into this topic and summarised their efforts online on Best Evidence Topics, best bets.org. In this blog they review 13 relevant articles on the use of subglottic suctioning and conclude: subglottic suction significantly reduces the incidence of VAP in high risk patients - which means a NNT of 8 if ventilated for more than 3 days. They also mention that this measure is cost effective, despite the more expensive tubes.
In the same year Dezfulian et al. presented a systematic meta-analysis of randomized trials in the American Journal of Medicine. They ended up with 5 studies including 869 patients. They also came to the conclusion that subglottic secretion drainage is effective in preventing VAP in patients expected to be ventilated for more than 72 hours.
In 2011 Hallais et al. looked into the issue of cost-effectiveness with a cost-benefit analysis. Even when assuming the most pessimistic scenario of VAP incidence and costs the replacement of conventional ventilation with continuous subglottic suctioning would still be cost-effective.
In 2011 Muscedere et al. published an 'official' review article in Critical Care Medicine and also ended up with 13 randomised clinical trial, most of them the same 'BestBETs' had already identified 6 years before. It is therefore not surprising to see that they also found a highly significant reduction in VAP. They were also able to demonstrate a reduction in ICU length of stay and duration of mechanical ventilation, although the strength of this association was weakened by heterogeneity of study results.
We finally would like to mention the latest randomised controlled trial on this topic which was published in Critical Care Medicine this January 2015. Damas et al. randomly assigned 352 patients to either receive subglottic suctioning or not. Again sublottic suctioning significantly reduced VAP prevalence and therefore also antibiotic use.
At least we have identified one area in critical care where an impressive pile of evidence supporting the use of subglottic suctioning in long-term intubated patients is present... and even better: cost-effective analyses also come out in great favour for this measure!
Take-home message: Subglottic suctioning does prevent VAP in patients likely to be ventilated more than (48-) 72 hours and should be used in these situations.
Review BestBETs 2005
Dezfulian C et al. Am J Med. 2005 Jan;118(1):11-8
Hallais C. et al. Infect Control Hosp Epidemiol. 2011 Feb;32(2):131-5
Muscedere J et al. Crit Care Med. 2011 Vol. 39, No. 8
Damas P et al. Crit Care Med. 2015 Jan;43(1):22-30
Just recently in 2014 the WHO has requested to develop a draft global action plan to combat emergent antimicrobial resistance (AMR). AMR is present in all parts of the world, new resistance mechanisms emerge and spread globally. And most importantly: Patients with infections by drug-resistant bacteria are generally at risk of worse clinical outcome and death.
On the background of this the recent publication in Nature by Ling et al. is remarkable as it might offer the key to a new antimicrobial weapon in the near future. Teixobactin is the name of a macrocylic peptide representing a new class of antibiotics. It appears to be potent bactericidal agent against a broad panel of bacterial pathogens, especially gram-positive bacteria including MRSA, enterococci and VRE as well as M. tuberculosis, C. difficile and Anthrax. Teixobactin inhibits cell wall synthesis and most remarkably showed no development of resistance so far.
Teixobactin is produced by E. terrae, a microorganism discovered in the soil of a grassy field in Maine. As mentioned in the article, these 'uncultured' bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics.
An interesting article, especially if you want to see what's going on outside the hospital!
Ling LL et al. Nature 2015; doi:10.1038/nature14098
Ventilator associated pneumonia (VAP) is a problem in ICU around the world and methicillin-resistant Staphylococcus aureus (MRSA) is the most common multi-drug resistant pathogen to deal with. Current guidelines mostly recommend vancomycin as a first line treatment and linezolid as an alternative, considering both drugs at a similar level of efficacy. The question remained whether linezolid might be superior to vancomycin.
So far only one prospective, randomised, double-blind trial looked at this question and found a better success rate for linezolid, which was not statistically significant though.
To look at this issue the IMPACT-HAP investigators (Improving Medicine through Pathway Assessment of Critical Therapy in Hospital Acquired Pneumonia) performed a multicenter, retrospective, observational study on 188 patients in 5 hospitals of the U.S.
They found a significantly higher success rate with linezolid compared to vancomycin in the means of improvement or resolution of the signs and symptoms of VAP (primary endpoint). The study did not identify any difference though between linezolid- and vancomycin-treated patients in regards to mortality, development of thrombocytopenia, anaemia, or nephrotoxicity, days of mechanical ventilation or length of stay ion ICU or the hospital itself (secondary outcomes).
Looking into the trial there appear to be several confounding reasons why patients treated with linezolid had better clinical success rate like less severity of sickness in linezolid patients, possible suboptimal vancomycin through levels etc.
Overall there seems no good reasons at this stage to change current guidelines.
Wunderink RG et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia, Clin Infect Dis; 2012, 54:621–629
Peyrani P et al. Crit Care 2014; 18:R118 doi:10.1186/cc13914
Antibiotic-associated diarrhoea and antibiotic induced Clostridium difficile diarrhoea are a constant problem in the ICU, especially in the elderly patient. There is still some debate going on about prescribing lactobacilli or bifidobacteria for the prevention and treatment of this sort of complication. In this Lancet multi centre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial this was studied on almost 3000 patients: 10.8% diarrhoea with lactobacilli or bifidobacteria versus 10.4% diarrhoea in the placebo group. No difference!
One drug less to prescribe...
Lancet 2013 Oct 12;382(9900):1249-57
This months issue of the American Journal of Respiratory and Critical Care Medicine presents a retrospective cohort study comparing patients with acute exacerbation of COPD receiving either lower-dose methylprednisolone (<240mg/d) or high-dose methylprednisolone (>240mg/d). They looked at 17'239 patients. The primary outcome was mortality.
Despite the possibility of some selection bias they conclude that high doses of methylprednisolone are associated with worse outcomes and more frequent adverse effects (like prolonged hospital and ICU length of stay, higher hospital costs, increased length of invasive ventilation, increased need for insulin therapy and higher rate of fungal infections). Mortality itself did not significantly differ.
It is remarkable to note that in this study doses below 240mg of methylprednisolone are considered low-dose. This is equivalent to 300mg of prednisolone and is relatively high for exacerbations of COPD. As we mentioned in a post in November 2013 the REDUCE trial in JAMA compared 5 days to 14 days of steroids in exacerbated COPD. The dosage used there was 40mg of prednisone. The results showed that a 5-day treatment was non-inferior to a 14-day treatment with regard to re-exacerbation within 6 months but significantly reduced glucocorticoid exposure.
In summary it seems to be advisable to use lower doses and short treatment periods in acute exacerbated COPD.
Am J Respir Crit Care Med. 2014 May 1;189(9):1052-64
After the 2013 publication by Ghareed et al. (see BIJC post here) on fist bumps in the health care setting in order to prevent transmission of pathogens JAMA now joins in the discussion. Sklansky M et al. published a viewpoint on the banning of the handshake from the health care setting. In their paper they point out that the hands of health care workers often serve as vectors for transmission of organisms and disease. The fact is highlighted that adherence of health care providers with hand hygiene remains rather low and that handshakes have shown to be able to transmit pathogens. In their article they draw parallels between the ban of handshakes in a health care setting and the ban of smoking in public places and finally offer a variety of alternative greetings methods like: the 'hand wave' and placement of the right palm over the heart, or the Namaste gesture also practiced in yoga around the world.
This offers an interesting viewpoint worth reading indeed but I might add a few remarks and questions to this article. Apart from the fact that I still struggle to follow the link between hand shakes and smoking in public and would like to highlight following:
- The link between pathogen transmission by handshakes and consecutive patient outcome is totally unclear. At this stage there is no evidence indicating that handshakes themselves impose a serious threat to patients.
- Banning handshakes in hospitals might sound like a good idea, but the main problem remains unaffected. Multi-resistant bacterias are the logical result of inappropriate prescription and usage of antibiotics. It certainly is advisable to prevent the spread of these pathogens but it would be better to prevent their man made evolution.
- Physical contact with patients in the ICU is an essential part in patient care (e.g. nursing or medical examination) and socialising might be even more important when you're unwell. Of course contact isolation has been found to help prevent the retransmission of pathogens. We tend to forget though that all these measures at the same time might have other unintended consequences. From 1999 to 2003 three articles showed that patients in contact isolation got half as many visits from health care providers resulting in 20% less contact time (Morgan DJ et al. Infect Control Hosp Epidemiol. 2013;34(1):69-73). Remarkably, similar effects were found also a decade later. Evidence has continued to accumulate that patients on contact precautions may experience worse outcomes, including more delirium, more depression, worse discharge instructions, and less smoking cessation counselling.
Withholding a handshake sounds simple but might actually further contribute to patient's isolation and there is also some research out there actually showing on how important this gesture actually might be (Dolcos S et al. J Cogn Neurosci 2012 Dec;24(12):2292-305).
The first sentence of the Conclusion by Sklansky et al. reads as follows: 'Banning the handshake from the health care environment may require further study to confirm and better describe the link between handshake-related transmission of pathogens and disease.'... I couldn't agree more!
I think we might have to be very careful on already starting to talk about 'hand shake free zones' as long as there are so many unanswered questions. Many things have been done in the past to prevent infections and finally have been proven to be completely inutile (e.g. changing peripheral lines after three days, read post here). Maybe we she focus more on avoiding overprescribing antibiotics instead.
What do you think...?
Sklansky et al. JAMA. Published online May 15, 2014. doi:10.1001/jama.2014.4675
The picture displayed above is take from the New York Times
A situation often encountered in hospitals... also in Ireland. You have to urgently review a patient on the ward but are stuck in theatre. Of course you would like to get changed first (as hospital policy asks you to) but there are no scrubs available anymore or there are no white coats to cover your scrubs, or ... so you end up going to the ward in your scrubs... as a walking threat to patients?
Apart form the fact that changing your clothes might be appropriate to do there is this recent article of Hee at al. in Anaesthesia giving you a little chance for forgiveness. Although small in numbers these researches found no evidence that visits to ward or office significantly increase bacterial contamination of scrub suits.
Hee HI et al. Anaesthesia April 18 2014
Picture above taken from the US series 'Scrubs'
Just this week the World Health Organisation WHO has issued a warning that resistance of organisms to antibiotics will become one of the biggest challenges of the upcoming decade. Indeed, the correct prescription of antibiotics is crucial for successful treatment and the WHO states that completing the full length of the treatment is just as important.
But what is actually the correct length of treatment for all the different antibiotics and diseases? How many ward rounds on ICU's have I spent with microbiologists (the maybe most important specialists on our sides!) wondering on how they always had a straight answer on the correct length of treatment. 7 days, 10 days or sometimes 21 days... a little mystery to most intensivists, until now!
Hitchhiking though the the wide space of the internet I finally found secret to this question. Back in the year 2010 Paul E. Sax, a Professor of Medicine at Harvard Medical School him self, posted an excellent blog for the NEJM Journal Watch website. Inspired by a New York Time article by Harvard Professor Daniel Gilbert he finally gave insight into one of the great mysteries of medicine:
To figure out how long antibiotics need to be given, use the following rules:
That did not occur by chance
Wow, not much more I can add!
Paul E. Sax, NEJM Journal Watch HIV/AIDS Clinical Care, October 22nd 2010
NYT article by Daniel Gilbert from October 2010
Fist Bumps Prevent Spread of Bacteria... And Why This Study Won’t Change Social Behaviour (Well, at least not in Ireland)
Some studies are fascinating and disconcerting at the same time... but at least they’re good for a smile!
In this paper by Ghareeb et al. the authors addressed the question whether a handshake or a fist bump is more effective in preventing or reducing pathogen transmission in the setting of a hospital, where most of us work of course. Unsurprisingly they found that using the fist bump instead of handshakes made skin contact 2.7 times shorter and this reduced spread of bacteria. They concluded that the fist bump is an effective alternative to the handshake in the hospital setting and that bumping might lead to decreased transmission of bacteria and improved health and safety of patients and health care workers alike.
So shall we all start bumping around the hospital?
We performed an observational study in our medium sized ICU in Galway (without approval of any committee and of course without any statistical evidence to be presented, actually just out of interest and for fun). We might also mention beforehand that working atmosphere in our unit is very good and nurses and doctors work very closely together.
Interestingly, neither nursing staff nor doctors shake hands when they meet and greet each other in the ICU. The only occasions handshakes were observed are when relatives are met for a discussion or a representative of some company comes in for a visit.
In regards of the study mentioned above I have some serious concerns: I wonder how many health care professionals out there would welcome a family fist bumping that has come in to discuss an end-of-life issue for instance. Also when representing the unit towards someone outside of hospital a fist bump carries some substantial risk of giving a very unprofessional impression... at least in Europe! And in very few occasions also a warm hug will be irreplaceable by some awkward bump. Social behavior is also a way on communicating... and anyhow, who pays for such studies?
Ghareeb PA et al. J Hosp Infect. 2013 Dec;85(4):321-3
Picture displayed above is taken from the New York Times
Hypothermia is back in the focus of discussions and was not only used for treatment after cardiac arrest. If hypothermia would protect after cerebral ischemia after an arrest it might be also useful after other impacts like stroke or meningitis.
To answer this question a french multi-center study was started involving 49 intensive care units. Patients with communitiy acquired bacterial meningitis and a GCS of less than 8 for less than 12 hours were enroled. The hypothermia group was cooled to 32-34°C for 48 hours and then passively rewarmed. Primary outcome was GCS at three months. After including 98 patients the study had to be stopped on the request of the data ans safety monitoring board due to concerns over excess mortality in the hypothermia group. Analysis showed no improve of outcome but might actually be harmful to patients.
Hypothermia doesn’t seem to be the magic bullet here either.
Mourvillier B, et al. JAMA. 2013 Nov;310(20):2174-83