Introduction

If, for a septic patient, severity of illness progressed in a predictable linear fashion then there would be no reason to consider the concepts of severity and time separately.  Knowing the severity of illness would accurately define the stage of the illness.  However, biological models of sepsis demonstrate that sepsis passes through distinct non-linear stages.  An initial uncontrolled and overwhelming pro-inflammatory response evolves into a pathology dominated by anti-inflammatory cytokines and immunosuppression.(1)  There are accompanying changes in endocrine,(2) metabolic and mitochondrial(3) phenotypes.  Similar severities of illness may therefore conceal different pathophysiological clinical syndromes.  An important corollary is that a therapy modulating any of these pathways may be less effective or even harmful in these late phenotypes.(4-7).

Contemporary Relevance

Now, in addition, critical care is an expensive and scarce resource.  The UK in particular has seven fold fewer critical care beds than Germany.(8)  Intensive Care Units must run at maximum occupancy, and there is a continual process of triage.  Evaluation of ward patients and early recognition of severe illness has become a national priority.(9)  There is a paradox here.  To merit admission to ICU, a patient has to reach a certain severity threshold.  Now sometimes that threshold may be breached suddenly as with, for example, a heart attack (myocardial infarction).  In other cases, and here the paradigm is sepsis, then a patient progresses at varying speed from early and mild disease to late and severe disease.  In such circumstances, the process of triage, by selecting only the severest cases, may delay access to the benefits of critical care.  While there have been great efforts to predict which ward patients are likely to require critical care(10), there has not as yet been a systematic evaluation of how this delay affects outcome.

There is biological and clinical evidence that delay in antibiotics(11, 12) and in fluid resuscitation reduces survival.  But these are treatments which may be administered on the ward.  With regard to organ support, which may only be provided in critical care areas, the picture is less clear.  On the one hand there is weak evidence that early renal replacement therapy is of benefit.(13)  With mechanical ventilation (the prototypical ICU intervention) the issue is more subtle with some patient groups showing benefit(14) whilst others appear to be safe to ‘watch and wait’.(15)

This means there is a lack of knowledge as to which patients might benefit most from early admission.  With a fixed number of beds, admitting one patient who gains less benefit from an early therapy, simultaneously delays the admission of another patient who may respond better.  Even when there is evidence that delay to admission is harmful(16), it is not known whether there is a linear relationship between the timeliness of therapy and benefit.  If, after an early window of opportunity, the response to prompt intervention flattens out then it may in fact be best to triage those with early mild disease than those with late severe disease.  These are unanswered questions.

Pathophysiological versus Organisational Timing

SPOT(light) is one of two studies jointly hosted by ICNARC and London School of Hygiene and Tropical Medicine, which aims to characterise how severity changes with time.  Timing will be considered from two perspectives.  The first of these begins logically with onset of the pathology.  With the exception of conditions such as myocardial infarction or trauma where this moment is marked by a classic symptom or an external event, then defining time zero is difficult.  For this reason, an organisational frame of reference, such as hospital admission or time of referral to specialist team, is more commonly used.  Delay following this organisational time is important because it is often a modifiable factor with regard to the delivery of health care.  However, pathophysiological timing remains relevant because if the disease process is dynamic (as per the underlying hypothesis of this study) then it determines the phenotype of disease at any particular moment.

SPOT(light)

The SPOT(Light) study will distinguish itself from previous work by asking not just whether delay causes harm, but how the magnitude of delay modifies its effect, and repeat this using two metrics: organisational and pathophysiological timing.

Methodology:  All patients evaluated on the ward by a critical care decision maker and subsequently admitted to critical care will be eligible.  Severity of illness and the timing of the initial evaluation will be recorded and linked to severity of illness at admission and timing of organ support (via the ICNARC Case Mix Programme and Department of Health’s Critical Care Minimum Data Set respectively).  A typical centre would recruit 3 patients per week (total sample size 50 centres, 9000 patients).  Survival at 90 days will be evaluated using the NHS Medical Research Information Service.  A multilevel cox proportional hazards model will be used to evaluate the effect of the duration of organ dysfunction prior to organ support on survival and resource utilisation (organ support free days).  Secondly, a trajectory of illness will be constructed from severity of illness before and at admission, and a similar model will be developed to evaluate how trajectory, as a marker of pathophysiological duration, modulates outcome.

Acknowledgements

These studies are supported via a Wellcome Trust Clinical Research Training Fellowship for Dr Steve Harris.  They will be submitted as a doctoral thesis at the London School of Hygiene and Tropical Medicine, and are sponsored by Intensive Care National Audit & Research Centre.

References

1. L. Ulloa, K. J. Tracey, Trends Mol Med 11, 56 (2005).
2. G. Van den Berghe, F. de Zegher, R. Bouillon, J Clin Endocrinol Metab 83, 1827 (1998).
3. D. Brealey et al., Lancet 360, 219 (2002).
4. O. Boyd, M. Hayes, Br Med Bull 55, 125 (1999).
5. M. A. Hayes et al., N Engl J Med 330, 1717 (1994).
6. E. Rivers et al., N Engl J Med 345, 1368 (2001).
7. J. L. Vincent et al., Crit Care Med 33, 2266 (2005).
8. H. Wunsch et al., Crit Care Med 36, 2787 (2008).
9. R. Thomson, D. Luettel, F. Healey, S. Scobie, Patient Safety Observatory 1 (2007).
10. H. Gao et al., Crit Care 11, R113 (2007).
11. A. Kumar et al., J Infect Dis 193, 251 (2006).
12. A. Kumar et al., Crit Care Med 34, 1589 (2006).
13. K. D. Liu et al., Clinical journal of the American Society of Nephrology : CJASN 1, 915 (2006).
14. G. Hilbert et al., N Engl J Med 344, 481 (2001).
15. G. Conti et al., Intensive Care Med 28, 1701 (2002).
16. D. B. Chalfin et al., Crit Care Med 35, 1477 (2007).
17. G. Saka et al., Critical care (London, England) 11, R65 (2007).