Intravenous (IV) fluid resuscitation

Intravenous fluid resuscitation in sepsis and critical illnesses  p. 148
Prabhakar Gupta, Kuldeep Kumar Ashta
DOI:10.4103/jmms.jmms_9_18  
Intravenous (IV) fluid resuscitation, pioneered in 1832, is now one of the most common medical interventions in hospitalized patients. Up until the end of the 20th century, IV fluid prescriptions have been considered ancillary, benign interventions and rarely tested in good-quality randomized clinical trials (RCTs). Robust clinical research evidence emerging in the past decade and a half, however, has revealed counterintuitive findings. The emerging research has consistently demonstrated harm, including higher mortality, and questionable clinical benefits associated with protocolized aggressive fluid resuscitation, as espoused in the early goal-directed therapy. Conservative fluid management has been shown to be associated with better outcomes in most clinical settings. Recent RCTs have also revealed clinically relevant pharmacological differences between types of IV fluids, especially pertaining to predictable harms associated with some commonly used IV fluids. Concerns have emerged over risks of metabolic acidosis and renal failure associated with the use of normal saline. Balanced solutions have been found to be safe across a wide spectrum of conditions. Better understanding of the complex pathophysiology of sepsis and critical illnesses and recognition of newer concepts such as profound disruption of the endothelial glycocalyx layer leading to profound leakiness of vessels question the basic premise of injection of large quantities of IV fluids during resuscitation.
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Introduction

During the course of the past two centuries, due to a general absence of robust evidence, intravenous (IV) fluid use in resuscitation was largely guided by empirical institutional protocols or prescriber preferences.^[1]

A major inflection point in the history of IV fluid resuscitation was the publication of early goal-directed therapy (EGDT) model of IV fluid resuscitation as incorporated in the Surviving Sepsis Campaign Guidelines (SSCG).^[2] Although intended for use in sepsis, due to widespread popularity and endorsements, EGDT became a standard of care not just in sepsis but also in other critical illnesses necessitating fluid resuscitation.^[3] EGDT popularized infusions of large quantities (in some instances measurable in gallons) of crystalloids, in an effort to achieve, untested, arbitrarily predetermined, fixed metrics such as 8 mmHg of central venous pressure (CVP).^[4] Till date, there is no upper cutoff limit of dose of IV fluid to be infused within the first 6 h, prescribed in EGDT or SSCG.

Over the last decade, EGDT has been tested in several large, high-quality clinical trials and the results have been counterintuitive and consistent across various studies and diverse settings.^[5],[6],[7]

In a patient-level meta-analysis of ProMISe, ARISE, and ProCESS, which analyzed data of 3723 patients at 138 centers, in seven countries spread over three continents, the use of EGDT versus usual care did not result in any difference in mortality at 90 days. EGDT was also associated with greater use of intensive care and cardiovascular support and treatment costs. Moreover, EGDT was not beneficial even in specific subgroups of more severely ill patients such as those with hyperlactatemia, hypotension with hyperlactatemia, or higher predicted risk of death.^[8]

A review of basic research and clinically relevant newer insights into the complex pathophysiology of circulatory system and transmembrane fluid shifts during acute illnesses may tender some explanations and may help us understand the consistent, counterintuitive results of harm from aggressive IV fluid resuscitation as shown in recent high-quality randomized clinical trials (RCTs) and meta-analyses.

Resuscitation Physiology

Classic model

Classic model of resuscitation physiology envisages (a) a circulatory system with "physical or mechanical plumbing" characteristics defined by forward and backward hydrostatic pressures, (b) the cardiac activity serving as the "motor" of the pump, (c) sympathetic activity, which may increase cardiac output and arterial and venous tones and pressures, and (d) compartment model of diffusion of fluids which presumes that only the capillaries and postcapillary venules permit transmembrane fluid flow.

These mechanisms were postulated to explain circulatory and fluid physiology in health and/or simplified deviations from healthy state. Clinical conditions meriting IV fluid resuscitation such as sepsis, burns, and trauma, however, have an exceedingly complex, dynamically changing circulatory, hemodynamic, endothelial, and neurohormonal pathophysiology.^[9]

Current Approaches to Resuscitation Physiology

Aggressive fluid resuscitation may have been predicated on the rather reductionist premise that hypotension in critical illnesses is a consequence of volume loss and that mechanically pumping large quantities of IV fluid on the venous side of the circulation may faithfully and incrementally be transformed into raised hydrostatic pressure and forward flow in the arterial circulation.

Robust RCTs in the past two decades have shown that this is not the case and a closer examination of certain key aspects of resuscitation physiology may illustrate the mechanisms of potential harm and lack of intended therapeutic gains of aggressive fluid therapy in resuscitation. A focused discussion of key aspects of resuscitation physiology specifically relevant to bolus IV fluid resuscitation is attempted below.

Venous system

The arterial system and the left side of the heart are usually the focus of deliberations in ischemic heart disease. Due to certain unique characteristics, however, the venous system acquires more significance in resuscitation physiology and critical illnesses. During resuscitation, for example, large quantities of fluids are directly injected into the venous system. Compliance of veins is 30-fold higher than arteries and the venous system accommodates 70% of the total blood volume as compared to only 18% in the arteries.^[10]

Unstressed volume, stressed volume

The blood volume which can be accommodated in the venous system without exerting any hydrostatic pressure is the unstressed volume. The volume of blood, over and above the unstressed volume, which stretches the veins and results in the emergence of positive hydrostatic pressure in the venous system is called the stressed volume.^[4]

Theoretically, when the heart is stopped (zero flow), the hydrostatic pressure exerted by the intravascular volume on the vasculature is called the mean circulatory filling pressure (MCFP).

Stressed volume in the venous system is the major contributor for the MCFP, which in turn is the major determinant of venous return. Venous return occurs when the MCFP, which normally is 8–10 mmHg, exceeds the CVP.^[4]

Circulatory hemodynamic effects of intravenous fluid boluses

Due to a large capacitance and a constant compliance, the venous system can accommodate large IV infusion volumes resulting in relatively small increases in MCFP. Conversely, due to restraining effects of the pericardium and the cardiac cytoskeleton, the diastolic compliance of both ventricles rapidly reduces with increasing distending volumes resulting in relatively large and rapid increases in the CVP.^[11]

Therefore, with bolus infusions, the CVP increases disproportionately faster than the MCFP, thereby reducing the gradient of blood flow from the venous system to the right atrium (the venous return).

The driving force for organ blood flow is the pressure difference between the mean arterial pressure and the CVP. Thus, a rapidly rising CVP (as might happen during IV bolus) not only reduces the gradient for venous return but also reduces forward blood flow through the organs.^[11]

CVP is the major determinant of capillary blood flow. The higher the CVP, the lesser the capillary flow.^[11]

Thus, we see that rapid infusion of fluid boluses may not improve circulatory hemodynamics and, on the contrary, may actually impede forward flow in the circulation and venous return.

Vasoplegia

A primary pathology in severe sepsis, septic shock, and critical illnesses is vasoplegia and not dehydration which may or may not be present as an epiphenomenon.^[12]

Vasoplegia leads to arterial dilatation resulting in systemic hypotension. More importantly, there is profound venodilation, especially in the splanchnic and cutaneous vascular beds.

There is no mechanism by which IV fluid infusion can improve vasoplegia. Bolus IV fluid infusions in the setting of profound vasoplegia can however rapidly increase the unstressed volume and CVP, thereby reducing venous return and cardiac output. Vasoplegia improves either with vasopressors or with spontaneous homeostasis over time.

Cardiac Physiology

Fluid administration will only result in increase of stroke volume (SV) when both of two conditions are met, namely (i) the fluid bolus increases the MCFP more than the CVP. We have seen in the preceding discussion that rapid fluid boluses are likely to raise the CVP more than the MCFP^[13] and (ii) both ventricles are functioning on the ascending limb of the Frank–Starling curve.

Sepsis-associated myocardial dysfunction tends to flatten the Frank–Starling curve. Up to 50% of patients with sepsis may have systolic dysfunction.^[14]

Furthermore, due to high prevalence of lifestyle diseases in the hospitalized population, left ventricular diastolic dysfunction is emerging as an important finding in patients with severe sepsis and septic shock.^[15] Patients with diastolic dysfunction respond very poorly to fluid loading. In such patients, fluid challenges will result in increased cardiac filling pressures, increased pulmonary and venous hydrostatic pressures, increased release of natriuretic peptides, with minimal, if any rise in SV.^[4],[16]

Endothelial and Microcirculatory Dysfunction

There is a marked endothelial dysfunction in sepsis characterized by increased expression and activation of endothelial adhesion molecules, resulting in increased adhesion and activation of leukocytes and platelets, and the net effect is marked leakiness and heterogeneous abnormalities in microcirculatory blood flow.^{[9],[17],[18],[19]}

Furthermore, aggressive fluid therapy leads to increased cardiac filling pressures which results in release of natriuretic peptides. Natriuretic peptides profoundly disrupt the glycocalyx structure and function, leading to increased vascular leakiness.^[18],[19] Increased natriuretic peptides also reduce lymphatic drainage by reducing lymphatic propulsive motor activity.^[20]

Fluid Responsiveness

A significant finding from fluid resuscitation studies over the years is that only 50% of the patients are fluid responders.

Here, three key concepts need to be emphasized.

1. There is no physiologic rationale for bolus IV fluid infusions in fluid nonresponders
2. Even in the fluid responders, once the optimal preload is achieved, any additional increase in preload does not result in any appreciable increase in SV and results in harm, in that, right atrial pressure (RAP) rapidly increases resulting in increased pulmonary and venous hydrostatic pressures, release of natriuretic peptides resulting in shift of fluid into the interstitial tissue causing pulmonary and tissue edema. In addition, due to sepsis-associated myocardial dysfunction, these adverse hemodynamic effects may appear at a lower fluid dose, even before the optimal preload is achieved^[20]
3. Disproportionately large fraction of the infused fluid will promptly leak out into the extravascular space. In healthy volunteers, of the infused volumes of crystalloids, only 15% remains in the intravascular space at 3 h. Due to endothelial disruption, in sepsis, less than 5% of a crystalloid bolus remains in the intravascular space at 1 h^[21]

Thus, the intended hemodynamic gains of IV fluid bolus, even in fluid responders, are short-lived, and most of the infused bolus will rapidly accumulate in the interstitial space leading to tissue edema.

Implications on Intravenous Fluid Therapeutics

It is obvious from the above discussion that aggressive, goal-directed IV fluid resuscitation algorithmized to meet externally decided static metrics such as CVP is fraught with pitfalls. It may be noted that while residents and house officers may have a liking for customized algorithms, these, as is the case of EGDT, have been proven to be harmful. Rather, under the following subheadings, we propose suggestions, based on the emerging evidence, on caution and discretion in the use of volumes and types of IV fluids in day-to-day settings with an aim to reduce harm arising from individual fluid prescriptions.

Dose of Fluid Therapy

Initial bolus

Ideally, the initial fluid bolus should aim to replace the extant volume lost and the anticipated ongoing losses in the next few hours.

Many conditions with hypotension, however, may not be fluid depleted states. In sepsis, the dominant physiology is of profound vasoplegia, vascular leakiness, and fluid redistribution, rather than dehydration, unless there are other associated causes of fluid loss such as fever and poor oral intake.

Till date, the best trial comparing the effects of IV fluid boluses with no boluses in critical illness is the landmark Fluid Expansion as Supportive Therapy trial (FEAST). In this multicenter RCT involving 3141 children with severe sepsis and demonstrated evidence of fluid depletion, any fluid boluses, when compared to no fluid bolus, were strongly associated with higher mortality and morbidity. The statistical significance was of such magnitude that the trial had to be stopped on ethical grounds.^[22] These findings are congruent with other high-quality clinical research in fluid therapeutics emerging over the past decade.^{[5],[6],[7],[8]}

The fact that, in the FEAST trial subjects, even in patients with proven volume depletion, IV fluid boluses, when compared to no bolus resulted in higher mortality, should compel us to revisit the widely held premise that IV fluid therapy is a central pillar of management of critical illnesses.^[4]

Considering the above, a reasonable approach may be using a therapeutic trial of a small bolus, approximately 250–500 mL of a crystalloid, in the setting of systolic hypotension and oliguria. If the blood pressure does not respond, consideration should be given for addressing possible concomitant vasoplegia with vasopressors. If the initial bolus has failed, repeat "fluid challenges" have no role and may prove counterproductive.^[4],[23]

Maintenance fluids

After initial fluid resuscitation, a subset of patients, especially those who have poor oral intake, may need maintenance fluids, with an aim to preserving the extracellular volume while maintaining a normal electrolyte balance.

However, in actual practice, maintenance fluids are often routinely prescribed. Some of these patients may have already received a large positive balance in the acute resuscitation period. Subjecting them to further daily prescriptions of maintenance fluids without compelling indications may lead to a large cumulative fluid balance over several days.^[24],[25]

In a high-quality, prospective RCT, conservative late fluid management was associated with lesser morbidity and mortality as compared to liberal fluid policy.^[26]

Maintenance fluids should only be prescribed if there are clear indications. Maintenance fluids should be actively stopped if there is no compelling indication for ongoing fluid administration. The quantity of maintenance fluids should be estimated individually in each patient with an emphasis on frequent audits of cumulative fluid balance since admission, aiming to avoid positive balance.^[1],[26]

Type of Fluid Therapy

The composition of IV fluids may have a bearing on context-specific outcomes, especially related to potential harm. Different types of IV fluids should be prescribed after factoring in patient-specific and context-specific differences.^[1],[23]

Colloids

The findings of the landmark saline versus albumin fluid evaluation (SAFE) and FEAST studies assuaged concerns about safety of albumin raised in a Cochrane review. However, the data did not reveal any significant advantage of albumin over saline, thereby challenging long-held concepts about the advantages of albumin as a resuscitation solution.^[27],[28]

In volume-depleted states requiring resuscitation, it appears that albumin, which is more expensive and less easily available, offers no distinct advantages over saline in patient-centered outcomes.

Semisynthetic colloids

A range of semisynthetic colloids including HES solutions, succinylated gelatin, and dextran solutions were developed to offset the constraints of cost and availability of albumin. However, research has revealed clinically relevant safety concerns with the use of semi-synthetic colloids.^{[29],[30],[31]}

In view of the lack of clinical benefit, evidence of potential nephrotoxicity, decreased availability, and higher costs, the inclusion of semisynthetic colloids in fluid resuscitation protocols in critically ill patients is questionable.

Crystalloids

Normal saline

Worldwide, sodium chloride (normal saline) is the most commonly used crystalloid solution.

Due to the strong ion difference of 0.9% saline being zero, administration of large quantities of normal saline leads to hyperchloremic metabolic acidosis.

The hyperchloremic metabolic acidosis related to large volume bolus infusion of normal saline may lead to immune and renal dysfunction, including reduced renal blood flow, electrolyte disturbances, acute kidney injury, renal replacement therapy utilization, postoperative infections, acidosis investigations, and costs.^[32],[33]

Hence, normal saline should not be the first choice of IV fluid in most critical illnesses necessitating IV fluid resuscitation. Normal saline may be an appropriate choice in conditions associated with alkalosis such as dehydration resulting from protracted emesis. To avoid the potential hypotonicity associated with balanced solutions, normal saline may be the preferred choice among maintenance fluids.^[23]

Balanced solutions

Crystalloids designed to have a pH and chemical composition similar to extracellular fluid are called "balanced" or "physiologic" solutions. The most widely used of such solutions are Hartmann's and Ringer's solutions and their derivatives. However, none of these solutions achieve the true composition of extracellular fluid.

Due to a sodium concentration lower than the extracellular fluid, balanced solutions are hypotonic. To offset the instability of bicarbonate-containing balanced solutions in plastic containers, other anions, such as lactate, acetate, gluconate, and malate are used.

Administration of large quantities of balanced solutions may theoretically lead to hyperlactatemia, metabolic alkalosis, and hypotonicity (with compounded sodium lactate) and cardiotoxicity (with acetate). The calcium contained in some balanced solutions may lead to production of microthrombi when co-administered with citrate-containing red-cell transfusions.^[23]

However, when tested in a wide spectrum of clinical settings, among all IV fluids, balanced solutions have shown the best safety profile including burns, diabetic ketoacidosis, and trauma and patients undergoing surgery.^{[34],[35],[36],[37]}

Conclusions

The physiology of sepsis and other similar critical illnesses is dynamically dysfunctional and dominated by marked vascular leakiness, myocardial depression, and profound vasoplegia. Most of the injected IV fluid rapidly leaks into the interstitial compartment, even in healthy individuals, and more promptly and profoundly so in critically ill patients.

The findings of FEAST, ProMISe, ProCESS, ARISE, PRISM, and CHEST are particularly important because they reveal potential harm or lack of benefit of widely practiced and advocated aggressive fluid resuscitation policies such as espoused in the EGDT protocol. The evidence is relatively robust, congruent across various studies, and in line with newer understanding of the complex, biologically dynamic physiology of acute illnesses.

These vital findings of high-quality clinical research emerging in the preceding two decades represent a paradigm change in our understanding of fluid therapeutics and critical illness physiology. This paradigm shift should be discussed widely so that the newly recognized potential harms related to the extant practice of algorithmized aggressive fluid resuscitation may be mitigated and patients may benefit with a more informed and judicious use of IV fluids in sepsis and critical illnesses.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

References

1.	McDermid RC, Raghunathan K, Romanovsky A, Shaw AD, Bagshaw SM. Controversies in fluid therapy: Type, dose and toxicity. World J Crit Care Med 2014;3:24-33.
2.	Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
3.	Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304-77.
4.	Marik P, Bellomo R. A rational approach to fluid therapy in sepsis. Br J Anaesth 2016;116:339-49.
5.	Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015;372:1301-11.
6.	ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, et al. Arandomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-93.
7.	ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-506.
8.	PRISM Investigators, Rowan KM, Angus DC, Bailey M, Barnato AE, Bellomo R, et al. Early, goal-directed therapy for septic shock – A patient-level meta-analysis. N Engl J Med 2017;376:2223-34.
9.	Levick JR, Michel CC. Microvascular fluid exchange and the revised starling principle. Cardiovasc Res 2010;87:198-210.
10.	Funk DJ, Jacobsohn E, Kumar A. The role of venous return in critical illness and shock-part I: Physiology. Crit Care Med 2013;41:255-62.
11.	Vellinga NA, Ince C, Boerma EC. Elevated central venous pressure is associated with impairment of microcirculatory blood flow in sepsis: A hypothesis generating post hoc analysis. BMC Anesthesiol 2013;13:17.
12.	Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med 2001;345:588-95.
13.	Marik PE. The physiology of volume resuscitation. Curr Anesthesiol Rep 2014;4:353-9.
14.	Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984;100:483-90.
15.	Sanfilippo F, Corredor C, Fletcher N, Landesberg G, Benedetto U, Foex P, et al. Diastolic dysfunction and mortality in septic patients: A systematic review and meta-analysis. Intensive Care Med 2015;41:1004-13.
16.	Ognibene FP, Parker MM, Natanson C, Shelhamer JH, Parrillo JE. Depressed left ventricular performance. Response to volume infusion in patients with sepsis and septic shock. Chest 1988;93:903-10.
17.	Ait-Oufella H, Maury E, Lehoux S, Guidet B, Offenstadt G. The endothelium: Physiological functions and role in microcirculatory failure during severe sepsis. Intensive Care Med 2010;36:1286-98.
18.	Woodcock TE, Woodcock TM. Revised starling equation and the glycocalyx model of transvascular fluid exchange: An improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth 2012;108:384-94.
19.	Lee WL, Slutsky AS. Sepsis and endothelial permeability. N Engl J Med 2010; 363:689-691.
20.	Nunes TS, Ladeira RT, Bafi AT, de Azevedo LC, Machado FR, Freitas FG, et al. Duration of hemodynamic effects of crystalloids in patients with circulatory shock after initial resuscitation. Ann Intensive Care 2014;4:25.
21.	Hilton AK, Bellomo R. A critique of fluid bolus resuscitation in severe sepsis. Crit Care 2012;16:302.
22.	Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364:2483-95.
23.	Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med 2013;369:1243-51.
24.	Acheampong A, Vincent JL. A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care 2015;19:251.
25.	Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, et al. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: A systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther 2014;46:361-80.
26.	National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564-75.
27.	Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: Systematic review of randomised controlled trials. BMJ 1998;317:235-40.
28.	Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R, et al. Acomparison of albumin and saline for fluid resuscitation in the Intensive Care Unit. N Engl J Med 2004;350:2247-56.
29.	Hartog CS, Reuter D, Loesche W, Hofmann M, Reinhart K. Influence of hydroxyethyl starch (HES) 130/0.4 on hemostasis as measured by viscoelastic device analysis: A systematic review. Intensive Care Med 2011;37:1725-37.
30.	Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125-39.
31.	Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, et al. Hydroxyethyl starch 130/0.42 versus ringer's acetate in severe sepsis. N Engl J Med 2012;367:124-34.
32.	Kellum JA, Song M, Li J. Science review: Extracellular acidosis and the immune response: Clinical and physiologic implications. Crit Care 2004;8:331-6.
33.	Hadimioglu N, Saadawy I, Saglam T, Ertug Z, Dinckan A. The effect of different crystalloid solutions on acid-base balance and early kidney function after kidney transplantation. Anesth Analg 2008;107:264-9.
34.	Haberal M, Sakallioglu Abali AE, Karakayali H. Fluid management in major burn injuries. Indian J Plast Surg 2010;43:S29-36.
35.	Chua HR, Venkatesh B, Stachowski E, Schneider AG, Perkins K, Ladanyi S, et al. Plasma-lyte 148 vs. 0.9% saline for fluid resuscitation in diabetic ketoacidosis. J Crit Care 2012;27:138-45.
36.	ATLS Subcommittee, American College of Surgeons' Committee on Trauma, International ATLS working group. Advanced trauma life support (ATLS®): The ninth edition. J Trauma Acute Care Surg 2013;74:1363-6.
37.	Soni N. British consensus guidelines on intravenous fluid therapy for adult surgical patients (GIFTASUP): Cassandra's view. Anaesthesia 2009;64:235-8.