Introduction
Our vastly improved ability to support failed organs over the past three decades should be balanced by the stark realization that outcomes have not improved commensurately. For example, crude mortality rates from infectious diseases in the United States have not altered since before the inception of intensive care [1]
Clearly, there has been a signifi cant change in case-mix that can be used in part- mitigation. Many patients being routinely admitted and aggressively treated in intensive care units (ICUs) in 2005 would not have been contemplated for such a degree of intervention twenty years previously. Advanced age, severe immuno- suppression and a poor underlying prognosis are no longer absolute contrain- dications to ICU admission. Provision of intensive care is steadily increasing worldwide and there is no political will at present to curb this growing demand.
Current growth rates in the requirement for intensive care, compounded in many cases by the ability to prolong death for weeks if not months, and a fi nite staff re- source with the appropriate level of expertise, requires us to re-evaluate current management practices to improve both our quality of care and our effi ciency.
A minority of ICU patients consumes approximately half the total resource in terms of bed days [2]. The relatively short-lived acute infl ammatory phase of multi-organ dysfunction is often followed by a prolonged period of established organ failure with a continued need for mechanical and/or drug support, close monitoring and nursing care. These periods are punctuated by further bouts of infection plus other causes of infl ammation and cardio-respiratory instability.
These downturns serve to prolong the organ dysfunction still further, and/or provide the excuse for withholding or withdrawing life-sustaining treatments.
Advances in pharmacological treatments are heavily trumpeted but, in real terms, have limited impact. For example, use of activated protein C in the UK is currently limited to approximately 2-3% of total ICU admissions. Given a number-needed-to-treat of 10 to save a life of the more severe septic patient cohort (i.e., APACHE II >24), few additional survivors will emerge as a conse- quence. Clearly, there could be an advantage to the individual patient from such a treatment, yet major reductions in overall ICU mortality will only be seen with generic treatments that are applicable across a signifi cant proportion of the ICU population.
It could be reasonably argued that the recent large multicenter studies show-
ing the biggest overall improvement to a general ICU cohort are those involving
M. Singer
reduced intervention, such as a lower hemoglobin threshold for blood transfu- sion [3] or reduced tidal volumes [4]. This signals an important point that will be expanded further in this chapter, namely an increased recognition of the potential harm we are infl icting on our patients by current ‘established’ thera- pies. I would extend this beyond mechanical ventilation and blood to encompass sedation, antibiotics, nutrition, inotropes and antipyretics as but fi ve common examples.
This chapter will be structured into four components and I will unashamedly adopt a philosophical slant. First, I will briefl y address the simple but crucial question as to what process exists whereby systemic infl ammation leads to mul- ti-organ failure (MOF)? This is a fundamental point that we have failed to prop- erly consider over several decades. Indeed, many of the assumptions currently harbored are not borne out by the existing literature. Improved understanding of these ‘organ failure’ inducing pathways will clearly lead to more appropriate treatments, both in terms of timing and mechanism of action. Second, I will suggest that MOF may actually be misunderstood and could well represent a last-ditch adaptive response by which the organs retain the potential to recover normal functioning after passage of the acute systemic infl ammatory insult [5].
Third, I will address the possibility that many of our current therapies may con- tribute to the development and/or delayed resolution of organ dysfunction. Last, I will attempt to predict how organ dysfunction will be managed 10 years from now, and this will encompass the fi rst three points.
How Does Systemic Infl ammation Lead to Multi-Organ Failure?
An acute insult such as infection, trauma or hemorrhage can provoke an acute, exaggerated systemic infl ammatory response. Clearly, there are genetic, exog- enous and other endogenous factors that determine why some individuals are affected more than others, and why different various combinations of organ dys- function occur. Our current knowledge base does not as yet permit identifi cation of high-risk individuals other than the recognition that patients with chronic organ disease are, in general, more susceptible.
The excess production of infl ammatory mediators leads to activation of mul-
tiple systems within the body, including immune, coagulation, hormonal, meta-
bolic and bioenergetic pathways. The circulation is affected early on, both at the
macro- and microcirculatory level. Myocardial depression, endothelial activa-
tion, increased capillary leak, intravascular coagulation, adherent neutrophils
and generalized loss of vascular tone are well-established phenomena. Howev-
er, these standard textbook descriptions belie certain facts, particularly in the
human being as opposed to the short-term, aggressive and often lethal animal
models upon which much of our knowledge of pathophysiology is based. For
example, acute tubular necrosis is a misnomer as the failed kidney in MOF usu-
ally looks remarkably normal; disseminated intravascular coagulation (DIC)
– particularly apparent with meningococcal sepsis – is a predominantly dermal
phenomenon with deeper organs essentially unaffected; lactic acidosis in sepsis
is not generally an ischemic phenomenon; while the overall loss of vascular tone
camoufl ages multiple areas of microvascular vasoconstriction within different organs.
Microvascular disruption has been elegantly demonstrated in sepsis, the de- gree of which has been associated with subsequent mortality [6]. However, the traditional concept of a disrupted microvasculature leading to tissue hypoxia, widespread cell death and organ dysfunction/failure is undermined and contra- dicted by a number of reproducible fi ndings in both patients and animal models.
First, tissue oxygen tensions are raised in established sepsis-induced organ fail- ure, and this has been demonstrated in organs as varied as skeletal muscle, gut and bladder [7–9]. Second, these failed organs look remarkably normal despite severe functional and biochemical abnormality [10, 11]. Hotchkiss et al. [10]
sampled multiple tissue biopsies soon after death in patients with MOF, specifi - cally seeking evidence of necrosis and/or apoptosis. Apart from a small degree of apoptosis found in spleen, gut epithelium, and lymphocytes, they highlight- ed the relative normality and remarkable lack of cell death in organs that may have been totally dysfunctional pre-mortem. Third, recovery of organ function occurs within days to weeks, well beyond the regenerative capacity of many of these tissues.
A new paradigm of organ failure must therefore be developed which encom- passes microvascular disruption though necessarily excludes large-scale cell death as a direct cause of organ dysfunction. We, and others, have demonstrated mitochondrial dysfunction in multiple organs in both patients and laboratory models [11, 12]. The rate of onset appears to be dictated by the severity of in- sult as contradictory results have been reported in short-term studies. However, all models lasting in excess of 16 hours uniformly show ultrastructural dam- age and/or biochemical dysfunction manifest as decreased respiratory enzyme activity or ATP levels [13]. Similar fi ndings have been made in muscle biopsies taken from patients in septic shock [12]. Of note, patients undergoing tight gly- cemic control showed preservation of hepatic mitochondrial ultrastructure and function, in marked contradistinction to patients conventionally managed in terms of blood sugar control [14].
The presence of mitochondrial dysfunction implies a decrease in energy pro- duction. In health, glycolytic generation of ATP accounts for <5% of total energy production with the remainder arising from mitochondrial respiration. In dis- ease states such as heart failure where oxygen supply is limited, the glycolytic contribution will increase though only by a relatively small amount. It is thus reasonable to assume that ATP production is compromised. The corollary of this reduction in energy availability is a direct down-regulatory effect on metabo- lism. As a consequence, the various physiological and biochemical processes of the cell become compromised. If severe enough, this will lead to clinically mani- fest organ dysfunction and failure.
At present, the link between mitochondrial dysfunction and organ failure is
only by association. Direct causation has yet to be established. There appears
to be a parallel deterioration during the onset of critical illness and a concur-
rent improvement seen on disease resolution. There is also good direct and cir-
cumstantial evidence to suggest plausible mechanisms for mitochondrial dys-
function. First, excess production of nitrogen and oxygen reactive species will
directly inhibit mitochondrial activity [15] and sepsis is the condition par ex- cellence associated with increased whole body generation of nitric oxide (NO).
Second, mitochondria are under direct hormonal regulatory control. Many of the effects of the thyroid hormones, for instance, are mediated through changes in mitochondrial activity. In prolonged sepsis, down-regulation in endocrine activity is well recognized, for example, relative adrenal defi ciency, hypoleptine- mia and the low T3 syndrome [16–18]. It is thus reasonable to assume that this downturn may impact upon energy production in prolonged sepsis. Third, the microvascular disturbance seen particularly in early, unresuscitated sepsis will also infl uence cellular oxygen availability and thus mitochondrial respiration.
In contrast to cardiac arrest, the reduction in oxygen transport will not be so massive or abrupt with sepsis or other infl ammatory insults. The cells thus have some time to adapt to hypoxia induced by hypovolemia, hypoxemia, microvas- cular fl ow redistribution, increased capillary leak and myocardial depression.
This includes an augmented production of reactive oxygen and nitrogen species and cytokine production. Thus, tissue hypoxia has an amplifying effect on the initiating infl ammatory insult.
This synergism between infl ammation and tissue hypoxia could reasonably explain the improved outcome shown by the early goal-directed therapy ap- proach reported by Rivers et al. [19], and the failure of a similar approach in patients with established MOF [20, 21]. The persistence of an abnormal micro- vasculature in prolonged sepsis could arguably be a reactive phenomenon. The decrease in cellular metabolism will reduce oxygen requirements; the tissue PO
2is thus high so there is little need for the microcirculation to deliver unnecessary oxygen.
Could ‘Multi-Organ Failure’ Represent a Last-Ditch Adaptive Response?
If the cell continues to function normally in the face of mitochondrial dysfunc- tion, ATP stores would be rapidly depleted. Below a certain threshold this is a recognized trigger for stimulating necrotic or apoptotic death pathways. The failure of this to occur suggests a reduction in energy-consuming cellular proc- esses that preserve the ATP supply-demand balance, thereby maintaining the ATP level. Indeed, we reported this fi nding in muscle biopsies taken from pa- tients in septic shock who subsequently survived [12], and have recently re- ported similar fi ndings in muscle and liver in a long-term rodent model of fecal peritonitis [11]. This is analogous to the hibernation occurring with prolonged myocardial ischemia, and the numerous correlates seen in nature including cold weather hibernation, hot weather estivation and bacterial dormancy.
This suggests the fascinating concept that MOF may actually be a good thing
[5]! If the patient is able to withstand the acute infl ammatory insult, it would
indeed be a Pyrrhic victory if the organs failed to recover and he/she died as a
result. Yet we recognize that organs that were normal before the initiating in-
fl ammatory event, and were not irreparably harmed by the insult itself, will usu-
ally regain normal functioning unless iatrogenic complications ensue. A large
Scottish audit of patients with previously normal renal function who survived
their critical illness yet required acute renal replacement therapy revealed that only 1.5% required long-term dialysis [22].
It may be pertinent to consider MOF as a three-phase process with multiple in- teractions between infl ammatory, immune, hormonal, bioenergetic, metabolic, and other pathways. Initially, the organism will meet an acute infl ammatory in- sult ‘head-on’. This ‘acute phase response’ is well-recognized with an increase in pro-infl ammatory mediators, immune stimulation, stress hormones, mitochon- drial and metabolic activity all individually reported. The temporal relationship between these different pathways still needs to be established. A proportion of patients will die in this phase due to the consequences of overwhelming infl am- mation. The majority of deaths, however, occur in the subsequent downturn phase. In the face of a prolonged and severe infl ammatory insult there is reduced activity in all of the above pathways with immune paresis [23], endocrine down- regulation [24], metabolic suppression [25], and the bioenergetic shutdown de- scribed previously. The patient is thus more susceptible to secondary bouts of in- fection and infl ammation, and perhaps less well able to respond. The fi nal phase represents recovery, with restoration of organ function, an increase in energy expenditure and a general anabolic state with enhanced protein synthesis.
The Covert Harm from Established Therapies
We blithely assume that our current therapies and management strategies con- fer benefi t, otherwise we would not be using them. Unfortunately, the evidence base for much of what we do in intensive care is rather paltry. More than half the recommendations within the Surviving Sepsis Campaign guidelines [26] were graded ‘E’, i.e., only supported by anecdote, uncontrolled or historically con- trolled case series and studies, and expert opinion. Many of the original papers upon which the recommendations were based are also of dubious merit. Thus, it is highly likely that practice in the future will differ considerably from contem- porary practice. In much the same way that we scoff at what we were doing way back in 1995 (Table 1), we are likely to be denigrating many of our current ideas in the future – and rightly so.
We are increasingly recognizing that ‘less is best’. Most of the major advances in recent years have arisen from this concept. The Canadian multicenter trial- lists showed how a transfusion trigger of 7 g/dl improved outcomes compared to a 10 g/dl trigger point [3]. Likewise, the ARDS-NET group demonstrated signifi - cant outcome benefi t from lower tidal volumes (approximating 6–7 ml/kg) [4].
Intuitively, we are using less sedation and, in many countries, shorter courses of antibiotics as the perception takes hold (albeit in the absence of much hard data) that earlier weaning and a lower antibiotic load reduce complications and hospital stay.
We have perhaps failed to properly consider the notion that many of our
standard therapies may, in fact, be covertly harmful and may act counter to the
body’s attempts to adapt to a prolonged, acute illness. In heart failure, for ex-
ample, there is increasingly compelling evidence that two of our mainstay treat-
ments over the past two decades, dobutamine and phosphodiesterase inhibitors,
actually worsen long-term outcomes [27, 28]. A variety of mechanisms have been proposed including increased fatty acid oxidation, arrhythmogenesis, and decreased cardiac effi ciency. Norepinephrine and dobutamine have also been shown to accelerate both Gram-positive and Gram-negative bacterial growth [29, 30] while dopamine is a potent suppressor of prolactin secretion, even at low doses [31].
All sedatives commonly in use today have potent effects, at least in vitro, on immune function [32-34] while a single dose of etomidate can compromise ad- renal function in critically ill patients for at least 24 hours [35]. Sedatives also af- fect mitochondrial function in vitro and this may be amplifi ed in sepsis or other conditions with increased levels of NO [36]. Likewise, antibiotics affect in vitro mitochondrial activity and biogenesis, though at concentrations equivalent to in vivo therapeutic levels [37, 38]. If the hypothesis that organ failure is related to mitochondrial dysfunction is borne out, then recovery will depend upon new mitochondrial protein formation, a process that could be delayed by antibiotics, sedatives, hormonal modulators, and so forth.
The harmful effects from blood transfusion suggested by the prospective TRICC study and other, non-randomized studies [39] may potentially arise from
Table 1. Examples of changing fashions 1995-2005
Example 1995 2005
Respiratory
tidal volume 10 ml/kg 5–6 ml/kg steroids for ARDS rarely used increasing use nitric oxide fashionable limited use inhalation
Hemodynamic
O
2delivery/ ‘supranormal’ normal consumption
vasopressin not used fashionable
Sepsis expensive HA-1A
anti-endo- activated
(until 1993)immunotherapy toxin antibody Protein C
steroids derided in vogue
Hematological
transfusion threshold 10 g/dl 7 g/dl
Renal hemofi ltration10 ml/kg, high-fl ow,
lactate buffer bicarbonate
Monitoring
pulmonary artery gold standard on the wane catheter
gastric tonometry fashionable forgotten
Endocrine
glycaemic control glucose <10 mmol/l 4–7 mmol/l
Gastrointestinalgastric protection sucralfate, ranitidine omeprazole
effects on the recipient’s immune response. This is implied by the recent study by Hebert and colleagues who found better outcomes in patients transfused with leukoreduced blood [40]. Similarly, the benefi ts of lower tidal volume ventilation may be related to reduced production of local and systemic cytokines [41].
This concern of unrecognized detriment can be transmitted to many other areas of intensive care medicine that we perhaps take for granted. For example, we make no attempt to modulate nutritional inputs and constituents in the dif- ferent phases of an acute illness, and the trend to an increased mortality found by many of the immunonutrition trials [42, 43] should not necessarily be dis- missed as chance fi ndings. The gut that is not absorbing enteral feed is driven with prokinetics and persisting attempts to establish an adequate nasogastric intake. What are the consequences of enterally feeding a patient with a bloated, distended and painful abdomen? They are unlikely to be positive. Likewise, as an article of faith we treat pyrexia as patients feel better and vasopressor re- quirements are often reduced. However, there are numerous experimental studies to suggest that an important protective response may be overridden by our attempts to normalize temperature. The vogue for corticosteroid therapy waxes and wanes; currently, it is fashionable for catecholamine-resistant sep- tic shock and acute respiratory distress syndrome (ARDS). However, reports of an increased incidence of myopathy in which high-dose steroids are implicated (Bernard et al NIH NHLBI ARDS Network: Report on ongoing clinical trials.
Presented at: Annual meeting of the American Thoracic Society; May 24, 2004;
Orlando) should encourage some caution until we better understand when, how much, for how long and to whom steroids should be prescribed.
Management in the Future
By 2015, I am confi dent that advances in our understanding of the disease proc-
esses underlying critical illness and organ failure will considerably alter much of
our current practice. This will be augmented by major developments in bedside
monitoring technology that will enable more individualized interventions at the
appropriate time as we gain a better grasp of underlying immune, hormonal,
bioenergetic and metabolic function. I feel that we will be intervening less and
tolerating greater degrees of abnormality, be it for hypotension, hypoxemia, aci-
dosis, etc. I am less confi dent that major blockbusting anti-infl ammatory ther-
apies will arise over the next decade that will signifi cantly impact upon large
numbers of critically ill patients. However, we should be starting to focus more
upon prophylactic measures, particularly in the high-risk elective surgical pa-
tient and in the period of acute illness before admission to the ICU. We will also
be developing and trialling novel agents that will hasten the resolution of organ
failure as it dawns on both clinicians and industry that this is now the major
sticking point for many critically ill patients and the major drain on our limited
resources. We can generally tide our patients through the acute infl ammatory
phase, yet the prolonged period of established organ failure punctuated by epi-
sodes of decompensation and further infl ammation (e.g., nosocomial infection,
bleeding) is where most of them die – or are allowed to die. Table 2 highlights
Table 2. Areas of potential practice in 2015 Diagnostic and
monitoring tools
• rapid, bedside monitoring of infl ammatory, immune, hor- monal, metabolic and bioenergetic status, and a happy/un- happy intracellular milieu
• rapid and reliable, non-invasive macro- and microcirculatory and tissue/cellular oxygen monitoring at whole body and re- gional level
• rapid diagnosis of infection and identifi cation of pathogen and antimicrobial sensitivities
• ready availability of, and expertise with, portable diagnostic devices such as ultrasound and echo
• improved monitoring of sedation, ‘useful’ sleep and neuro- logical function
• computer-aided diagnosis
• servo-controlled delivery systems for targeted controlled infu- sions, e.g., for glycemic control, plasma antibiotic therapeutic levels
Prophylaxis
• rapid, goal-directed cardio-respiratory resuscitation of criti- cally ill patients
• goal-directed cardio-respiratory optimization of high-risk elective surgical patients
• genetic identifi cation of at-risk patients
• non-antibiotic means of controlling/preventing infection
• up-regulation of endogenous protective mechanisms, e.g., pre- conditioning, heat shock protein, heme oxygenase-1 induction
• antioxidant supplementation, immunomodulation
• viral transfection of protective proteins
Prevention of short/long-term complications
• muscle wasting/weakness
• ventilator-induced lung injury and lung fi brosis
• neuropsychiatric complications
Reductionism
• acceptance of physiological/biochemical abnormality (e.g., blood pressure, hypoxemia, hypercapnia, Hb) titrated indi- vidually and temporally
• reduction in overall use of sedation, antibiotics, inotropes, blood, etc.. but improved targeting
• recognition and avoidance of currently accepted yet covertly harmful therapies, e.g. etomidate
Awakening ‘sleeping’
organs
• metabolic/mitochondrial switches to hasten resolution of or- gan failure
Modulation of metabolic, endocrine and immune pathways
• providing substrate to optimize effi ciency of organ function and immune status, and to prevent autocannibalism
• optimizing type and timing of substrate, hormone or immu- notherapy to patient status – may involve up- or downregula- tion of endogenous pathways
Specifi c treatments,
for example
