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[Blue Journal在线发表]:Vrije大学阿姆斯特丹医学中心重症医学推荐阅读
2018年02月15日 研究点评, 进展交流 暂无评论

Recommended Reading from the Vrije Universiteit Amsterdam Medical Center Critical Care Medicine Fellows

Mirjam Kop, Nicolas F. Schroten, Sharon Soe-Loek-Mooi, et al

Am J Respir Crit Care Med Published on 18-October-2017 as 10.1164/rccm.201701-0245RR

Keh D, et al. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis. The HYPRESS randomized clinical trial. JAMA (1)

Reviewed by Mirjam Kop

Corticosteroids have been used for the treatment of patients with severe infections for more than six decades. The use in sepsis has been a subject for research and debate, and remains controversial (2). Because earlier studies showed that the use of low dose hydrocortisone improved reversal of septic shock (3), the authors of the HYPRESS study hypothesized that hydrocortisone might prevent the progression from severe sepsis to septic shock.

This multicentre, randomized, placebo controlled, double-blind trial, is the first one to investigate the effects of hydrocortisone to prevent progression to shock in patients with severe sepsis. The main exclusion criterion was septic shock, e.g. hypotension despite adequate volume status. A total of 380 patients were randomised to either continuously hydrocortisone 200mg daily for five days (n=190) followed by dose tapering or to placebo (n=190). A continuous infusion of hydrocortisone was preferred to avoid undulation of blood cortisol concentrations, resulting in poor glycemic control. The primary outcome, development of shock within 14 days, occurred in 36 of 170 patients in the hydrocortisone group (21,2%) versus 39 of 170 patients in the placebo group (22.9%), p=0.70. Among the secondary outcomes no significant differences between the two groups regarding mortality rates at day 28 (8.8 vs 8.2%), at day 90 (19.9 vs 16.7%) and at day 180 (26.8 vs 22.2%) as well as in time until shock development, secondary infections, weaning failure and muscle weakness were observed. In 206 patients a corticotropin test was performed. Those with critical illness related corticosteroid insufficiency (CIRCI) had a higher risk of developing shock than without CIRCI, but there were no significant differences between the placebo and hydrocortisone group. Patients treated with hydrocortisone had a higher risk of developing hyperglycemia and a lower risk of developing delirium in a post-hoc analysis, but the data on delirium should be interpreted with caution because of incomplete data sets, once daily assessments and interrater variability.

The results of this trial suggest no role for low dose corticosteroids in patients with severe sepsis in absence of septic shock. This result is compatible with the current surviving sepsis guidelines (4) limiting corticosteroids only for patients with septic shock when fluid resuscitation and vasopressors are insufficient. The results are in contrast with the modest efficacy seen in patients with pneumonia and high inflammatory response, where steroids reduced length of stay and treatment failure (5, 6). In this study, a post-hoc analysis of 54 patients with CAP did not reveal significant differences for primary or secondary end-points between patients treated with hydrocortisone vs placebo. An important limitation of the current study is the exclusion of 61% of patients before enrolment due to septic shock. This compromises generalisability to daily practise. At the bedside it still remains difficult to identify which individual patient will benefit from corticosteroids and which patients might be harmed. Hopefully future investigations, which are underway, will clarify this longstanding issue.


1. Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S, Bogatsch H, Briegel J, Engel C, Gerlach H, Goldmann A, Kuhn S-O, Huter L, Meier-Hellmann A, Nierhaus A, Kluge S, Lehmke J, Loeffler M, Oppert M, Resener K, Schadler D, Schuerholz T, Simon P, Weiler N, Weyland A, Reinhart K, Brunkhorst FM. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA 2016;316:1775–1785.

2. Annane D. The Role of ACTH and Corticosteroids for Sepsis and Septic Shock: An Update. Front Endocrinol (Lausanne) 2016;7:70.

3. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating sepsis. Cochrane database Syst Rev 2015;CD002243.doi:10.1002/14651858.CD002243.pub3.

4. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent J-L, Moreno R. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637.

5. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della Porta R, Giorgio C, Blasi F, Umberger R, Meduri GU. Hydrocortisone Infusion for Severe Community-acquired Pneumonia. Am J Respir Crit Care Med 2005;171:242–248.

6. Blum CA, Nigro N, Briel M, Schuetz P, Ullmer E, Suter-Widmer I, Winzeler B, Bingisser R, Elsaesser H, Drozdov D, Arici B, Urwyler SA, Refardt J, Tarr P, Wirz S, Thomann R, Baumgartner C, Duplain H, Burki D, Zimmerli W, Rodondi N, Mueller B, Christ-Crain M. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015;385:1511–1518.


Prandoni P, et al. Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope. N Eng J Med (7)

Reviewed by Nicolas F. Schroten

Identifying the cause for syncope, is often a diagnostic challenge but vital, since the differential diagnosis includes potentially life threatening diseases. The European Society of Cardiology and American Heart Association focus mostly on cardiac causes for syncope (8, 9). They mention pulmonary embolism (PE) as one of the alternative causes, but lack clear recommendations when to test for PE. Until now, testing for PE is not routine practice in patients admitted for syncope. But this may change following the PESIT study published recently in the New England Journal of Medicine (7).

The PESIT study investigated the prevalence of PE in 560 patients admitted for syncope to one of 11 hospitals in Italy. Syncope was defined as transient loss of consciousness with rapid onset, short duration (<1 minute) and spontaneous resolution, with obvious causes such as epileptic seizure, stroke and head trauma ruled out. They found an alarming percentage of 17,3% patients (95% CI, 14.2 to 20.5) had PE. Even in patients with an alternative explanation for syncope, 12,7% patients (95% CI, 9.2 to 16.1) were diagnosed with PE. Patients with clinical signs of PE, namely tachycardia, tachypnea, hypotension or signs of deep-vein thrombosis, were more likely to have pulmonary embolisms. However, 24,7% of the patients diagnosed with PE had no clinical signs at all, next to the syncope. These observations might plea for routine testing for PE in patients admitted for syncope, without a clear explanation. However, these results need to be interpret with caution.

This cross-sectional study is remarkable for its standardized diagnostic work-up, which may account for the high prevalence of PE compared to other studies. The pretest clinical probability of pulmonary embolism was defined according to the simplified Wells score. In patients who had a low pretest clinical probability and a negative D-dimer assay, no further testing was performed, but in patients who had a high pretest clinical probability, a positive D-dimer assay or both, a computed tomographic pulmonary angiography or ventilation perfusion scan was performed. This can be easily translated into clinical practice. A potential bias of the study is the study demographic consisting of mostly elderly (75% were ≥70 years old) with a high probability of cardiovascular syncope. It can be argued that not every PE found is clinically significant or the cause of syncope and there are no data on treatment decision or follow-up to evaluate the effect of anticoagulation therapy on outcome. However, in 67.1% patients who had a pulmonary embolism diagnosed on computed tomography, the most proximal location of the embolus was a main pulmonary artery or lobar artery. In 50% of patients who had ventilation perfusion scanning, the perfusion defect was larger than 25% of the total lung area, therefore likely to cause an obstruction of blood flow that resulted in loss of consciousness and withholding treatment seems unethical.

In conclusion, this study needs to be repeated elsewhere. For now, it seems reasonable to perform CT-angiography to detect pulmonary embolism in patients admitted to the hospital with syncope and either Wells score =>4 or positive D-Dimer, unless a clear other explanation is available.


7. Prandoni P, Lensing AWA, Prins MH, Ciammaichella M, Perlati M, Mumoli N, Bucherini E, Visona A, Bova C, Imberti D, Campostrini S, Barbar S. Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope. N Engl J Med 2016;375:1524–1531.


8. Moya A, Sutton R, Ammirati F, Blanc J-J, Brignole M, Dahm JB, Deharo J-C, Gajek J, Gjesdal K, Krahn A, Massin M, Pepi M, Pezawas T, Ruiz Granell R, Sarasin F, Ungar A, van Dijk JG, Walma EP, Wieling W. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009;30:2631–2671.

9. Strickberger SA, Benson DW, Biaggioni I, Callans DJ, Cohen MI, Ellenbogen KA, Epstein AE, Friedman P, Goldberger J, Heidenreich PA, Klein GJ, Knight BP, Morillo CA, Myerburg RJ, Sila CA. AHA/ACCF Scientific Statement on the Evaluation of Syncope. Circulation 2006;113:316 LP-327.


Girardis M, et al. Effect of Conservative vs Conventional Oxygen therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA (10)

Reviewed by Sharon Soe-Loek-Mooi

Oxygen therapy is one of the main pillars of the treatment for acutely ill patients. Historically emphasis was placed on avoiding hypoxemia in these patients. Therefore, clinical practice guidelines generally target for normal levels of oxygen (11). Often these patients spend a substantial period in a hyperoxemic state and too much oxygen can also have adverse effects, through free radical formation, peripheral vasoconstriction and attenuated cytokine production (12).

This background provides the context for the Oxygen-ICU Trial (10), a single center randomized trial comparing conservative oxygen supplementation (PaO₂70-100mmHg, SpO₂ 96-98%) with usual care (PaO₂ < 150 mmHg, SpO₂ 97-100%).

In a period of 31 months, 480 adult patients with an expected ICU stay of ≥ 72 hours were included. Median PaO₂ was significantly lower in the conservative group compared to the conventional group (87 mmHg [IQR 79-97] vs 102 mmHg [88-116]). The primary outcome, ICU mortality was lower in the conservative group (11.6% vs 20.2%), as were the secondary outcomes hospital mortality, new episodes of shock, liver failure, bacteremia and hours on mechanical ventilation. Highest mortality was observed in patients exposed to an overall average time-weighted PaO₂ of 107 mmHg or higher during their ICU stay. The results of the study are provocative, however they should be interpreted with caution. Results of this trial maybe overestimated through limitations in its design, such as the unblinded single center design, poor monitoring of PaO₂, unplanned early termination of the study, small number of outcome events and baseline imbalances in study population favoring the conservative group.

The results from this trial are in line with a recent meta-analysis showing increased in-hospital mortality in critically ill patients exposed to arterial hyperoxia (13). Conservative oxygen therapy (SpO2 of 90-92%) was also a safe approach in a before and after study, examining 105 adult ICU patients mechanically ventilated for > 48 hours (14). Feasibility of a conservative oxygenation strategy was also supported from a recent randomized multicenter study comparing a conservative oxygen strategy (mean PaO₂ and 95% CI: 70 [68-73] mmHg) with a liberal strategy (PaO₂ 92 [89-96] mmHg) in 103 adult ICU patients likely to require > 24 hours of mechanical ventilation.(15) In this study the exposure to hyperoxia was reduced in the conservative approach. However exposure to hypoxemia was also marginally higher.

The results of the Girardis trial (10) should be interpreted with caution since unplanned termination of the trial may have overestimated the effect size, and the sample size did not allow a detailed analysis of hyperoxia in different population subsets. Larger clinical trials are needed. In addition, the optimal thresholds for oxygen saturation and PaO₂ have to be determined. As a clinician preventing desaturation and low oxygen levels by giving oxygen is a good idea, but also being aware of the downsides of arterial hyperoxia is also important.


10. Girardis M, Busani S, Damiani E, Donati A, Rinaldi L, Marudi A, Morelli A, Antonelli M, Singer M. Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA 2016;316:1583–1589.

11. O’Driscoll BR, Howard LS, Davison AG. BTS guideline for emergency oxygen use in adult patients. Thorax 2008;63 Suppl 6:vi1-68.

12. Sjoberg F, Singer M. The medical use of oxygen: a time for critical reappraisal. J Intern Med 2013;274:505–528.

13. Helmerhorst HJF, Roos-Blom M-J, van Westerloo DJ, de Jonge E. Association Between Arterial Hyperoxia and Outcome in Subsets of Critical Illness: A Systematic Review, Meta-Analysis, and Meta-Regression of Cohort Studies. Crit Care Med 2015;43:1508–1519.

14. Suzuki S, Eastwood GM, Glassford NJ, Peck L, Young H, Garcia-Alvarez M, Schneider AG, Bellomo R. Conservative oxygen therapy in mechanically ventilated patients: a pilot before-and-after trial. Crit Care Med 2014;42:1414–1422.

15. Panwar R, Hardie M, Bellomo R, Barrot L, Eastwood GM, Young PJ, Capellier G, Harrigan PWJ, Bailey M. Conservative versus Liberal Oxygenation Targets for Mechanically Ventilated Patients. A Pilot Multicenter Randomized Controlled Trial. Am J Respir Crit Care Med 2016;193:43–51.


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