Fluid Resuscitation in Acute Illness — Time to Reappraise the Basics- NEW ENGLAND JOURNAL OF MEDICINE

Editorial
Fluid Resuscitation in Acute Illness — Time to Reappraise the Basics

John A. Myburgh, M.B., B.Ch., Ph.D.

May 26, 2011 (10.1056/NEJMe1105490)

Article
References

Fluid resuscitation is a fundamental intervention in the treatment of critically ill patients. However, there is little conclusive evidence to guide clinicians about the best type of resuscitation fluid; the appropriate timing, volume, and rate of fluid administration; and the optimal way to adequately monitor the efficacy and safety of fluid resuscitation in various clinical conditions.1

Although the complications associated with excessive volume of resuscitation fluid — such as pulmonary and interstitial edema — are well recognized, an emerging body of evidence suggests that the type of resuscitation fluid may adversely affect the outcomes in specific clinical conditions; for example, albumin is associated with increased mortality in patients with traumatic brain injury,2 and high-molecular-weight preparations of hydroxyethyl starch are associated with acute kidney injury in patients with severe sepsis.3

Conversely, improved outcomes associated with the use of albumin for resuscitation have been shown in children with severe malaria4 and in a subgroup of adults with severe sepsis in the Saline versus Albumin Fluid Evaluation study (SAFE; Current Controlled Trials number, ISRCTN76588266).5,6 However, these reports were not sufficiently conclusive to justify the adoption of strong clinical recommendations.

The results of the Fluid Expansion as Supportive Therapy (FEAST) trial,7 reported in this issue of the Journal, are an important contribution to the literature. This remarkable, pragmatic, randomized, controlled trial, conducted in six hospitals in Kenya, Tanzania, and Uganda, assessed the effects of bolus-fluid resuscitation with albumin or saline as compared with no bolus fluid in children with febrile medical illness and impaired perfusion. Children with severe hypotension, or decompensated shock, received boluses of either albumin or saline for resuscitation. The trial centers had no access to intensive care units, and the trial included a comprehensive education program aimed at optimizing early case recognition and by training in emergency pediatric life support. The primary outcome was 48-hour mortality — a relevant patient-centered outcome in regions in which the high prevalence of severe sepsis in children, often due to malaria, is associated with high early mortality.8

The trial was powered to determine a plausible absolute risk reduction in 48-hour mortality (as derived from power calculations described in the Methods section in the article) of 5 percentage points and was conducted with high standards of internal validity — excellent randomization procedures, a high rate of adherence to the protocol, concealment of the treatment assignments, a minimal loss to follow-up, the use of the intention-to-treat principle for the analyses, and performance of analyses according to prespecified subgroups. The sample size was appropriately increased from 2800 patients to 3600 patients after an interim analysis showed that the rate of death was lower than predicted in the intervention groups. However, the trial was stopped after the recruitment of 3141 patients when bolus-fluid resuscitation with albumin or saline was shown to increase the absolute risk of death at 48 hours by 3.3 percentage points and the risk of death, neurologic sequelae, or both at 4 weeks by 4 percentage points. No difference in mortality was observed in patients with decompensated shock, although these patients were few in number and had significantly higher mortality. The excess mortality associated with bolus-fluid resuscitation was consistent across all prespecified subgroups, which included subgroups according to age, lactate level, base deficit, presence or absence of severe anemia, and status with respect to coma and malaria.

These results will have an immediate effect on the way children presenting with febrile illness due to medical causes and with associated hypotension are treated in resource-poor settings. In conjunction with a program of education and training, discontinuation of the practice of bolus-fluid resuscitation in patients with febrile illness due to medical causes and impaired perfusion or compensated shock must be recommended. Given that 2 million children die from this condition each year in sub-Saharan Africa, the potential impact is enormous. Extrapolating these results to children with other hypotensive conditions, such as severe dehydration from gastroenteritis and malnutrition, burns, and surgery, is not justified on the basis of these data; further research would be required.

The results of the FEAST trial, as with those of other trials that generated results contrary to clinical opinion and practice,9,10 make it imperative that we reappraise the fundamentals. Early identification of shock, basic life support, and early antimicrobial therapy remain at the forefront of the clinical care of young patients with severe infection and shock. It is highly probable that education, training, and participation in a high-quality, randomized, controlled trial itself had a substantive positive effect on the overall rate of death, although these factors were not directly assessed in this trial. However, the entrenched practice of fluid-bolus resuscitation in patients with compensated shock remains highly questionable.

We can only speculate about the mechanisms by which bolus-fluid resuscitation had adverse biologic effects in these patients. Potential mechanisms may include the interruption of genetically determined catecholamine-mediated host defense responses by the rapid increase in plasma volume, which might result in a reperfusion injury. Similarly, transient hypervolemia or hyperosmolality might exacerbate capillary leak in patients who are susceptible to intracranial hypertension2 or pulmonary edema, with fatal consequences.

How should clinicians who work under circumstances different from those in this trial — that is, in high-income countries with access to intensive care units — or clinicians who care for adult patients interpret the results of this important trial? It seems clear that the results of this trial indicate that bolus-fluid resuscitation with either crystalloids or colloids in patients with compensated shock who do not have a clinical fluid deficit must be practiced with much greater caution than is now the case and with increased vigilance.

Fluid resuscitation is such a fundamental intervention in acute medicine that these results indicate that further high-quality research is urgently required to define appropriate practice for fluid resuscitation, including a study of the timing and rates of fluid administration and ways to monitor its effects. Similarly, a careful assessment of the safety, efficacy, and cost-effectiveness of various resuscitation fluids is mandatory before their incorporation into clinical practice.

The courage and dedication of the FEAST investigators and attending clinicians must be acknowledged, not only because of the quality of the research they conducted in this vitally important area of acute medicine, but also because they conducted a landmark trial in such challenging economic conditions in sub-Saharan Africa.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

This article (10.1056/NEJMe1105490) was published on May 26, 2011, at NEJM.org.
Source Information

From the George Institute for Global Health and University of New South Wales, Sydney.

Dr Chow Yok Wai - MD, MRCP(UK), AM(Mal)

1. Education
Basic Medical Qualification
University Attended: University of Science Malaysia
Degree Obtained: Doctor of Medicine (MD)
Date Awarded: 25th July 1999

MRCP (Member of the Royal College of Physicians)
Date Awarded: 22nd July 2003

2. Working Experience and Present Appointment
July 1999-October 2000
• Commenced internship training in Sultanah Aminah Hospital Johor Bahru
(HSAJB), Malaysia
• Underwent 18 months training in General Medicine, General Surgery
(Including Plastic Surgery, Urology, Neurosurgery and Paediatric Surgery),
Obstetrics and Gynaecology, Orthopaedics and General Paediatrics.
November 2000-March 2001
• Joined the Department of Medicine HSAJB as a medical officer
• Commenced subspeciality rotation in Nephrology
April 2001-October 2001
• Haematology rotation
November 2001-March 2002
• Neurology rotation
April 2002-November 2002
• Infectious Disease and Intensive Medicine rotation
December 2002-July 2003
• Cardiology, Respiratory Medicine, Gastroenterology and Endocrinology
rotation

July 2003-December 2004
• Granted membership to the Royal College of Physicians of United Kingdom
• Assigned to a 35 bedded general medical ward as general physician in Sultanah Aminah Hospital Johor Bahru, Malaysia upon completion of MRCP
January 2005-June 2006
• Commencement of Nephrology Subspeciality Training
(Nephrology Followship Programme) in HSAJB
July 2006-December 2007
• Completion of Nephrology Subspeciality Training in Kuala Lumpur
Hospital, Malaysia
January 2008- February 2010
• Attached to the Nephrology Unit, Department of Medicine, HSAJB as Consultant Nephrologist and Physician.

February 2010 – to date
• Consultant Nephrologist and Physician,
Hospital Pantai Ayer Keroh
75450, Melaka

3. Registration as a Medical Practitioner
5th July 2000
• Full registration with the Malaysian Medical Council

12th November 2008
• Full registration with the General Medical Council of United Kingdom

4. Official Gazettement by the Government of Malaysia (Ministry of Health)
22nd January 2005
• Gazetted as a Internal Medicine specialist

1st January 2008
• Gazetted as a Nephrologist


5. Professional Activities
2003
Clinical attachment in the New Royal Infirmary of Edinburgh, Scotland
Department of Nephrology

Position: Visiting Registrar
Supervisor: Dr Robin Winnie
Consultant Nephrologist
New Royal Infirmary of Edinburgh
Edinburgh


2008
Attended the Malaysian Nephrology Board Examination on 9th May 2008
Conducted by the Nephrology Board Malaysia
(Malaysian Society of Nephrology, Ministry of Health Malaysia, Academy of
Medicine, Malaysia)
Obtained the highest marks in the 2008 cohort


2008-2009
Awarded a full scholarship by the Public Services Department of Malaysia to
pursue a one year advance nephrology training in the field of vasculitis in Addenbrooke’s Hospital Cambridge University Hospitals NHS Foundation Trust


Position: Honorary Clinical Research Fellow

Supervisor: 1) Dr David Jayne
Director of Lupus and Vasculitis,
Addenbrooke’s Hospital
Cambridge University Hospitals NHS Foundation Trust

2) Professor Kenneth Smith
Cambridge Institute of Medical Research,
University of Cambridge,
United Kingdom.


2008- 2010
Coordinator for National Glomerulonephritis Registry, National Renal Registry
(Johor Bahru)


6. Professional Bodies
National
Member of the Malaysian Medical Association
Member of the Malaysian Society of Nephrology
Member of the Postgraduate Renal Society, Malaysia
International
Member of the Royal College of Physicians of Edinburgh
Member of the International Society of Nephrology
Member of the IgA International Network





7. Research Activities
Publications:-
Acute renal failure in the same hospital 10 years apart; A comparison of two prospective studies in Sultanah Aminah Hospital, Johor Bahru
Medical Journal of Malaysia Vol 62 No1 March 2007

Lactic acidosis in HIV patients receiving highly active antiretroviral therapy- the Johor Bahru experience
Medical Journal of Malaysia Vol 62 No 1 March 2007

Quality improvement in Department of Nephrology, Kuala Lumpur Hospital- an audit on clinical performance indicators
Journal of Quality Improvement Vol 10 No 2 2007

Rituximab in Behcet’s Disease
Submitted to Annals of Rheumatic Diseases for publication (May 2009)

Participation in clinical studies:-
National
HDP study- Hospitalisation rate among Dialysis Patients study (2007)

International
GIANT study- Greatest International Antibiotic Trial study (2006)

A randomized double blind placebo controlled multicenter study to evaluate the efficacy and safety of two doses of Ocrelizumab in patients with WHO or ISN Class III or IV nephritis due to systemic lupus erythematosus (2008)

A phase III multicentre, double blind, double dummy, randomized flexible dose comparative study of MCI-196 versus Simvastatin for the treatment of dyslipidaemia in subjects with chronic kidney disease on dialysis (2009)

Evaluation of chronic kidney disease patterns through the global information database (GRID) (2009)

Biologic therapies in neuro-behcet’s disease, an international collaborative case-series- neurobehcet study group, International Society of Behcet’s Disease (2009)

CHiC-TRIAD (Cambridge Hinxton Centre for Translational Research In Autoimmune Disease) (2008-2009)

MY-CYC (A randomised clinical trial of mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA associated vasculitis) (2008-2009)



Abstracts:-
National
OUTCOME OF A COMMUNITY BASED HEALTH SCREENING PROGRAMME DURING THE PUBLIC AWARENESS CAMPAIGN ON KIDNEY CARE IN JOHOR BAHRU, MALAYSIA
Oral Presentation- 22nd MSN Annual Seminar in Nephrology
Prevention of Chronic Kidney Disease

MYCOPHENOLATE MOFETIL IN RELAPSING LUPUS NEPHRITIS
23rd Malaysian Society of Nephrology Annual Seminar
Johor Bahru, Malaysia
11-13th April 2007

MYCOPHENOLATE MOFETIL IN MEMBRANOUS NEPHROPATHY
23rd Malaysian Society of Nephrology Annual Seminar
Johor Bahru, Malaysia
11-13th April 2007

International
ACUTE RENAL FAILURE IN THE SAME HOSPITAL 10 YEARS APART;
A COMPARISON OF TWO PROSPECTIVE STUDIES IN SULTANAH AMINAH
HOSPITAL, JOHOR BAHRU, MALAYSIA
Poster Presentation- 3rd World Congress of Nephrology
Post Congress Satellite Symposium
Acute Renal Failure: From Bench to Bedside
1st -3rd July 2005

LACTIC ACIDOSIS IN HIV PATIENTS RECEIVING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY- THE JOHOR BAHRU EXPERIENCE
Oral Presentation
14th IUSTI Asia Pacific International Conference- 27th to 30th July, 2006

ADULT POLYCYSTIC KIDNEY DISEASE IN PATIENTS ON DIALYSIS IN MALAYSIA
11th Asian Pacific Congress of Nephrology 2008

ELDERLY PATIENTS INITIATING DIALYSIS IN MALAYSIA
11th Asian Pacific Congress of Nephrology 2008

MALIGNANCY POST RENAL TRANSPLANTATION: A 25 YEAR EXPERIENCE
11th Asian Pacific Congress of Nephrology 2008

LATE ACUTE ANTIBODY MEDIATED REJECTION ASSOCIATED WITH CALCINEURIN INHIBITOR MINIMISATION
11th Asian Pacific Congress of Nephrology 2008

CASTLEMAN’S DISEASE OF THE KIDNEY IN PATIENT WITH SLE
11th Asian Pacific Congress of Nephrology 2008

CLINICAL BENEFITS OF ICODEXTRIN: A SINGLE CENTRE EXPERIENCE
11th Asian Pacific Congress of Nephrology 2008

‘SUDOKU’ INCREASES COGNITIVE FUNCTION IN HAEMODIALYSIS PATIENTS- A PROSPECTIVE PILOT STUDY (Awarded Best Abstract)
11th Asian Pacific Congress of Nephrology 2008

SHORT TERM INFECTIOUS COMPLICATIONS POST RENAL TRANSPLANT
11th Asian Pacific Congress of Nephrology 2008