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Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysisFluid Resuscitation in Sepsis

Bram Rochwerg, MD; Waleed Alhazzani, MD; Anees Sindi, MD; Diane Heels-Ansdell, MSc; Lehana Thabane, PhD; Alison Fox-Robichaud, MD; Lawrence Mbuagbaw, MSc; Wojciech Szczeklik, MD; Fayez Alshamsi, MD; Sultan Altayyar, MD; Wang-Chun Ip, MD; Guowei Li, MSc; Michael Wang, MD; Anna Włudarczyk, MD; Qi Zhou, PhD; Gordon H. Guyatt, MD; Deborah J. Cook, MD; Roman Jaeschke, MD; Djillali Annane, MD, PhD, for the Fluids in Sepsis and Septic Shock Group
[+] Article and Author Information

This article was published online first at www.annals.org on 22 July 2014.


From McMaster University, Hamilton, Ontario, Canada; Prince Sultan Military Medical City, Riyadh, Saudi Arabia; King Abdulaziz University, Jeddah, Saudi Arabia; Jagiellonian University Medical College, Krakow, Poland; and University of Versailles Saint-Quentin-en-Yvelines, Garches, France.

Note: Dr. Cook coauthored a fluid trial cited in this review, and Dr. Annane was principal investigator of a fluid trial cited in this review.

Acknowledgment: The authors thank Drs. J.L. Vincent (38, 42), L. Jie (40), S. Finfer (2), K. Reinhart (1), A. Chopra and J.L. Falk (38, 42), F. Schortgen (43), B. Wills and N. Haase (56), L.L. McIntyre (41), and K. Maitland and J. Myburgh (3) for providing information contributing to this article. They also thank librarians Lois Cottrell and Jean Maragno for their invaluable help with structuring and performing their search.

Financial Support: By the Hamilton Chapter of the Canadian Intensive Care Foundation and the Critical Care Medicine Residency Program and Critical Care Division Alternate Funding Plan, both at McMaster University. Dr. Cook is supported by the Canadian Institutes of Health Research.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0178.

Requests for Single Reprints: Deborah J. Cook, MD, Academic Chair, Critical Care Medicine, Room D176, St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, Ontario L8N 3A5, Canada; e-mail, debcook@mcmaster.ca.

Current Author Addresses: Dr. Rochwerg: Critical Care Program Office, 2V3, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.

Dr. Alhazzani: St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Dr. Sindi: Department of Anesthesia and Critical Care, King Abdulaziz University Hospital, PO Box 80215, Jeddah 21589, Kingdom of Saudi Arabia.

Ms. Heels-Ansdell: Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, HSC-2C13, Hamilton, Ontario L8S 4K1, Canada.

Dr. Thabane: St. Joseph's Healthcare Hamilton, 3rd Floor, Martha Wing, Room H-325, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Dr. Fox-Robichaud: McMaster University, DBRI C5-106, 237 Barton Street East, Hamilton, Ontario L2L 2X2, Canada.

Mr. Mbuagbaw: Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, 1280 Main Street West, HSC 2C7, Hamilton, Ontario L8S 4K1, Canada.

Drs. Szczeklik and Włudarczyk: Jagiellonian University Medical College, Skawińska 8, 31-066, Krakow, Poland.

Dr. Alshamsi: 1461 Upper Gage Avenue, Unit 7, Hamilton, Ontario L8W 1E6, Canada.

Dr. Altayyar: 67 Caroline Street South, Apartment 4A, Hamilton, Ontario L8P 3K6, Canada.

Dr. Ip: 602-10 John Street, Dundas, Ontario L9H 6J3, Canada.

Mr. Li: 49 Emerson Street, Hamilton, Ontario L8S 2X5, Canada.

Dr. Wang: Department of Internal Medicine, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 3Z5, Canada.

Dr. Guyatt: McMaster University Health Sciences Centre, 1280 Main Street West, Room HSC-2C12, Hamilton, Ontario L8S 4K1, Canada.

Dr. Cook: Academic Chair, Critical Care Medicine, Room D176, St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, Ontario L8N 3A5, Canada.

Dr. Jaeschke: 301 James Street South, Room F506, Hamilton, Ontario L8P 3B6, Canada.

Dr. Annane: General Intensive Care Unit, Raymond Poincaré Hospital (Assistance Publique-Hôpitaux de Paris), University of Versailles Saint-Quentin-en-Yvelines, 104 Boulevard Raymond Poincaré, 92380 Garches, France.

Author Contributions: Conception and design: B. Rochwerg, W. Alhazzani, A. Sindi, L. Thabane, L. Mbuagbaw, W. Szczeklik, G.H. Guyatt, R. Jaeschke, D. Annane.

Analysis and interpretation of the data: B. Rochwerg, W. Alhazzani, A. Sindi, D. Heels-Ansdell, L. Thabane, L. Mbuagbaw, W. Szczeklik, G.H. Guyatt, D.J. Cook, R. Jaeschke, D. Annane.

Drafting of the article: B. Rochwerg, W. Alhazzani, A. Sindi, W. Szczeklik, R. Jaeschke, D. Annane.

Critical revision of the article for important intellectual content: B. Rochwerg, W. Alhazzani, A. Sindi, L. Thabane, A. Fox-Robichaud, L. Mbuagbaw, W. Szczeklik, G.H. Guyatt, D.J. Cook, R. Jaeschke, D. Annane.

Final approval of the article: B. Rochwerg, W. Alhazzani, A. Sindi, D. Heels-Ansdell, L. Thabane, A. Fox-Robichaud, L. Mbuagbaw, W. Szczeklik, G. Li, G.H. Guyatt, D.J. Cook, R. Jaeschke, D. Annane.

Provision of study materials or patients: D. Annane.

Statistical expertise: B. Rochwerg, D. Heels-Ansdell, L. Thabane, L. Mbuagbaw, Q. Zhou.

Obtaining of funding: R. Jaeschke.

Administrative, technical, or logistic support: B. Rochwerg, W. Alhazzani, A. Sindi.

Collection and assembly of data: B. Rochwerg, W. Alhazzani, A. Sindi, L. Mbuagbaw, W. Szczeklik, F. Alshamsi, W.C. Ip, G. Li, A. Włudarczyk, R. Jaeschke, D. Annane.


Ann Intern Med. 2014;161(5):347-355. doi:10.7326/M14-0178
Text Size: A A A

Background: Fluid resuscitation is the cornerstone of sepsis treatment. However, whether balanced or unbalanced crystalloids or natural or synthetic colloids confer a survival advantage is unclear.

Purpose: To examine the effect of different resuscitative fluids on mortality in patients with sepsis.

Data Sources: MEDLINE, EMBASE, ACP Journal Club, CINAHL, HealthSTAR, the Allied and Complementary Medicine Database, and the Cochrane Central Register of Controlled Trials through March 2014.

Study Selection: Randomized trials that evaluated different resuscitative fluids in adult patients with sepsis or septic shock and death. No language restrictions were applied.

Data Extraction: Two reviewers extracted data on study characteristics, methods, and outcomes. Risk of bias for individual studies and quality of evidence were assessed.

Data Synthesis: 14 studies (18 916 patients) were included with 15 direct comparisons. Network meta-analysis at the 4-node level showed higher mortality with starches than with crystalloids (high confidence) and lower mortality with albumin than with crystalloids (moderate confidence) or starches (moderate confidence). Network meta-analysis at the 6-node level showed lower mortality with albumin than with saline (moderate confidence) and low-molecular-weight starch (low confidence) and with balanced crystalloids than with saline (low confidence) and low- and high-molecular-weight starches (moderate confidence).

Limitations: These trials were heterogeneous in case mix, fluids evaluated, duration of fluid exposure, and risk of bias. Imprecise estimates for several comparisons in this network meta-analysis contribute to low confidence in most estimates of effect.

Conclusion: Among patients with sepsis, resuscitation with balanced crystalloids or albumin compared with other fluids seems to be associated with reduced mortality.

Primary Funding Source: The Hamilton Chapter of the Canadian Intensive Care Foundation and the Critical Care Medicine Residency Program and Critical Care Division Alternate Funding Plan at McMaster University.

Figures

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Figure.

Summary of evidence search and selection.

AMED = Allied and Complementary Medicine Database; CENTRAL =Cochrane Central Register of Controlled Trials; RCT = randomized, controlled trial.

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Appendix Figure 1.

Network map for 4-node analysis.

HES = hydroxyethyl starch.

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Appendix Figure 2.

Network map for 6-node analysis.

BC = balanced crystalloid; H-HES = high-molecular-weight hydroxyethyl starch; L-HES = low-molecular-weight hydroxyethyl starch.

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Appendix Figure 3.

Forest plot for mortality in direct comparisons of all crystalloids vs. all colloids.

M–H = Mantel–Haenszel.

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Albumin administration in patients with sepsis
Posted on August 1, 2014
Mao Zhang, PhD, MD, Libing Jiang, Yuefeng Ma Ph.D M.D
Zhejiang University
Conflict of Interest: None Declared

We have read the article “Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysis” by Rochwerg et al (1). In this net meta-analysis, the authors concluded that albumin is superior to crystalloids and starches. However, several studies comparing albumin and other fluids directly were not included in their study. Therefore, we performed an updated meta-analysis, based on a previous meta-analysis (2). 6 studies by Dr. Joachim Boldt (because of suspected lack of integrity) and 3 studies focused on pediatric population were excluded. In addition, we added 3 recently published studies (CRISTAL, EARSS and ALBIOS). Finally, 9 studies compared albumin with crystalloid solutions (OR, 0.91 [0.77 to 1.06]), 7 studies compared albumin with starches (OR, 0.92 [0.48 to 1.76]), and 1 study compared albumin with gelofusine (OR, 1 [0.09 to 11.03]). After excluding the SAFE study, the pooled RR was 0.99 (95%CI, 0.80 to 1.22), which also suggested that there was no difference on mortality between albumin and crystalloids. There was no heterogeneity between studies. In the ALBIOS study (3), we only included patients received albumin within 6 hours after randomization which is mainly used for resuscitation. Our results suggested that there were no significant effects of albumin on mortality rate, compared with other fluids, which is inconsistent with the conclusion of Rochwerg et al (1). Moreover, albumin can be anywhere between 20 and 100 times more expensive than crystalloids, and it has been reported that the cost per case avoided based on the results of the EARSS study is $31,220 (4, 5), and albumin cost effectiveness is most dependent on its ability to lower risk of death (4). In addition, there are several problems about albumin remains unclear. Firstly, which concentration of albumin should be used (4-5% vs 20-25%)? Secondly, how much albumin dose should be used? Thirdly, when to start using? Therefore, it would be better if the authors described the above mentioned affecting factors in more detail. And there might be potential publication bias in the study by Rochwerg et al (1). due to several studies have not been included in this meta-analysis. Given the limited ability to lower risk of death and high price of albumin, and several uncertainties, crystalloids should be the first choice for fluid resuscitation in sepsis patients.

 

Reference:

  1. Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, et al. Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysis. Ann Intern Med. 2014. [PMID: 25047428]
  2. Delaney AP, Dan A, McCaffrey J, Finfer S. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med. 2011;39(2):386-91. PMID: 21248514
  3. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370(15):1412-21. [ PMID: 24635772]
  4. Latour-Perez J. New recommendations for the use of serum albumin in patients with severe sepsis and septic shock. Crit Care Med. 2013;41(10):e289. [ PMID: 24060790]
  5. Lyu PF, Murphy DJ. Economics of fluid therapy in critically ill patients. Curr Opin Crit Care. 2014;20(4):402-7. [ PMID: 24979711]

 

Author's Response
Posted on October 20, 2014
Bram Rochwerg, MD, Waleed Alhazzani MD, Roman Jaeschke, MD, Deborah Cook, MD
McMaster University
Conflict of Interest: None Declared
We thank Zhang et al for their points concerning the administration of albumin for resuscitation in patients with sepsis. The methods of their meta-analysis differ from our network meta-analysis (NMA) in several respects, and it is thus unsurprising that our results are discordant. We used a NMA-framework which has the advantage of incorporating indirect evidence as opposed to only direct evidence as in a conventional meta-analysis. Regarding several prominent trials, we excluded ALBIOS[1] and EARSS[2] because albumin administration in these trials was independent of hemodynamic instability, and the focus of our NMA was resuscitation fluid. We only included the CRISTAL study[3] in the pair-wise meta-analysis of colloids versus crystalloids because patients were randomized to receive any colloids or any crystalloids. Although results were presented in the CRISTAL report based on specific fluid received, this was not a randomization characteristic; accordingly, we did not integrate these data in our NMA due to the potential for bias. Finally, we included the SAFE trial [4] whereas Zhang et al excluded it for unclear reasons

We agree that for most patients with sepsis, the first choice resuscitative fluid should be crystalloid. The results of our NMA suggest that a ‘balanced’ crystalloid solution with a more physiologic chloride concentration may be preferred, but we believe that more research is needed to confirm or refute this finding [5].

Although the confidence intervals around the mortality estimate comparing albumin to any crystalloid (NMA OR 0.83, 95% Credible Interval 0.65-1.04) include the potential that albumin confers mortality benefit, this must be balanced against important considerations of cost and transfusion risk. Our results show that albumin, at worst, appears to be similar to crystalloids with respect to mortality risk. When used for resuscitation, research is sparse to guide the choice of dose, concentration, or timing of albumin. Presently, we do not advocate that albumin be used as a first choice for resuscitation in sepsis. However, until further research becomes available suggesting otherwise, we believe that it is reasonable to include albumin as one potential resuscitative fluid.

Meanwhile, in clinical practice, most patients will continue to receive a combination of fluids for resuscitation rather than a single subtype, guided by physiologic parameters and sometimes factors such as institutional policies, physician preferences, or fluids readily at hand.


References:
1. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G et al: Albumin replacement in patients with severe sepsis or septic shock. The New England journal of medicine 2014, 370(15):1412-1421.
2. Charpentier J MJ, Group ES.: Efficacy and tolerance of hyperoncotic albumin
administration in septic shock patients: the EARSS study. Intensive care medicine 2011, 37(suppl 1):S115.
3. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declere AD, Preiser JC, Outin H, Troche G, Charpentier C et al: Effects of Fluid Resuscitation With Colloids vs Crystalloids on Mortality in Critically Ill Patients Presenting With Hypovolemic Shock: The CRISTAL Randomized Trial. JAMA : the journal of the American Medical Association 2013.
4. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. The New England journal of medicine 2004, 350(22):2247-2256.
5. Rochwerg B, Wludarczyk A, Szczeklik W, Alhazzani W, Sindi A, Guyatt G, Jaeschke R: Fluid resuscitation in severe sepsis and septic shock: systematic description of fluids used in randomized trials for researchers and clinicians. Polskie Archiwum Medycyny Wewnetrznej 2013.


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