Critical Care Reviews Newsletter 419 22nd December 2019

The Critical Care Reviews Newsletter includes the best critical care research and open access articles from across the medical literature over the past seven days.
The highlights of this week’s edition are randomised controlled trials on comparing rocuronium with succinylcholine on endotracheal intubation in out-of-hospital rapid sequence intubation & inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia; systematic reviews and meta analyses on adverse events during intrahospital transport of critically ill children & whether norepinephrine or vasopressin should be discontinued first in septic shock; and observational studies on vitamin E acetate in bronchoalveolar-lavage fluid associated with EVALI & the association of prehospital plasma transfusion with survival in trauma patients with hemorrhagic shock.
There are also narrative reviews on fluid administration strategies in traumatic brain injury & comparison between thromboelastography and thromboelastometry; editorials on controversies surrounding prevention of ventilator-associated pneumonia & anaesthetic management of the airway after blunt and penetrating neck injury; and commentaries on clinically meaningful benefit in clinical research & organising international research in critical care medicine.
The full text of the newsletters is available via this link.

Impact of obstructive sleep apnea on the obesity paradox in critically ill patients

This research by Bailly and others was published online in the Journal of Critical Care in December 2019
Objective:  Patients admitted to an intensive care unit (ICU) frequently suffer from multiple chronic diseases, including obstructive sleep apnea (OSA). Until recently OSA was not considered as a key determinant in an ICU patient’s prognosis. The objective of this study was to document the impact of OSA on the prognosis of ICU patients.
Methods:  Data were retrospectively collected concerning adult patients admitted to ICU at two university hospitals. In a nested study OSA status was checked using the hospital electronic medical records to identify exposed and unexposed cases. The following outcomes were considered: length of stay in the ICU, ICU mortality, in-hospital mortality, ventilator-associated pneumonia (VAP).
Results:  Out of 5146 patients included in the study, 289 had OSA at ICU admission (5.6%). After matching, the overall impact of OSA on length of ICU stay was not significant (p = .24). In a predefined subgroup analysis, there was a significant impact of OSA on the length of ICU stay for patients with BMI over 40 kg/m2 (IRR: 1.56 [1.05; 2.32], p = .03). OSA status had no impact on ICU or hospital mortality and VAP.
Conclusion:  In general, known OSA did not increase the ICU stay except for patients with both OSA and morbid obesity.
The full text of this article is available to subscribers via this link to the journal’s homepage.  The full text of articles from issues older than sixty days is available via this link to an archive of issues of Journal of Critical Care.  A Rotherham NHS Athens password is required.  Eligible staff can register for an Athens password via this link.  Please speak to the library staff for more details.

Muscle degradation, vitamin D and systemic inflammation in hospitalized septic patients

This article by Borges and colleagues was first published online in the Journal of Critical Care during December 2019.
Purpose:  To date, the relationship between systemic inflammation and muscle changes observed by ultrasonography in septic patients in clinical studies is not known. Furthermore, the role of vitamin D on muscle changes in these patients needs to be investigated.
Materials and methods:  Forty-five patients admitted to the ICU due to severe sepsis or septic shock. Blood samples were collected to evaluate systemic inflammation (interleukin (IL)-10, IL-1β, IL-1α, IL-6, IL-8 and tumor necrosis factor–α(TNF-α)) and vitamin D. Muscle mass was evaluated by ultrasound during hospitalization. Clinical tests of muscle strength (Medical Research Council (MRC) scale and handgrip) were performed after the awakening of patients.
Results:  There was a reduction in day 2 values to hospital discharge on TNF-alpha, IL-8, IL-6 and IL-10 (p < .05). The muscle mass showed a significant decline from day 6 of the ICU. After awakening, the patients had a significant increase in muscle strength (p < .05). There was a positive association between muscle mass variation (day 2 – ICU) with absolute values of IL-8 (r = 0.38 p = .05). For muscle strength, there was a negative association between handgrip strength with IL-8 (r = −0.36 p < .05) on ICU discharge. The vitamin D showed a positive association with the handgrip strength of the day 1 of the awakening (r = 0.51 p < .05).
Conclusions:  In septic patients, there is an association between inflammation and changes in muscle mass and strength during ICU stay, which is similar to those observed in experimental studies. In addition, there was an association of vitamin D with recovery of muscle strength during hospitalization.
The full text of this article is available to subscribers via this link to the journal’s homepage.  The full text of articles from issues older than sixty days is available via this link to an archive of issues of Journal of Critical Care.  A Rotherham NHS Athens password is required.  Eligible staff can register for an Athens password via this link.  Please speak to the library staff for more details.

Critical Care Reviews Newsletter 418 19th December 2019

The Critical Care Reviews Newsletter includes the best critical care research and open access articles from across the medical literature over the past seven days.
“The highlights of this week’s edition are randomised controlled trials on high-dose vitamin D3 for critically ill, vitamin D–deficient patients & fresh vs standard-issue red blood cell transfusions in critically ill pediatric patients; systematic reviews and meta analyses on return to work after critical illness & early versus delayed mobilization; and observational studies on frailty, cognition, activity of daily life and comorbidities on outcome in acutely admitted patients over 80 years in European ICUs, & assessment of variability in end-of-life care delivery in American ICUs.
There are also guidelines on lung–kidney interactions in critically ill patients & bleeding in patients hospitalized in the intensive cardiac care unit; narrative reviews on reversal of vasodilatory shock & drug-induced acute kidney injury; and commentaries on whether enteral nutrition can be given to patients on vasopressors  & whether critical care patients hibernate? There are also editorials on tranexamic acid and the CRASH III trial & the persistent potential of extracorporeal therapies in liver failure; as well as correspondence on how high PEEP may have reduced injurious transpulmonary pressure swings in the ROSE trial.”
The full text of the newsletters is available via this link.

Pulmonary mucormycosis in a patient with acute liver failure: A case report and systematic review of the literature

This article by Huang and colleagues was first published online in the “Journal of Critical Care” during December 2019.

Purpose:  Pulmonary mucormycosis is a highly lethal invasive fungal infection usually found in immunocompromised patients. We report herein the case of an adult woman who developed pulmonary mucormycosis with possible systemic dissemination after recovering from acute liver failure secondary to acetaminophen overdose.

Results:  Our case developed an invasive pulmonary mucormycosis with probable potential systemic dissemination. She did not suffer from any immunocompromising disease other than severe acute liver failure. She did not survive the disease, although she received appropriate antifungal treatment. We also performed a systematic review of the literature on pulmonary mucormycosis, with or without dissemination, in immunocompetent patients. We found 16 cases of pulmonary or disseminated mucormycosis in immunocompetent patients. Fifty-seven percent of them died and none occurred after an acute liver failure episode.

Conclusion:  This case report is the first one to present an invasive pulmonary mucormycosis infection after acute liver failure in an adult patient. The clinical course of this disease is highly lethal, even in immunocompetent adults.

The full text of this article is available to subscribers via this link to the journal’s homepage.  The full text of articles from issues older than sixty days is available via this link to an archive of issues of Journal of Critical Care.  A Rotherham NHS Athens password is required.  Eligible staff can register for an Athens password via this link.  Please speak to the library staff for more details.

Corticosteroids for treating sepsis in children and adults

This systematic review by Annane and colleagues was first published online during December 2019
Review question:  We reviewed the evidence on the effect on death of using corticosteroids in children and adults with sepsis.
Background:  Sepsis is present when an infection is complicated by organ failure. People develop rapid breathing, hypotension (low blood pressure), and mental confusion. Sepsis can interfere with the effectiveness of the body’s corticosteroids, which serve as a key defence against infection. Corticosteroids have been given for decades to people with infection resulting from various causes.
Search date:  The evidence provided in this review is current to July 2019.
Study characteristics:  This review included 61 trials (12,192 participants). Fifty‐eight trials compared corticosteroids to no corticosteroids (placebo or usual care in 48 and nine trials, respectively); three trials also compared continuous versus bolus administration of corticosteroids.
Study funding sources:  Three trials were funded by a drug company, 27 by public organizations or through charitable funding, and six by both a drug company and public organizations or charitable funding; 25 did not declare the source of funding.
Key results:  We have analysed the following two comparisons.
• Corticosteroids versus placebo/usual care.
Corticosteroids probably reduce the risk of death at 28 days by 9% (50 trials; 11,233 participants), with consistent treatment effects between children and adults. They also probably slightly reduce the risk of dying in hospital. There may be little or no effect of corticosteroids on risk of dying over the long term (longer than three months), but these results are less certain. Corticosteroids result in a large reduction in length of stay in the intensive care unit (ICU) and in hospital. Corticosteroids increase the risk of muscle weakness and hypernatraemia. They probably increase the risk of hyperglycaemia. They probably do not increase the risk of superinfection. There may be little or no effect of corticosteroids on risk of gastroduodenal bleeding, neuropsychiatric events, stroke, or cardiac events.
• Continuous infusion versus intermittent boluses of corticosteroids.
We are uncertain about the effects of continuous infusion of corticosteroids compared with intermittent bolus administration. Three studies reported data for this comparison, and the certainty of evidence for all outcomes was very low.
Certainty of evidence
• Corticosteroids versus placebo/usual care
We judged the certainty of evidence for 28‐day mortality as moderate due to some inconsistency related to differences among study populations, types of corticosteroids and how they were given, and use of additional interventions.
• Continuous infusion versus intermittent boluses of corticosteroids
We judged the certainty of evidence for 28‐day mortality as very low due to inconsistency and imprecision.
Implications for practice:  Moderate‐certainty evidence indicates that corticosteroids probably reduce 28‐day, 90‐day, and hospital mortality among patients with sepsis. Corticosteroids result in a large reduction in ICU and hospital length of stay (high‐certainty evidence). There may be little or no difference in the risk of major complications; however, corticosteroids increase the risk of muscle weakness and hypernatraemia (high‐certainty evidence), and probably increase the risk of hyperglycaemia (moderate‐certainty evidence). The effects of continuous versus intermittent bolus administration of corticosteroids are uncertain.
Implications for research:  The criteria for critical illness‐related corticosteroid insufficiency in septic shock remain to be defined.
Subgroup analyses suggest that additional studies are needed to address these topics related to the use of corticosteroids in patients with sepsis.

  • The role of a long course of low‐dose corticosteroids for treatment of septic shock in children.
  • The role of a long course of low‐dose corticosteroids for treatment of patients with sepsis without shock, or with a mild form of septic shock; patients with ARDS; and patients with sepsis related to community‐acquired pneumonia.
  • The role of mineralocorticoid replacement.
  • Optimal timing of initiation of treatment.
  • Optimal dose and duration of hydrocortisone (or equivalent).
  • Optimal modality to administer treatment that is continuous versus intermittent bolus.
  • Optimal modality to stop treatment with or without taper off.
  • The role of a long course of low‐dose corticosteroids for treatment of sepsis caused by different types of infections.
  • Long‐term neuromuscular effects of steroids.
    The full details of this Cochrane Systematic Review are available via this link.

Critical Care Reviews Newsletter 417 9th December 2019

The Critical Care Reviews Newsletter includes the best critical care research and open access articles from across the medical literature over the past seven days.
The highlights of this week’s edition are the VAPrapid2 randomised controlled trial investigating biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia; a systematic review and meta analysis investigating the effects of continuous epinephrine infusion on survival; and an observational studies assessing the association between supraphysiologic arterial oxygen levels and mortality. There is also a guideline on the transfer of the brain‐injured patient; narrative reviews on processed EEG monitoring for anesthesia and intensive care, ventricular assist device implantation in patients with a failing systemic right ventricle & monitoring of regional lung ventilation using electrical impedance tomography; and a commentary on producing and using trustworthy evidence.
The full text of the newsletters is available via this link.

C-reactive protein as a prognostic factor in intensive care admissions for sepsis: A Swedish multicenter study

This article by Koozi and others was first published online in the Journal of Crtical Care during December 2019
Purpose:  C-reactive protein (CRP) is not included in the major intensive care unit (ICU) prognostic tools such as the Simplified Acute Physiology Score (SAPS). We assessed CRP on ICU admission as a SAPS-3 independent risk marker for short-term mortality and length of stay (LOS) in ICU patients with sepsis.
Materials and methods:  Adult ICU admissions satisfying the Sepsis-3 criteria to four southern Swedish hospitals were retrospectively identified and divided into a low CRP group (<100 mg/L) and a high CRP group (>100 mg/L) based on the admission CRP level. The standardized mortality ratio (SMR) was calculated.
Results:  A total of 851 admissions were included. The SMR was higher in the high CRP group (0.85 vs. 0.67, P = .001 in the whole sepsis group and 0.85 vs. 0.59, P = .003 in the culture-positive subgroup). The CRP levels also correlated with ICU and hospital LOS in survivors (P < .001 and P = .002), again independent of SAPS-3.
Conclusion:  An admission CRP level >100 mg/L is associated with an increased risk of ICU and 30-day mortality as well as prolonged LOS in survivors, irrespective of morbidity measured with SAPS-3. Thus, CRP may be a simple, early marker for prognosis in ICU admissions for sepsis.
The full text of this article is available to subscribers via this link to the journal’s homepage.  The full text of articles from issues older than sixty days is available via this link to an archive of issues of Journal of Critical Care.  A Rotherham NHS Athens password is required.  Eligible staff can register for an Athens password via this link.  Please speak to the library staff for more details.

Pharmacological interventions for the treatment of delirium in critically ill adults

This Cochrane Systematic Review by Burry and others was published online during September 2019.

Review question:
We reviewed the evidence from randomized controlled trials for the benefits and safety of all prescription medicines used to treat critically ill adult patients with delirium in the intensive care units (ICUs) of hospitals.

Background:
Delirium is commonly associated with surgery, infection, or critical illness. It is experienced as new‐onset, generally short‐term inability to think clearly. Patients with delirium shift between periods of clear thinking and periods of agitation and/or great sleepiness and confusion. Lack of sleep, pain, a noisy environment, physical restraint, and the use of sedatives and strong analgesics are some of the contributing factors. Delirium affects both immediate and longer‐term health outcomes of critically ill patients as it can increase the length of time a breathing machine is required, time spent in the ICU and in hospital, and the chance of functional weakening and death. The odds of a poor outcome with delirium are increased with frail patients and those of advanced age and already present cognitive difficulties. Frequently, delirious ICU patients are given medicines to help treat symptoms such as agitation.

Study characteristics:

This review is current to 21 March 2019. We found 14 randomized controlled studies that enrolled a total of 1844 adult participants. Six different classes of medicines were tested. These were antipsychotic drugs used as tranquillizers in ten studies; the sedative alpha2 agonist dexmedetomidine in three studies; statins that reduce cholesterol in two studies; opioids as part of pain management in one study; serotonin antagonists for nausea and vomiting in one study; and cholinesterase inhibitors, which are medicines for Alzheimer’s disease, in one study. Ten studies compared medicine to placebo ‐ an inactive medicine also known as a sugar pill; four studies compared different drugs. Eleven studies with 1153 participants reported on the main outcome of this review ‐ duration of delirium.

Key findings:
When drug classes were directly compared with placebo, only the alpha2 agonist dexmedetomidine was found to reduce the duration of delirium, and the cholinesterase inhibitor rivastigmine was found to prolong the duration of delirium. Each of these results is based on findings from a single small study. The other drugs when compared to placebo did not change delirium duration. The Review authors used the statistical method of network meta‐analysis to compare the six different drug classes. Dexmedetomidine was ranked most effective in reducing delirium duration, followed by atypical antipsychotics. However, network meta‐analysis of delirium duration failed to rule out the possibility of no difference for all six drug classes compared to placebo. Using this method, we did not find that any drug improved the duration of coma, length of stay, long‐term cognitive outcomes, or death. The alpha2 agonist dexmedetomidine shortened time spent on a breathing machine. Adverse events often were not reported in these trials or were rare when reported. An analysis of reported events showed that events were similar to those reported with placebo. We found 10 ongoing studies and six studies awaiting classification that, once published and assessed, may change the conclusions of this review.

Quality of the evidence:
Most of the included studies were small but of good design. Nine of the 14 studies were considered to have low risk of bias.

Implications for practice:
In clinical practice, pharmacological interventions are commonly administered to critically ill patients to manage their symptoms of delirium (Burry 2017). We found evidence that the alpha2 agonist dexmedetomidine may have some role in shortening delirium duration, although this small effect was seen in pairwise analyses based on a single small study compared with placebo, and was not seen in the NMA results. No other pharmacological intervention including antipsychotics, the most commonly prescribed drug for delirium treatment, had any effect on delirium duration nor on any of our a priori selected secondary outcomes. It is also important to note that the cholinesterase inhibitor rivastigmine was associated with harm, and as such, guidelines suggest against its use for treatment of ICU delirium. The 10 ongoing studies and the six studies awaiting classification, once published and assessed, may alter the conclusions of this review; therefore, their results are much anticipated. The frequency of prescribing these drug classes for critically ill adults with delirium and the non‐significant findings of our review should be considered at the bedside and should be incorporated into future pain, agitation, and delirium guidelines.

Implications for research:
We identified 10 ongoing studies, of which seven have a large target enrolment number (100 to 1000 participants), suggesting growing interest in the treatment of ICU delirium. These RCTs should strengthen our results and may potentially alter the direction of our findings. For example, five ongoing trials are examining antipsychotics and three are examining the alpha2 agonist dexmedetomidine ‐ the drug classes found most promising in our analysis ‐ each trial with large target enrolment.
We note the promise of many new treatment trials on the horizon; however, we must acknowledge the need to standardize outcome reporting in ICU delirium trials to permit maximum pooling and interpretation of results. We found far greater variability in the definitions of study outcomes used than we had anticipated, which led us to modify our primary outcome and to limit pooling for some outcomes (e.g. mortality). We found no reporting on some clinically important outcomes such as symptom management (e.g. treating agitation, stopping treatment interferences) and long‐term cognitive outcomes, and we found new outcomes not listed in our protocol (e.g. number of days in coma) in multiple new RCTs and ongoing trials. The Del‐COrS (“Developmnt of core outcome sets for effectiveness trial of interventions to prevent and/or treat delirium”) Group is leading the development of international consensus on outcomes for trials of intervention to prevent and treat delirium in multiple patient populations (Rose 2017). Findings from this group should be used to guide future ICU delirium trials.
We also found that RCTs in this review rarely reported on the use of non‐pharmacological strategies. Among the trials that we identified, all but one showed poor utilization of non‐pharmacological strategies. For example, early mobilization has been shown to reduce the duration of delirium (Barr 2013), and its use in practice is encouraged. Therefore, future trials should clearly describe the use of such strategies in their methods and should report compliance in their results. We also found poor reporting on the use of physical restraints ‐ a non‐pharmacological intervention associated with delirium and prolonged duration of delirium (Rose 2016).
The full details of this Cochrane Systematic Review are available via this link.

Chlorhexidine bathing of the critically ill for the prevention of hospital‐acquired infection

This Cochrane Systematic Review by Lewis and colleagues was first published online in August 2019.

What is the aim of this review?
The aim of this review was to find out whether people who are critically ill in hospital should be bathed with the antiseptic chlorhexidine, in order to prevent them from developing infections. Researchers from Cochrane collected and analysed all relevant studies to answer this question and found eight relevant randomised trials. Randomised trials are medical studies where people are chosen at random to receive different treatments. This study design provides the most reliable evidence on whether treatments have a relationship with desired or undesired health outcomes.

Key messages
This review assesses whether using chlorhexidine (instead of soap and water) to bathe patients in an intensive care unit (ICU), or a high‐dependency or critical care unit reduces the number of hospital‐acquired infections. The evidence available from the studies we analysed was very low quality, meaning that we cannot be certain whether bathing with chlorhexidine reduces the likelihood of critically‐ill patients developing an infection, or dying. We are also uncertain whether bathing critically ill patients with chlorhexidine shortens the length of time people spend in hospital, or lowers their risk of developing skin reactions.

What was studied in the review?
People who are critically ill (in an ICU, or a high‐dependency or critical care unit) often catch infections during their time in hospital. These infections can lead to longer hospital stays, additional medical complications, permanent disability or even death. Patients in ICUs are particularly vulnerable to infections because the body’s ability to fight infection is reduced by illness or trauma. Surgical tubes and lines (for example to help with feeding or breathing) may enable bacteria to enter the body. Chlorhexidine is a low‐cost product which is used as an antiseptic and disinfectant in hospitals.

What are the main results of the review?
In December 2018 we searched for studies looking at the use of chlorhexidine for bathing critically ill patients. We found eight studies dating from 2005 to 2018, involving a total of 24,472 people across more than 20 ICUs. Seven studies included people who were adults, and one study included only children. All studies included both males and females. All studies compared bathing with chlorhexidine versus bathing with soap and water or non‐antimicrobial washcloths. Four studies received funding from independent funders (government organisations, or from hospital or university departments) or reported no external funding, and four studies received funding from companies that manufactured chlorhexidine products.

The evidence from all eight studies combined is not sufficient to allow us to be certain whether patients bathed in chlorhexidine are less likely to catch an infection during their stay in the ICU. We are also uncertain whether patients bathed in chlorhexidine are less likely to die, because the certainty of the evidence from the six studies that reported on this is very low. We did not pool the evidence from the six studies that reported how long patients had stayed in the ICU, because the results differed widely. We are also uncertain whether patients bathed in chlorhexidine are likely to be in the ICU for less time, because the certainty of the evidence is very low. Reports from five studies provided different evidence about whether chlorhexidine led to more or less skin reactions; we are uncertain whether patients bathed in chlorhexidine are likely to have more or less skin reactions, because the certainty of the evidence is very low.

How up to date is this review and Quality of evidence
We searched for studies that had been published up to December 2018.  Most studies did not use methods to conceal the type of bathing solution that staff were using, which increases the risk that staff may have treated patients differently depending on whether patients were in the chlorhexidine study group or the soap‐and‐water study group. Participants in some studies may have already caught an infection before the start of the study and we were concerned that this might have affected our results. We also noticed wide differences in some results, and some outcomes had few reported events. These were reasons to judge the quality of the evidence to be very low.

Implications for practice
It is not clear whether bathing with chlorhexidine reduces hospital‐acquired infections, mortality or length of stay in the intensive care unit, or whether chlorhexidine use results in more skin reactions, because the certainty of the evidence is very low. One study is awaiting classification and two studies are ongoing; we do not know if inclusion of these studies in future updates of this Cochrane Review will increase our certainty in the results of the review.

Implications for research
Additional research is needed to evaluate whether chlorhexidine bathing may reduce hospital‐acquired infections in the intensive care unit. We recommend that studies are sufficiently powered and methodologically robust, and that attention is paid to reduce the risk of performance bias through blinding of personnel. Cluster‐randomised studies and cross‐over trials would benefit from reporting data in more detail, including important parameters such as the intracluster correlation coefficient and interperiod correlation. Some consensus on the reporting of hospital‐acquired infection rates, for example through the adoption of a core outcome set for trials of infection prevention, would also be helpful.

The full details of this Cochrane Systematic Review are available via this link.