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Soares MO, Welton NJ, Harrison DA, et al. An Evaluation of the Feasibility, Cost and Value of Information of a Multicentre Randomised Controlled Trial of Intravenous Immunoglobulin for Sepsis (Severe Sepsis and Septic Shock): Incorporating a Systematic Review, Meta-Analysis and Value of Information Analysis. Southampton (UK): NIHR Journals Library; 2012 Feb. (Health Technology Assessment, No. 16.7.)

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An Evaluation of the Feasibility, Cost and Value of Information of a Multicentre Randomised Controlled Trial of Intravenous Immunoglobulin for Sepsis (Severe Sepsis and Septic Shock): Incorporating a Systematic Review, Meta-Analysis and Value of Information Analysis.

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2Survey of the management of severe sepsis in UK critical-care units

Objective

To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK.

Background

Most clinicians look to international guidelines for guidance on the management and treatment of patients with sepsis. The Surviving Sepsis Campaign (SSC), an initiative of the ESICM, the International Sepsis Forum and the SCCM, was developed (and updated in 2008) to improve the diagnosis, management and treatment of sepsis.18

The SSC partnered with the Institute for Healthcare Improvement (IHI) to incorporate its ‘bundle concept’ into the management and treatment of sepsis. A bundle was defined by the SSC/IHI as a group of interventions related to a disease process that, when implemented together, result in better outcomes than when implemented individually.19 The SSC claim that ‘the science behind the elements of the bundle is so well-established that their implementation should be considered a generally accepted practice’.20 They also indicate that bundle components can be easily measured as completed or not completed and, as such, the overall bundle (all of the elements taken together) can also be measured as completed or not completed.

Two bundles were developed: the resuscitation bundle (which must be completed within 6 hours) and the management bundle (which must be completed within 24 hours).19 The SSC describes the bundles as a distillation of the concepts and recommendations found in the first set of international clinical guidelines were originally published in 2004.21

Resuscitation bundle

  • Measure serum lactate.
  • Obtain blood cultures prior to antibiotic administration.
  • Administer broad-spectrum antibiotic within 3 emergency department (ED) hours/1 non-ED hour of admission.
  • In the event of hypotension and/or serum lactate > 4 mmol/l:

    deliver initial minimum of 20 ml/kg of crystalloid or equivalent

    apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) ≥ 65 mmHg.

  • In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/l:

    achieve a central venous pressure (CVP) ≥ 8 mmHg

    achieve a central venous oxygen saturation (ScvO2) ≥ 70% or mixed venous oxygen saturation (SvO2) ≥ 65%.

Management bundle

  • Administer low-dose steroids for septic shock in accordance with a standardised critical-care policy (if not administered, document why the patient did not qualify for low-dose steroids).
  • Administer recombinant human activated protein C (rhAPC) in accordance with a standardised critical-care policy (if not administered, document why the patient did not qualify for rhAPC).
  • Maintain glucose control ≥ 3.9 mmol/l, but ≤ 8.3 mmol/l.
  • Maintain a median inspiratory plateau pressure < 30 cmH2O for mechanically ventilated patients.

Methods

To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock), a national survey of clinical directors of adult, general critical-care units in the NHS in the UK was conducted in February 2010. The survey was designed and set up online using the online survey software, Smart-Survey™ version 4 (Smartline International Ltd, Tewkesbury, Gloucestershire, UK). The SSC guidelines were reviewed and items were selected for inclusion in the survey if ranked as 1A or 1B based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, which classifies quality of evidence as high (A), moderate (B), low (C) or very low (D) and recommendations as strong (1) or weak (2).22 In addition, items that are components of the resuscitation and management bundles (listed above) and not 1A or 1B were also included.

The 25 items selected for inclusion in the survey were reviewed by the Expert Group (see Acknowledgements) for content and clarity and grouped into six core domains as follows:

  • domain 1: resuscitation practices in the ED: critical-care clinicians' perceptions of management of severe sepsis/septic shock in their ED
  • domain 2: resuscitation practices in the critical-care unit
  • domain 3: use of adjuvant therapy in the critical-care unit
  • domain 4: use of IVIG in the critical-care unit
  • domain 5: safety interventions in the critical-care unit
  • domain 6: uptake of bundles-based management of severe sepsis/septic shock.

The layout of the survey was organised such that clinicians were first asked about specific aspects of patient care relating to resuscitation (domains 1 and 2) and management (domains 3–5) of patients with severe sepsis/septic shock, which included questions about the preferred choice of fluids and vasopressors, target levels for blood pressure, CVP and other physiological parameters, and administration of antibiotics and adjunctive therapies (including IVIG), prior to being asked about bundles-based management (domain 6).

Survey questions were further refined following piloting by the Expert Group and Clinical Research Associates working with ICNARC.

UK adult, general critical-care units (n = 231) were identified from a database of all UK critical-care units maintained by ICNARC. An e-mail was sent to the clinical director of each unit containing the online link for the survey (see Appendix 1). An e-mail reminder was sent to all non-responders after 4 weeks and repeated on a weekly basis for 3 months. As part of the ICNARC CMP, there is regular telephone contact with units, and this was used to facilitate reminders about the survey.

Statistical analysis

A descriptive analysis was conducted reporting proportion, mean with standard deviation (SD) or median with interquartile range (IQR), as appropriate. Given that for a future RCT of patients with severe sepsis, the recommendation for the control arm would be usual clinical care based on the best available evidence. Adoption of elements from the SSC guidelines ranked level 1A (indicating high-quality evidence and strongly recommended), but which are not included in the resuscitation and management bundles (described above), were examined and reported. These were:

  • use of a ventilation weaning protocol
  • use of either low-dose unfractionated heparin or low-molecular-weight heparin, unless contraindicated
  • use of a mechanical prophylaxis device such as a compression stocking or an intermittent device when heparin is contraindicated
  • provision of stress ulcer prophylaxis using an H2 blocker
  • contraindicated use of a pulmonary artery catheter (PAC) for routine monitoring of patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).

Components of the resuscitation and management bundles (described above) were also examined and reported. Although not included by the SSC, with strong evidence to support the use of selective decontamination of the digestive tract (SDD), SDD was also examined and reported.

Finally, current use of IVIG was examined and reported.

Results

Survey response

Of the 231 adult, general critical-care units, a senior clinician to complete the survey could not be identified for 14 of the units. Of the remaining 217 units, respondents at four (2%) units refused to complete the survey and completed surveys were received for 123 (57%) units.

Surviving Sepsis Campaign recommendations: level 1A (not included in the bundles)

Responses to the survey for each level 1A item in the SSC guidelines not included in the bundles are reported below.

  • Use of a ventilation weaning protocol.
    Sixty-three (51%) respondents reported using a ventilation weaning protocol for mechanically ventilated patients in their unit. Overall, respondents estimated that the median proportion of mechanically ventilated patients who were managed using a ventilation weaning protocol was 80% (IQR 50–100%).
  • Use of either low-dose unfractionated heparin or low-molecular-weight heparin, unless contraindicated, or a mechanical prophylaxis device such as a compression stocking or an intermittent device when heparin is contraindicated.
    All but one of the respondents (n = 122, 99%) reported that they used prophylaxis for deep-vein thrombosis.
  • Provision of stress ulcer prophylaxis using an H2 blocker.
    All but two of the respondents (n = 121, 98%) reported that they provided stress ulcer prophylaxis.
  • Contraindicated use of a PAC for routine monitoring of patients with ALI/ARDS.
    A small number of respondents (n = 5, 4%) reported using a PAC.

Resuscitation bundle

The elements that constitute the SSC resuscitation bundle are listed below, along with the strength of the recommendation (1 = strong or 2 = weak) and the quality of evidence (A = high, B = moderate or C = low) assigned by the SSC.18

  • Obtain blood cultures prior to antibiotic administration (1C).
  • Administer broad-spectrum antibiotic within 3 ED hours/1 non-ED hour of admission (1B).
  • In the event of hypotension and/or serum lactate > 4 mmol/l:

    deliver initial minimum of 20 ml/kg of crystalloid or equivalent (1B)

    apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain MAP ≥ 65 mmHg (1C).

  • In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/l:

    achieve a CVP of ≥ 8 mmHg (1C)

    achieve an ScvO2 ≥ 70% or SvO2 > 65% (1C).

Responses to the survey are reported for each component of the bundle below.

  • Obtain blood cultures prior to antibiotic administration (1C).
    Nearly all respondents reported that blood cultures are taken in the ED (95%) and in the critical-care unit (98%; Table 1). Respondents estimated that this is carried out for a high proportion of patients presenting at the ED (median 80%, IQR 60–90%) and in almost all patients who are admitted to the critical-care unit (median 100%, IQR 98–100%).
    In addition, a high proportion of respondents reported that imaging studies are carried out in the ED and critical-care unit. Although not part of the resuscitation bundle, they are recommended in the SSC guidelines as level 1C (see Table 1).
  • Administer broad-spectrum antibiotic within 3 ED hours/1 non-ED hour of admission (1B).
    Respondents reported that intravenous antibiotics are given within 1 hour of presentation to the ED (88%) and/or admission to the critical-care unit (93%) (see Table 1). However, they estimated that, on average, a higher proportion of patients receive intravenous antibiotics in the critical-care unit (median 90%, IQR 80–100%) than in the ED (median 60%, IQR 50–80%).
    The remaining elements of the resuscitation bundle require specific goals for serum lactate, MAP, CVP and either ScvO2 or SvO2. Goals require action that usually translates to the existence of a protocol. Therefore, the survey first asked whether or not the ED and critical-care unit have resuscitation protocols and, if yes, an indication of the clinical parameters included in the protocols.
    Forty-one (33%) respondents reported using a resuscitation protocol in the ED and 61 (50%) in the critical-care unit. For the latter, nearly half (n = 29, 48%) of respondents reported that the protocol commenced in the ED and transitioned to the critical-care unit. Although there was variation across hospitals, estimated compliance with the critical care resuscitation protocols was higher (median 77.5%, IQR 60–90%) than with the ED resuscitation protocols (median 60%, IQR 40–70%). The proportions of ED and critical-care unit resuscitation protocols that were reported to include MAP, CVP and ScvO2/SvO2 are shown in Figure 2. In addition, respondents reported that ED and critical-care resuscitation protocols also included targets for other parameters that are recommended in the SSC guidelines, but not included in the bundles, e.g. urine output (level 1C) and haemoglobin (level 1B). Nearly all of the critical-care unit resuscitation protocols included targets for cardiac output; however, this was not included in any of the ED resuscitation protocols (see Figure 2).
  • In the event of hypotension and/or serum lactate > 4 mmol/l:

    deliver initial minimum of 20 ml/kg of crystalloid or equivalent (1B)

    apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain MAP ≥ 65 mmHg (1C).

    Most ED and critical-care resuscitation protocols include serum lactate (see Figure 2) and, although all respondents who answered the question reported aiming to keep serum lactate levels < 4 mmol/l, many reported aiming for ≤ 2 mmol/l.
    Both crystalloid and colloid intravenous fluids are used for volume resuscitation; however, respondents reported greater use of crystalloid in the ED than in the critical-care unit, where colloid is used as much as crystalloid (see Table 1).
    All respondents reported that MAP is included in the both ED and critical-care unit resuscitation protocols and the majority reported aiming to keep the MAP > 65 mmHg. The reported preferred choice of ‘first-line’ vasopressor in both the ED and critical-care unit was noradrenaline (Figure 3) and the preferred choice of ‘first-line’ inotrope was either dobutamine or adrenaline, although dobutamine was more frequently used in the critical-care unit than in the ED (Figure 4). A small number of respondents (n = 10 and n = 13, respectively) reported that vasopressors and/or inotropes were not given in the ED or were used only with the involvement of critical-care clinicians.
  • In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/l:

    achieve a CVP of ≥ 8 mmHg (1C)

    achieve an ScvO2 ≥ 70% or SvO2 ≥ 65% (1C).

    Central venous pressure and ScvO2/SvO2 were reported less likely to be included in ED than in critical-care resuscitation protocols (see Figure 2). Although there was some variation, most respondents reported aiming for a non-ventilated CVP of ≥ 8 mmHg and a ventilated CVP of around 10–15 mmHg. All respondents reported that they aimed to achieve ScvO2 of ≥ 70%.
TABLE 1. Reported initial treatment and resuscitation in the ED and critical-care unit.

TABLE 1

Reported initial treatment and resuscitation in the ED and critical-care unit.

FIGURE 2. Reported components of the resuscitation bundle included in ED and critical-care resuscitation protocols.

FIGURE 2

Reported components of the resuscitation bundle included in ED and critical-care resuscitation protocols.

FIGURE 3. Reported preferred choice of ‘first-line’ vasopressor in the ED and the critical-care unit.

FIGURE 3

Reported preferred choice of ‘first-line’ vasopressor in the ED and the critical-care unit.

FIGURE 4. Reported preferred choice of ‘first-line’ inotrope in the ED and the critical-care unit.

FIGURE 4

Reported preferred choice of ‘first-line’ inotrope in the ED and the critical-care unit.

Management bundle

The elements that constitute the management bundle are listed below, along with the strength of the recommendation (1 = strong or 2 = weak) and the quality of evidence (A = high, B = moderate, C = low or D = very low) assigned by the SSC.18

  • Administer low-dose steroids for septic shock in accordance with a standardised critical-care policy (if not administered, document why the patient did not qualify for low-dose steroids) (2C).
  • Administer rhAPC in accordance with a standardised critical-care policy (if not administered, document why the patient did not qualify for rhAPC). [2B or 2C for postoperative patients; SSC guidelines state that adult patients with severe sepsis and low risk of death – typically, Acute Physiology and Chronic Health Evaluation (APACHE) II score < 20 or one organ failure – should not receive rhAPC (1A).]
  • Maintain glucose control ≥ 3.9 mmol/l but ≤ 8.3 mmol/l (2C).
  • Maintain a median inspiratory plateau pressure < 30 cmH2O for mechanically ventilated patients (1C).

Responses to the survey are reported for each component of the management bundle below.

  • Administer low-dose steroids for septic shock in accordance with a standardised critical-care policy (if not administered, document why the patient did not qualify for low-dose steroids) (2C).
    A high proportion of respondents (n = 116, 94%) reported that steroids were given in their units for persistent hypotension in septic shock. Although there was variation across units, it was estimated that a high proportion of patients with severe sepsis were given steroids (median 75%, IQR 43–99%).
  • Administer rhAPC in accordance with a standardised critical-care policy (if not administered, document why the patient did not qualify for rhAPC). [2B or 2C for postoperative patients; SSC guidelines state that adult patients with severe sepsis and low risk of death – typically, APACHE II score < 20 or one organ failure – should not receive rhAPC (1A).]
    A high proportion of respondents (n = 105, 85%) reported that rhAPC was administered to some patients in their unit with severe sepsis. There was variation across units in the proportion of patients who were estimated to receive rhAPC; however, overall, the median proportion was estimated to be 10% (IQR 5–21%).
  • Maintain glucose control ≥ 3.9 mmol/l, but ≤ 8.3 mmol/l (2C).
    Nearly all respondents (n = 119, 97%) reported that blood glucose control formed part of their unit's management of patients with severe sepsis. Respondents indicated that blood glucose levels were maintained somewhere within the range of 4–10 mmol/l, although there was variation as to how tightly clinicians aimed to control levels. For example, 35% of respondents reported aiming to keep blood glucose within the range 6–8 mmol/l and 31% within the range 8–10 mmol/l, the latter, higher range resulting from more recent results from a large, multicentre RCT of glucose control.23
  • Maintain a median inspiratory plateau pressure < 30 cmH2O for mechanically ventilated patients (1C).
    Of the 123 respondents, 110 (89%) reported that they aimed to keep the inspiratory plateau pressure < 30 cmH2O for mechanically ventilated patients. Overall, respondents estimated that this was done for a high proportion of their patients (mean 87.1%, SD 1.4).

Use of selective decontamination of the digestive tract

Only 11 (9%) respondents reported that their unit delivered SDD.

Use of intravenous immunoglobulin

Seventy (56.9%) respondents reported that they used IVIG for advanced management of patients. The clinical reasons given for administering IVIG included neurological diseases, e.g. myasthenia gravis and Guillain–Barré syndrome; toxin-mediated illnesses, e.g. invasive group A streptococcal disease, toxic shock syndrome, necrotising fasciitis, Clostridium difficile colitis, Panton–Valentine leukocidin toxin-producing staphylococcal infection; and other indications, e.g. severe sepsis, liver disease, haematological disease, bronchospasm and immunocompromised patients.

Adoption of resuscitation and management bundles

Overall, 91 (74%) respondents reported that they had adopted a resuscitation bundle and 97 (79%) respondents reported that they had adopted a management bundle. These were mostly the SSC bundles. In addition, 21 respondents reported using the Survive Sepsis UK Sepsis Six24 (Table 2).

TABLE 2. Resuscitation and management bundles for severe sepsis.

TABLE 2

Resuscitation and management bundles for severe sepsis.

Discussion

The survey indicated that there has been high uptake (> 70%) of bundles for the resuscitation and management of patients with severe sepsis, predominantly those recommended by the SSC. The responses to the survey indicated that, despite variation across units, usual clinical practice for patients with severe sepsis can be broadly summarised into immediate resuscitation and advanced management, as follows.

Resuscitation

  • Take blood cultures.
  • Give intravenous antibiotics within 1 hour.
  • Maintain serum lactate < 4 mmol/l.
  • Fluid resuscitate using a combination of crystalloids and colloids.
  • Maintain MAP ≥ 65 mmHg.
  • Maintain CVP ≥ 8 mmHg (or 10–15 mmHg for mechanically ventilated patients).
  • Give noradrenaline for hypotension not responding to initial fluid resuscitation.
  • Maintain ScvO2 or SvO2 ≥ 70%.

Management

  • Administer low-dose steroids in accordance with standardised critical-care protocol.
  • Administer rhAPC in accordance with standardised critical-care protocol.
  • Maintain blood glucose levels within the range 4–10 mmol/l.
  • Maintain inspiratory plateau pressure < 30 cmH2O for mechanically ventilated patients.
  • Give prophylaxis for deep-vein thrombosis.
  • Give stress ulcer prophylaxis.

These results suggest that a protocolised/bundle approach to immediate resuscitation and advanced management would need to be considered for the usual-care arm in any future multicentre RCT of IVIG as an adjunctive therapy in the advanced management of patients acutely ill with severe sepsis. However, specifically with regard to advanced management, a degree of clinical discretion would need to be maintained, illustrated by the high level of variation in compliance with bundle elements in the survey. This variation most likely relates to the heterogeneous nature of the severe sepsis population.

It should be noted that the main limitation of this survey is, despite regular follow-up of non-responders via e-mail and telephone, the low response rate. A major reason for the poor response, based on anecdotal evidence from critical-care clinicians, was the H1N1 swine influenza pandemic. Logistical and management issues took priority over research activities as senior clinicians were required to plan for the pandemic, such as extending critical care areas to be able to cope with additional demands for critical-care services. However, despite the poor response, data from the survey provide useful information on the now widespread adoption, initially resisted, of a protocolised approach to care for patients with severe sepsis in the UK.

Finally, these survey data provide the context for the case mix and outcome data, from the ICNARC CMP Database, used to inform the cost-effectiveness modelling.

© 2012, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK97442

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