Overall, we found moderate variation in resource and therapeutic modality use among patients with severe sepsis in academic centers. In general, this variation had little relationship to clinical outcomes, although clinical outcomes varied substantially between the centers. The exception is that, even adjusting for potential confounders, early antibiotic therapy was associated with a lower 28-day mortality rate. Increased use of some of the therapeutic modalities was associated with greater resource utilization.
Prior studies have shown variability in the use of therapeutic modalities (including PACs, ventilator, and intravenous vasoactive and inotropic agents) among ICU patients [21
] and different impacts on outcomes and use of hospital resources associated with these treatments [16
]. In general, with the exception of the recent trial demonstrating benefit of early goal-directed treatment involving oxygenation (including ventilatory support if necessary) and blood pressure (including intravenous pressors if necessary) [30
], few data are available that demonstrate that these modalities improve outcomes.
Colloids and crystalloid are equally effective in restoring tissue perfusion in patients with septic shock [31
]. However, the choice of fluid has considerable cost implications: colloids cost more for volume replacement. Largely inappropriate use of colloids was found in a survey of academic health centers despite guidelines from a US hospital consortium recommending that colloids be used in hemorrhagic shock only until blood products become available, and in nonhemorrhagic shock only if an initial infusion with crystalloid is insufficient [32
]. A recent systematic review of randomized controlled trials comparing colloids and crystalloid solutions for volume replacement found that resuscitation with colloids in critically ill patients was actually associated with an increased risk of mortality [10
In addition, vasopressors have been recommended to achieve end-points of hemodynamic, and normal or supranormal oxygen transport variables in sepsis patients who remain hypotensive despite adequate volume therapy. However, after reviewing the literature on the use of vasopressors in patients with sepsis syndrome, Rudis and colleagues [13
] found that catecholamine therapy resulting in increased hemodynamic and oxygen transport measures did not change the overall mortality, with the exception of two instances in which epinephrine (adrenaline) and norepinephrine (noradrenaline) were given alone after volume repletion. The results from a recent trial of low-dose dopamine in critically ill patients, who had systemic inflammatory response syndrome and were at risk for renal failure, did not show benefit in renal protection and survival from the treatment [34
]. However, a very recent trial of early goal-directed therapy in treatment of sepsis did demonstrate substantial improvement in outcome [30
Another technology is monitoring central pressures by PAC, which is often used in ICUs to assess the effect of pharmacotherapy on the cardiac index in patients with septic shock. This is done even though the efficacy of the PAC has never been demonstrated convincingly in a large randomized controlled trial. A number of randomized controlled trials have examined the effectiveness of PACs or PAC-guided strategies in sepsis patients [16
] and other specific patient groups [29
], with conflicting results. A recent case mix adjusted observational study of a large sample of ICU patients found that PAC use was associated with increased risk for mortality and resource use [28
Mechanical ventilation in patients with ARDS has been reported to be associated with pneumonia and lung injury [44
]. Properly constructed trials are still needed to define the best use of mechanical ventilation in sepsis, although early ventilatory support was a component of the recent early goal-directed intervention by Rivers and coworkers [30
Use of some therapeutic modalities does appear correlated with organizational characteristics. For example, results from a national ICU survey conducted by Greoger and colleagues [21
] showed that more technologies were used in surgical units as compared with other units, as well as in larger versus smaller hospitals, and in university-affiliated facilities. In addition, a large prospective multicenter study evaluated the differences in ICU characteristics and performance among teaching and nonteaching hospitals [48
]. The results of that study revealed more frequent use of monitoring and therapeutic interventions, and greater resource utilization in teaching hospital ICUs. Also, a recent report from a large retrospective database study of ICU patients [27
] confirmed that organizational characteristics of ICUs were associated with variation in PAC use. In addition, that report indicated that economic incentives and insurance coverage, as well as clinical variables, were associated with PAC use. Similarly, much of the variation in resource use and modality use across centers in the present study may not be due to patient-related factors, but rather to organizational factors and physician beliefs.
We did find a number of relationships between modality use and resource utilization. In particular, there were associations between LOS in the ICU and use of PACs, pressor support, and albumin infusion. These may probably be accounted for in part by the fact that patients with longer LOS in the ICU were more likely to be treated with supportive technologies. In general, however, modalities with higher variation profiles reflect areas of greater disagreement in terms of treatment decision-making. Such areas may be fertile for additional investigation.
It is striking that delay in antibiotic therapy was associated with a higher mortality rate and that some delays were present in this very ill population. Delays are common in American medicine [49
], even in urgent situations such as treatment of life-threatening laboratory abnormalities [50
]. Although we do not know the causes of delays in antibiotic initiation, they appeared more common in some institutions than in others. We speculate that some may have occurred because of problems related to crowding; for example, emergency rooms or ICUs might have been full, resulting in delayed transfer, or the clinical importance of changes in vital signs might not have been recognized. Approaches such as protocols for early recognition and treatment of severe sepsis, and facilitation of medication orders that are really needed urgently may be helpful. Guidelines for the management of severe sepsis are probably most applicable for certain treatment modalities, such as PACs, albumin, dextran, and hetastarch. Even use of organ failure treatment modalities such as ventilator support and renal replacement therapies might be different if such guidelines were developed.
An important underlying issue is why variation occurs [51
]. It should not be surprising that it is present in this domain, because the pioneering work of Wennberg [52
] identified variation across a broad array of domains. One of the major causes of variation is probably physician uncertainty regarding what interventions are truly beneficial, and clinician beliefs, where training occurred, and regional practices probably also play roles. Uncertainty may be especially problematic in conditions such as sepsis, in which mortality is high, and clinicians strongly want to do everything possible. Variation is likely to diminish as more evidence becomes available and is brought to the point of care. Analysis of variation can be very useful for identifying areas of high uncertainty [52
This study has a number of limitations. We had information only on hospital charges, rather than hospital costs. We did not have information on organizational variables such as organizational setting, staffing, or leadership of practices, and the study included only academic centers. Also, our data did not include the indications for use of therapeutic modalities.
In conclusion, significant variations were present in hospital resource use and patient outcome among sepsis patients across eight academic medical centers. In general, variation in therapeutic modality use did not correlate with clinical outcomes, suggesting that some use of these modalities may be of limited value, and that further evaluation of these modalities is warranted. The exception was that delay in giving antibiotics to sepsis patients was associated with a higher 28-day mortality rate. Approaches to eliminate these delays may improve outcomes.