Other bulletins in this series include:

Breast Surgery

Monday, 6 July 2020

Causes and characteristics of death in patients with acute hypoxemic respiratory failure and acute respiratory distress syndrome: a retrospective cohort study

by Scott W. Ketcham, Yub Raj Sedhai, H. Catherine Miller, Thomas C. Bolig, Amy Ludwig, Ivan Co, Dru Claar, Jakob I. McSparron, Hallie C. Prescott and Michael W. Sjoding

Critical Care volume 24, Article number: 391 (2020)

Acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS) are associated with high in-hospital mortality. However, in cohorts of ARDS patients from the 1990s, patients more commonly died from sepsis or multi-organ failure rather than refractory hypoxemia. Given increased attention to lung-protective ventilation and sepsis treatment in the past 25 years, we hypothesized that causes of death may be different among contemporary cohorts. These differences may provide clinicians with insight into targets for future therapeutic interventions.
We identified adult patients hospitalized at a single tertiary care center (2016–2017) with AHRF, defined as PaO2/FiO2 ≤ 300 while receiving invasive mechanical ventilation for > 12 h, who died during hospitalization. ARDS was adjudicated by multiple physicians using the Berlin definition. Separate abstractors blinded to ARDS status collected data on organ dysfunction and withdrawal of life support using a standardized tool. The primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support.
We identified 385 decedents with AHRF, of whom 127 (33%) had ARDS. The most common primary causes of death were sepsis (26%), pulmonary dysfunction (22%), and neurologic dysfunction (19%). Multi-organ failure was present in 70% at time of death, most commonly due to sepsis (50% of all patients), and 70% were on significant respiratory support at the time of death. Only 2% of patients had insupportable oxygenation or ventilation. Eighty-five percent died following withdrawal of life support. Patients with ARDS more often had pulmonary dysfunction as the primary cause of death (28% vs 19%; p = 0.04) and were also more likely to die while requiring significant respiratory support (82% vs 64%; p <  0.01).
In this contemporary cohort of patients with AHRF, the most common primary causes of death were sepsis and pulmonary dysfunction, but few patients had insupportable oxygenation or ventilation. The vast majority of deaths occurred after withdrawal of life support. ARDS patients were more likely to have pulmonary dysfunction as the primary cause of death and die while requiring significant respiratory support compared to patients without ARDS.

Acute complications and mortality in hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis

by Nicola Potere, Emanuele Valeriani, Matteo Candeloro, Marco Tana, Ettore Porreca, Antonio Abbate, Silvia Spoto, Anne W. S. Rutjes and Marcello Di Nisio

Critical Care volume 24, Article number: 389 (2020) 

The incidence of acute complications and mortality associated with COVID-19 remains poorly characterized. The aims of this systematic review and meta-analysis were to summarize the evidence on clinically relevant outcomes in hospitalized patients with COVID-19.
MEDLINE, EMBASE, PubMed, and medRxiv were searched up to April 20, 2020, for studies including hospitalized symptomatic adult patients with laboratory-confirmed COVID-19. The primary outcomes were all-cause mortality and acute respiratory distress syndrome (ARDS). The secondary outcomes included acute cardiac or kidney injury, shock, coagulopathy, and venous thromboembolism. The main analysis was based on data from peer-reviewed studies. Summary estimates and the corresponding 95% prediction intervals (PIs) were obtained through meta-analyses.
A total of 44 peer-reviewed studies with 14,866 COVID-19 patients were included. In general, risk of bias was high. All-cause mortality was 10% overall (95% PI, 2 to 39%; 1687/14203 patients; 43 studies), 34% in patients admitted to intensive care units (95% PI, 8 to 76%; 659/2368 patients; 10 studies), 83% in patients requiring invasive ventilation (95% PI, 1 to 100%; 180/220 patients; 6 studies), and 75% in patients who developed ARDS (95% PI, 35 to 94%; 339/455 patients; 11 studies). On average, ARDS occurred in 14% of patients (95% PI, 2 to 59%; 999/6322 patients; 23 studies), acute cardiac injury in 15% (95% PI, 5 to 38%; 452/2389 patients; 10 studies), venous thromboembolism in 15% (95% PI, 0 to 100%; patients; 3 studies), acute kidney injury in 6% (95% PI, 1 to 41%; 318/4682 patients; 15 studies), coagulopathy in 6% (95% PI, 1 to 39%; 223/3370 patients; 9 studies), and shock in 3% (95% PI, 0 to 61%; 203/4309 patients; 13 studies).
Mortality was very high in critically ill patients based on very low-quality evidence due to striking heterogeneity and risk of bias. The incidence of clinically relevant outcomes was substantial, although reported by only one third of the studies suggesting considerable underreporting.

Therapeutic Hypothermia in Critically Ill Patients: A Systematic Review and Meta-Analysis of High Quality Randomized Trials*

by Kim, Jun Hyun; Nagy, Ádám; Putzu, Alessandro; Belletti, Alessandro; Biondi-Zoccai, Giuseppe; Likhvantsev, Valery V.; Yavorovskiy, Andrey G.; Landoni, Giovanni

Objectives: To investigate the effect of the application of therapeutic hypothermia (32–35°C) on survival and major clinical endpoints in critically ill patients.
Data Sources: We searched online database and clinical trial registries dated up to April 30, 2019, and references of relevant studies. Study Selection: Low risk of bias randomized trials which compared hypothermia applied for at least 24 hours and conventional therapy in critically ill patients were included. We excluded trials investigating therapeutic hypothermia in indications already supported by international guidelines (adult cardiac arrest and hypoxic-ischemic encephalopathy of newborns) or intraoperative hypothermia.
Data Extraction: Titles and abstracts were reviewed independently by two authors. If the articles seemed eligible, full-text articles were reviewed, and data were abstracted using a structured template.
Data Synthesis: Our search retained 14 low risk of bias randomized trials (2,670 patients) performed in three different settings: traumatic brain injury, serious infections, and stroke. Therapeutic hypothermia was associated with an increase in mortality at longest follow-up available (432/1,375 [31%] vs 330/1,295 [25%]; risk ratio, 1.24; 95% CI, 1.10–1.39; p = 0.0004; I2 = 0%). Pooled results showed no difference of good neurologic outcome among survivors between the two treatment arms (493/1,142 [43%] vs 486/1,067 [46%]; risk ratio, 1.04; 95% CI, 0.97–1.12; p = 0.27; I2 = 1%). Arrhythmias were significantly increased among patients undergoing therapeutic hypothermia. We found no difference between groups in pneumonia, serious infections, any infection, hemorrhage, renal failure, deep vein thrombosis, and uncontrollable intracranial hypertension.
Conclusions: High-quality randomized evidence indicates that therapeutic hypothermia is associated with higher mortality and no difference in good neurologic outcome compared with normothermia in critically ill patients. Although there still might be a possibility that therapeutic hypothermia is beneficial in a specific setting, routine application of therapeutic hypothermia would better be avoided outside the settings indicated by international guidelines (adult cardiac arrest and hypoxic-ischemic encephalopathy of newborns).

COVID-19: ICU delirium management during SARS-CoV-2 pandemic—pharmacological considerations

by Lauren J. Andrews and Scott T. Benken 

Critical Care volume 24, Article number: 375 (2020) 


The recent article by Kotfis and colleagues provides great insight regarding newly identified COVID-related risk factors contributing to ICU delirium, while also presenting valid potential solutions to barriers surrounding the implementation of the ABCDEF safety bundle for ICU liberation [1]. However, we feel that the omission of pertinent medication availability and selection limitations currently afflicting healthcare teams around the world warrants further discussion.
In the setting of medication shortages and anecdotally high sedation requirements in COVID patients, it has become increasingly necessary to utilize various combinations of second-line and adjunct therapy options in order to maintain appropriate levels of sedation, with indications for neuromuscular blockade and prone positioning further exacerbating this need [1]. Keeping the known sedation limitations of dexmedetomidine in mind [2], clinicians may be more inclined to use benzodiazepine infusions if unable to obtain adequate supplies of common first-line agents (e.g., fentanyl, propofol). Despite the well-documented association between benzodiazepines and delirium, this approach may be unavoidable for a large number of institutions. Ketamine may be a possible solution, however, as more data has recently emerged regarding its safety and efficacy as an adjunct therapy for analgosedation [3]….

Preventive use of respiratory support after scheduled extubation in critically ill medical patients—a network meta-analysis of randomized controlled trials

by Xiaoyang Zhou, Shengmi Yao, Pingping Dong, Bixin Chen, Zhaojun Xu and Hua Wang 

Critical Care volume 24, Article number: 370 (2020)

Respiratory support has been increasingly used after extubation for the prevention of re-intubation and improvement of prognosis in critically ill medical patients. However, the optimal respiratory support method is still under debate. This network meta-analysis (NMA) aims to evaluate the comparative effectiveness of various respiratory support methods used for preventive purposes after scheduled extubation in critically ill medical patients.
A systematic database search was performed from inception to December 19, 2019, for randomized controlled trials (RCTs) that compared a preventive use of different respiratory support methods, including conventional oxygen therapy (COT), noninvasive ventilation (NIV), high-flow oxygen therapy (HFOT), and combinational use of HFOT and NIV (HFOT+NIV), after planned extubation in adult critically ill medical patients. Study selection, data extraction, and quality assessments were performed in duplicate. The primary outcomes included re-intubation rate and short-term mortality.
Seventeen RCTs comprising 3341 participants with 4 comparisons were included. Compared with COT, NIV significantly reduced the re-intubation rate [risk ratio (RR) 0.55, 95% confidence interval (CI) 0.39 to 0.77; moderate quality of evidence] and short-term mortality (RR 0.66, 95% CI 0.48 to 0.91; moderate quality of evidence). Compared to COT, HFOT had a beneficial effect on the re-intubation rate (RR 0.55, 95% CI 0.35 to 0.86; moderate quality of evidence) but no effect on short-term mortality (RR 0.79, 95% CI 0.56 to 1.12; low quality of evidence). No significant difference in the re-intubation rate or short-term mortality was found among NIV, HFOT, and HFOT+NIV. The treatment rankings based on the surface under the cumulative ranking curve (SUCRA) from best to worst for re-intubation rate were HFOT+NIV (95.1%), NIV (53.4%), HFOT (51.2%), and COT (0.3%), and the rankings for short-term mortality were NIV (91.0%), HFOT (54.3%), HFOT+NIV (43.7%), and COT (11.1%). Sensitivity analyses of trials with a high risk of extubation failure for the primary outcomes indicated that the SUCRA rankings were comparable to those of the primary analysis.
After scheduled extubation, the preventive use of NIV is probably the most effective respiratory support method for comprehensively preventing re-intubation and short-term death in critically ill medical patients, especially those with a high risk of extubation failure.

Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring

by Sophie Susen, Charles Ambroise Tacquard, Alexandre Godon, Alexandre Mansour, Delphine Garrigue, Philippe Nguyen, Anne Godier, Sophie Testa, Jerrold H. Levy, Pierre Albaladejo and Yves Gruel

Critical Care volume 24, Article number: 364 (2020) 

COVID-19 is an infection induced by the SARS-CoV-2 coronavirus, and severe forms can lead to acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) management. Severe forms are associated with coagulation changes, mainly characterized by an increase in D-dimer and fibrinogen levels, with a higher risk of thrombosis, particularly pulmonary embolism. The impact of obesity in severe COVID-19 has also been highlighted.
In this context, standard doses of low molecular weight heparin (LMWH) may be inadequate in ICU patients, with obesity, major inflammation, and hypercoagulability. We therefore urgently developed proposals on the prevention of thromboembolism and monitoring of hemostasis in hospitalized patients with COVID-19.
Four levels of thromboembolic risk were defined according to the severity of COVID-19 reflected by oxygen requirement and treatment, the body mass index, and other risk factors. Monitoring of hemostasis (including fibrinogen and D-dimer levels) every 48 h is proposed. Standard doses of LMWH (e.g., enoxaparin 4000 IU/24 h SC) are proposed in case of intermediate thrombotic risk (BMI < 30 kg/m2, no other risk factors and no ARDS). In all obese patients (high thrombotic risk), adjusted prophylaxis with intermediate doses of LMWH (e.g., enoxaparin 4000 IU/12 h SC or 6000 IU/12 h SC if weight > 120 kg), or unfractionated heparin (UFH) if renal insufficiency (200 IU/kg/24 h, IV), is proposed. The thrombotic risk was defined as very high in obese patients with ARDS and added risk factors for thromboembolism, and also in case of extracorporeal membrane oxygenation (ECMO), unexplained catheter thrombosis, dialysis filter thrombosis, or marked inflammatory syndrome and/or hypercoagulability (e.g., fibrinogen > 8 g/l and/or D-dimers > 3 μg/ml). In ICU patients, it is sometimes difficult to confirm a diagnosis of thrombosis, and curative anticoagulant treatment may also be discussed on a probabilistic basis. In all these situations, therapeutic doses of LMWH, or UFH in case of renal insufficiency with monitoring of anti-Xa activity, are proposed.
In conclusion, intensification of heparin treatment should be considered in the context of COVID-19 on the basis of clinical and biological criteria of severity, especially in severely ill ventilated patients, for whom the diagnosis of pulmonary embolism cannot be easily confirmed.

First do no harm—beware the risk of therapeutic plasma exchange in severe COVID-19

by Klaus Stahl, Christian Bode and Sascha David 

Critical Care volume 24, Article number: 363 (2020)

Letter to the editor:

With great interest, we read the article by Keith et al. [1] suggesting adjunctive therapeutic plasma exchange (TPE) as a potential novel treatment approach for severe COVID-19. The basis for their hypothesis builds on the observation that patients with deleterious systemic response to severe infections such as sepsis do not usually die from the underlying pathogen itself but rather from the overwhelming pathological host response to it.

Compassionate use of others’ immunity — understanding gut microbiome in Covid-19

by Prashanth Thalanayar Muthukrishnan and Robert Faillace 

Critical Care volume 24, Article number: 358 (2020)

Disease is a complex interaction between disease-causing agent, host, and the environment. About 90–95% of the public that test positive for coronavirus recover; hence, most of us have inbuilt host response that creates a life-sustaining relationship with coronavirus. Shen and colleagues have used plasma from survivors to study the amplification of host response in severe Covid-19 patients [1]. Modern medicine has been documenting the evidence behind the ancient wisdom—“home of immunity is the gut microbiome” [2]. Hence, we address the scope of understanding host response and immunity during this time of global emergency…

Invasive mechanical ventilation in COVID-19 patient management: the experience with 469 patients in Wuhan

by Jing Hua, Chenchen Qian, Zhibing Luo, Qiang Li and Feilong Wang 

Critical Care volume 24, Article number: 348 (2020) 

Research letter:
Since the first case of COVID-19 was reported in Wuhan, this new respiratory disease has evolved rapidly and been found in almost all the countries in the world. From our clinical experiences during managing COVID-19 patients, we observed an extremely high fatality rate in invasive ventilation (IV) patients which was astonishing and unexpected.
To validate our assumption, we collected and analyzed the data of 469 ICU COVID-19 patients who were hospitalized from February 2020 to the end of March in 13 ICUs in Wuhan. At the time of data collection, all of the patients were either discharged or deceased (Table 1)...

A plea for avoiding systematic intubation in severely hypoxemic patients with COVID-19-associated respiratory failure

by Eduardo Villarreal-Fernandez, Ravi Patel, Reshma Golamari, Muhammad Khalid, Ami DeWaters and Philippe Haouzi

Critical Care volume 24, Article number: 337 (2020)

Letter to the editor:
In early February 2020, Yang et al. [1] reported an alarming high mortality rate in patients with COVID-19-associated acute respiratory failure requiring mechanical ventilatory support. Such a dreadful outcome was regarded as the fundamental tenet dictating our strategy to treat patients with COVID-19 acute respiratory failure. Two essential recommendations were offered to the medical community in keeping with these first reports: (1) early intubation of hypoxemic patients [2]. Indeed, since a profound hypoxemia appears to be the hallmark of COVID-19-associated pneumonia, the initial consensus [2] was to start invasive mechanical ventilation as soon as possible due to the overwhelming number of patients in respiratory failure presenting at the same time in a hospital and to prevent the risk of hypoxic cardiac arrest; (2) avoidance of high-flow nasal cannula (HFNC) to reduce respiratory droplet aerosolization for healthcare workers [3] in what was seen as “inevitable” intubations.

Potential benefit of angiotensin II in COVID-19 patients: beyond reasonable doubt?

by António Tralhão, Luís Ferreira Moita and Pedro Póvoa 

Critical Care volume 24, Article number: 324 (2020) 

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease 2019 (COVID-19) have wreaked havoc on healthcare systems globally. The potential for spread of this highly infectious virus, which is more transmissible and lethal than influenza, has reached pandemic proportions and has left many clinicians scrambling to provide care with scarce resources, all in the setting of no curative treatment, immunization, or effective therapy. Some candidate therapies include antivirals (remdesivir), antimalarials (hydroxychloroquine), and vaccines (mRNA-1273). Moreover, as we learn more about this virus, we have begun to draw some noteworthy conclusions regarding currently available ancillary “therapies” which may affect the natural history of the COVID-19 infection. Some of these “therapies” may actually be the avoidance of certain medications, like ibuprofen. Likewise, patients on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) could be at a greater risk due to the mechanism by which SARS-CoV-2 enters the cell. It stands to reason that therapeutics that act counter to this mechanism may confer protection.

Caution about early intubation and mechanical ventilation in COVID-19

by Martin J. Tobin, Franco Laghi and Amal Jubran 

Annals of Intensive Care volume 10, Article number: 78 (2020)

A fear of ventilator shortage with COVID-19 panicked politicians into demanding automakers to branch into ventilator manufacture.
Some experts have argued that mechanical ventilation should be employed early in order to prevent COVID-19 patients progressing from mild disease to more severe lung injury. This viewpoint has been expressed most forcefully by Marini and Gattinoni in a JAMA Editorial [1], where they attest that vigorous spontaneous inspiratory efforts can rapidly lead to patient self-induced lung injury (P-SILI).

Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19

by Akshay Shah, Joe N. Frost, Louise Aaron, Killian Donovan and Hal Drakesmith 

Letter to the Editor: Critical Care volume 24, Article number: 320 (2020) 

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) was declared a pandemic on March 11, 2020 [1]. Risk factors associated with respiratory failure in patients with COVID-19 include older age, neutrophilia and elevated inflammatory and coagulation markers [1]. Inflammation is often accompanied by systemic hypoferremia and low iron levels may impair hypoxia sensing and immunity [2], and increase the risk of thromboembolic complications [3]—which are all of significant concern in COVID-19. However, the iron status of COVID-19 patients is unclear. Therefore, we sought to characterise iron parameters, including serum iron, in COVID-19 intensive care unit (ICU) patients and relate these to disease severity.

Management of critically ill patients with COVID-19 in ICU: statement from front-line intensive care experts in Wuhan, China

by You Shang, Chun Pan, Xianghong Yang, Ming Zhong, Xiuling Shang, Zhixiong Wu, Zhui Yu, Wei Zhang, Qiang Zhong, Xia Zheng, Ling Sang, Li Jiang, Jiancheng Zhang, Wei Xiong, Jiao Liu and Dechang Chen

Annals of Intensive Care volume 10, Article number: 73 (2020) 

The ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept all over the world, posing a great pressure on critical care resources due to large number of patients needing critical care. Statements from front-line experts in the field of intensive care are urgently needed.
Sixteen front-line experts in China fighting against the COVID-19 epidemic in Wuhan were organized to develop an expert statement after 5 rounds of expert seminars and discussions to provide trustworthy recommendation on the management of critically ill COVID-19 patients. Each expert was assigned tasks within their field of expertise to provide draft statements and rationale. Parts of the expert statement are based on epidemiological and clinical evidence, without available scientific evidences.
A comprehensive document with 46 statements are presented, including protection of medical personnel, etiological treatment, diagnosis and treatment of tissue and organ functional impairment, psychological interventions, immunity therapy, nutritional support, and transportation of critically ill COVID-19 patients. Among them, 5 recommendations were strong (Grade 1), 21 were weak (Grade 2), and 20 were experts’ opinions. A strong agreement from voting participants was obtained for all recommendations.
There are still no targeted therapies for COVID-19 patients. Dynamic monitoring and supportive treatment for the restoration of tissue vascularization and organ function are particularly important.

PEEP levels in COVID-19 pneumonia

by Vasiliki Tsolaki, Ilias Siempos, Eleni Magira, Stelios Kokkoris, George E. Zakynthinos and Spyros Zakynthinos

Research letter: Critical Care volume 24, Article number: 303 (2020)

To the Editor:
Recently, the Surviving Sepsis Campaign COVID-19 guidelines and ATS suggest that a ventilatory strategy complying with the ARDSnet protocol should be applied to manage COVID-19 pneumonia [1,2,3]. However, “COVID-19 lung” pathophysiology seems to be divergent from the “ARDS lung”; hence, heart-lung interactions may be more pronounced than initially considered [23]…