Treatment with recombinant human activated protein C (aPC) has shown a significant reduction in mortality in patients with severe sepsis/septic shock  and has been included in the Surviving Sepsis Campaign guidelines . The benefits of aPC are limited to the most severe cases [1,3,4], especially if used within 24 h after the first organ dysfunction . However, the rate of aPC use in patients with septic shock varies across ICUs, reflecting uncertainty of some clinicians [6,7]. Two main concerns are probably responsible for this fact. The risk for haemorrhage is increased in patients treated with aPC, especially in the case of surgical patients [8,9]. Furthermore, although the use of aPC has been proved to be cost-effective in the most severely affected patients [7,10,11], the high cost of the drug (average cost per 96 h infusion around 6000 Euro) probably contributes to restricting its use.
The indications for aPC treatment, based on clinical criteria (sepsis and organ failure), as well as the dose (24 μg kg−1 h−1) and duration of the treatment (96 h) were established in the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial . However, recent data have demonstrated that common clinical practice differs from the original protocol . The association between low levels of protein C and a higher risk of mortality has been recently shown . A phase II trial [the Research Evaluation Serial Protein C levels in severe sepsis patients On Drotrecogin alfa (activated) (RESPOND) study] is being conducted to analyse whether the levels of protein C can be used as a steering parameter to adjust the dose and duration of administration of aPC in individual patients . This would represent a significant change with respect to the actual protocol.
Early improvement in cardiovascular function is associated with an increased probability of survival in septic shock [14,15]. We observed that, in patients with septic shock in whom vasopressors had been withdrawn, the interruption of aPC treatment due to coagulation disorders before the 96 h period was completed was not associated with a clinical deterioration. We hypothesized that a strict adherence to the PROWESS protocol (fulfilment of a 96 h treatment independent of the clinical progress) was not necessary in these cases and decided to include in our practice the interruption of aPC treatment after vasopressor withdrawal. We have explored whether this practice was in any way deleterious to the patients and report our experience.
Data were obtained from a 3-year septic shock database that included 157 patients from an 11-bed surgical ICU in a university hospital. All data were collected by the authors. Our protocols include noradrenaline as the only vasopressor agent to be used in septic shock. All patients required noradrenaline and in all cases the initial dose was at least 0.1 μg kg−1 min−1 [cardiovascular Sequential Organ Failure Assessment (SOFA) 4] and served for the diagnosis of septic shock. Noradrenaline was titrated to maintain a mean arterial pressure of at least 65 mmHg . According to standard criteria in our ICU (SOFA score ≥3 in, at least, two organs), aPC was retrospectively considered to be indicated in 111 cases. We reviewed these medical records and found 20 consecutive surgical septic shock patients in whom aPC treatment was suspended before 96 h after noradrenaline withdrawal (NA−). Patients' characteristics, severity scores observed on the day of septic shock diagnosis [Acute Physiology and Chronic Health Evaluation (APACHE) II and SOFA], source of infection and use of low-dose steroids (50 mg 6 h−1) were obtained. We compared these patients with a group of patients in whom aPC was definitively suspended for coagulation disorders or surgical reasons while still receiving noradrenaline treatment (NA+, n = 11), with patients not treated with aPC, although presenting criteria for its use (aPC−, n = 31), and with patients completing a standard 96 h protocol with aPC (aPC+, n = 49). Following our hospital protocol, we routinely obtain written consent from the closest relatives of patients with septic shock that permits the use of clinical data from these patients in retrospective studies. Specific informed consent was waived, as the study was retrospective and observational, without any additional procedure. Our end point was to assess whether early suspension of aPC had been followed by a haemodynamic impairment (need to restore vasopressor agents). We also analysed the effect on mortality of this approach. Our hypothesis was that if aPC improves the patients' response to sepsis independently from the haemodynamics, a detrimental effect should be observed after its suspension.
Statistical analysis was carried out with the SPSS for Windows system (Release 9.0) and SAS Enterprise Guide 3.0. Quantitative data are described as the mean, median and standard deviation (minimum–maximum), and qualitative data as the count and percentages. For qualitative data (sex, source of infection, use of low-dose steroids and survival), differences between groups were tested by the χ2 test, and for quantitative data (age, severity scores) by means of the Kruskal–Wallis test. The Mann–Whitney U-test was used to analyse the probability of mortality related to age and severity scores. The nQuery program was used to calculate the power and the sample size. A two-sided test was used and a P value less than 0.05 was considered statistically significant.
No differences in age, sex, severity scores, use of low-dose steroids or source of infection (mainly peritonitis) were found between groups (Table 1). aPC was suspended after 55 ± 17 h and 34 ± 19 h of treatment in the NA− and NA+ groups, respectively (P = 0.006). Noradrenaline had been withdrawn for 26 ± 17 h (1–57 h) before the suspension of aPC treatment and was not required by any NA− patient within 24 h after aPC withdrawal. Overall mortality was 41% (64/157). In the study groups, there was a statistically nonsignificant trend to a lower mortality in the NA− patients (20 vs. 46% in NA+, 58.1% in aPC− and 45% in aPC+ patients, P = 0.066, Fig. 1, Table 2). Mortality was associated with age (P < 0.001) and APACHE II (P = 0.021), but not with the SOFA score (P = 0.076).
Among the 80 cases treated with aPC, three cases of gastrointestinal haemorrhage requiring the transfusion of, at least, one haemoconcentrate (incidence 3.75%) were observed (one patient in the NA− group and two patients in the NA+ group). The NA− patient died 1 week after aPC suspension as a result of mesenteric ischaemia and multiple bowel perforations. In the NA+ group, one patient died 5 days after aPC suspension due to refractory shock and the other patient survived. Haemorrhage was not considered as a main factor related to mortality in any of these cases. No other major haemorrhagic episodes were observed.
In the present study, we observed that the early suspension of aPC administration in a small series of patients with septic shock after vasopressor withdrawal is not associated with deleterious effects. Of note is the lack of rebound effect (need for new vasopressor therapy within 24 h after aPC interruption) and the low mortality found in these patients.
Although sepsis guidelines support the adherence to protocols, current practice does not always follow them strictly. For instance, with respect to aPC, Wheeler et al. observed that almost 50% of their aPC-treated patients would have not been enrolled in the PROWESS trial. On the other hand, aPC is not used in cases in which this treatment is indicated [6,7] for reasons that may include safety or economic concerns.
Owing to the chaotic nature of organ failure, the efficacy of any therapy using mortality as an end point has been questioned, at least with currently used statistical methods . A decrease in mortality has been observed in patients in whom an early improvement in cardiovascular function is observed [14,15]. On the other hand, multivariate analysis has shown that many factors such as the need for renal replacement therapies during ICU stay are associated with a lower probability for survival, independent of severity scores on admission . This implies that outcome is not predictable merely based on the severity of the illness upon septic shock diagnosis. In apparently similar clinical cases, the initial response to the treatment is crucial and probably reflects a different adaptation mechanism mediated by variable inflammatory responses.
It is difficult to detect potential responders to the different treatments after the diagnosis of septic shock. For instance, the adrenocorticotropic hormone (ACTH) test, initially proposed for the diagnosis of relative adrenal insufficiency, is no longer recommended . In the case of aPC, the levels of protein C are promising and an ongoing study will probably give an answer to this important issue . Thus, until new data are available, our sepsis protocol includes the use of aPC in all septic patients meeting the criteria of multiorgan failure. However, a rapid improvement in the physiological variables (mostly haemodynamic) that led to the administration of the treatment may indicate that it is no longer needed (‘deescalating therapy’). In the survey by Rowan et al., the authors state that aPC treatment was withdrawn before completing the 96 h period in some cases due to patient improvement. This implies that the approach that we propose based on our results is already being used in some ICUs. We may speculate that, in these cases, the efficacy of the drug is maximal in the first hours (or days), similar to what is observed with early resuscitation . But our results may indicate that, despite initial similar severity scores, an early favourable inflammatory response in some patients determines a better prognosis. These patients are not as sick as initially estimated and may not require adjunctive therapies with potential deleterious effects. As the beneficial effect of aPC is closely related to early treatment , waiting for a favourable inflammatory response before starting aPC might be harmful in some cases. This fact supports that, in our ICU, patients meeting septic shock criteria are actually being treated with aPC as soon as possible, ‘deescalating’ the therapy according to their response. Similarly, early suspension of steroids might be indicated when vasopressors have been withdrawn, and we have started to study this approach .
In NA− patients, the vasopressor had been withdrawn for 26 ± 17 h before the suspension of aPC treatment. The wide range observed is explained by the fact that aPC was usually suspended when the syringe infusing the drug had to be reloaded, and it required that every individual case was discussed with the rest of the staff. This implies that, in some cases, the decision to suspend the treatment after noradrenaline withdrawal was delayed (up to 57 h in one of the first cases).
The present study has important limitations, as it is retrospective and not controlled. Although an important reduction in mortality was observed in the subgroup of patients in whom aPC was suspended, the lack of statistical significance is probably related to the small size of the sample. This assertion was confirmed by the calculation of the power of the α equal to 0.05 level χ2 test, which showed an underpowered test (60%). For the same level and an 80% power, the sample size across the groups required was 169 cases. Of note is the low mortality observed in this subgroup of patients with septic shock (20%) as compared with that reported in the literature (around 50%) , which implies that this approach is, at least, not deleterious. There seems to be little theoretical basis for using the reversal of shock as an indicator for stopping aPC. However, as stated earlier, a rapid improvement in cardiovascular function is related to a better prognosis [14,15]. In our ICU, shock (defined as the need for vasopressors despite adequate resuscitation) represents the main indication for aPC treatment, whenever it is associated with failure of another organ. This is the reason why we considered the cardiovascular status as the main parameter to adjust aPC treatment with apparent favourable results. According to our data, the effect of ‘deescalating’ aPC treatment in this context deserves further studies.
We conclude that early reversal of septic shock seems to be related to a better prognosis. According to the sepsis guidelines, aPC should be used in septic shock, but in this limited series, no detrimental effect was seen when aPC was discontinued after shock reversal.
The authors are grateful to Elia Pérez-Fernández and Rosario Madero for the statistical analysis.
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