Review Article

Management of Severe Sepsis: Role of Bundles

G.C. Khilnani and Vijay Hadda
Department of Medicine, All India Institute of Medical Sciences, New Delhi, India

ABSTRACT
Sepsis is the leading cause of hospital admissions, morbidity and mortality. Treating sepsis is expensive resulting in consumption of major health care resources. With development of newer and potent antimicrobial agents, moratlity due to sepsis has reduced markedly, but remains unacceptably high. Recently, various strategies like fluid therapy, low dose corticosteroids, tight glycaemic control, recombinant human activated protein C [(rhAPC), drotrecogin alfa] and lung protective ventilation have shown favourable results. Further, it is thought that combination of these strategies in the form of bundles can further improve the outcome. Concerted utilisation of the "sepsis bundles" is likely to improve outcome of this serious disorder. [Indian J Chest Dis Allied Sci 2009;51:27-36]
Key words: Sepsis, Septic shock, Sepsis bundle.

INTRODUCTION
Conventionally, sepsis has been defined as the systemic , host response to an infection. Previously, sepsis was believed to be associated with the presence of bacteria in the blood (bacteramia), and the terms: sepsis and septicamia were frequently interchanged in the clinical setting. In 1989, Bone et al1 established a simple definition for sepsis syndrome, which was based on specific clinical symptoms and included a known source of infection. However, these were frequently seen in the absence of measurable levels of bacteria in the blood, also in non-infectious conditions, like acute pancreatitis and trauma. Consensus conference held by the Society of Critical Care Medicine and the American College of Chest Physicians in 1992 resolved these discrepancies and introduced the term systemic inflammatory response syndrome (SIRS), for which no definable presence of bacterial infection was required. 2,3 Additionally, the terms severe sepsis septic shock and multiple organ dysfunction syndrome were introduced to differentiate between various stages of diseases (Table 1). Population data suggest that severe sepsis is the leading cause of hospitalisation. Sands et al, in a study involving a sample of in-patients from eight hospitals during a 16-month period, observed that sepsis accounted for two percent of all hospitalisations, with 59% of patients with sepsis requiring admissions to the intensive care units (ICUs). In addition, the incidence of sepsis is incresing and projected to grow at a rate of 1.5% per year. Almost

every discipline in medicine deals with this entity, though much of the management is rendered by critical care physicians in the ICUs. Care of patients with sepsis is a costly affair resulting in substantial consumption of health care resources.5,6 Sepsis is often lethal, with mortality of 25% to 30% and 40% to 70% in severe sepsis and septic shock, respectively. 7 It is the second leading cause of death among patients in non-coronary ICUs.8 Furthermore, sepsis also substantially reduces the quality of life of those who survive. 9 Despite availability of potent antibiotic the mortality with sepsis is very high.7,10 There is ongoing effort to find out and try strategies which would improve outcome of this population. An international consensus committee was formed in 2002 and evidence-based guidelines were elaborated to increase overall clinician's awareness and improving outcome in severe sepsis and septic shock. 11 This was termed Surviving Sepsis Campaign (SSC). The SSC aims to achieve a 25% reduction in sepsis mortality within five years.11 Over the last few years several strategies, like fluid resuscitation, early antibiotics, tight glycemic control, administration of corticosteroids and rhAPC, and lung protective ventilation have been tried with favourable results. However, not all the studies have uniform outcome in terms of beneficial effect on mortality. This is not unexpected, given the fact that pateints with sepsis are heterogeneous group with different diseases and co-morbid conditions. It is thought that when all these strategies are combined in the form of "bundle" the outcome will improve

[Received: August 21, 2007; accepted after revision: March 19, 2008]

Correspondence and reprint requests: Dr G.C. Khilnani, Professor, Department of Medicine, All India Institute of Medical Sciences, New Delhi-110 029; Phone: 91-11-26593488; Fax: 91-11-26588663, 26588641; Email: gckhil@hotmail.com

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Table 1. Clinical definition of sepsis SIRS Temperature > 38 oC or < 36 o C Heart rate >90 beats per minute Respiratory rate > 20 per minute or PaCO 2<32 mmHg White blood cell count > 12,000/cumm, <4,000/cumm, or >10% immature (band) forms Two or more conditions of SIRS with evidence of infection Sepsis-associated organ dysfunction, hypoperfusion, hypotension, lactic acidosis or acute alteration in mental state Sepsis associated with refractory hypotension (systolic blood pressure <90 mmHg or fall in blood pressure >40 mmHg) even after adequate fluid resuscitation along with lactic acidosis, oliguria or alteration in mental state The presence of two or more organ dysfunction in acutely ill patient which require intervention for maintenance homeostasis

Sepsis Severe sepsis Septic shock

MODS

SIRS = systemic inflammatory response syndrome; MODS = multi organ dysfunction syndrome.

significantly. This review summarises new strategies and interventions in improving outcome of sepsis in terms of reduced mortality and ICU stay.

SEVERE SEPSIS BUNDLES

Two sets of severe sepsis bundles are defined, i.e., the resuscitation bundle and the sepsis management bundle. Implementation of resuscitation bundle is recommended within first six hours of hospitalisation and sepsis management bundle should be implemented as early as possible and should not be delayed for more than 24 hours after hospitalisation.

Sepsis Resuscitation Bundle

Sepsis resuscitation bundle consists of: (i) serum lactate measurement; (ii) blood culture obtained prior to antibiotic therapy; (iii) improve time to broadspectrum antibiotic; and (iv) in case of hypotension and/or elevated lactate (4 mmol/L or 36 mg/dL): (a) initial fluid challenge of 20 mL/kg within 30 minutes, (b) apply vasopressors for ongoing hypotension, (c) maintain adequate central venous pressure (CVP), and (d) maintain adequate central venous oxygen saturation (ScvO 2).

with severe sepsis or septic shock represents anaerobic metabolism secondary to tissue hypoperfusion. It can be measured easily and results are usually available within minutes. Although its elevation may be multifactorial, values greater than 4 mmol/dL (36 mg/dL) are associated with poor prognosis, particularly if the high levels persist. 12-14 Studies have shown association of mortality with gastric mucosal pH measured by gastric tonometry but, interventions designed for correction of regional acidosis did not influence mortality. 15-17 In addition, blood lactate levels have been shown to have greater prognostic value than oxygen-derived variables. 18 In patients with persistent hyperlactataemia, effort should be made to improve haemodynamic support. Serum lactate measurement is recommended for identifying tissue hypoperfusion in pateints who are not yet hypotensive but are at risk for septic shock. Blood cultures obtained prior to antibiotic therapy. Both timing and volume of blood sample are important while obtaining blood sample for culture. Collecting blood cultures prior to antibiotic administration offers the best hope of identifying the organism that caused severe sepsis in an individual patient. Failure to check blood cultures prior to antibiotic infusion will perhaps affect the growth of any blood-borne bacteria and prevent a culture from becoming positive later. The yield of blood cultures depends on the volume of blood cultured, and recommended that blood cultures for adults should contain at least 10mL per culture, preferably 20 mL.19,20 At least two blood cultures should be obtained one of which should be drawn through lumen of intravascular catheter.11 Improve time to broad-spectrum antibiotics. Once severe sepsis is identified, appropriate antibiotics must be started without delay. Although most of the times, antibiotic administration seems to be in time, the effective antibiotics are often delayed. Several studies 21-23 have confirmed the mortality benefit associated with appropriate anti-microbials in pateints with severe sepsis. In general, pneumonia

Sepsis Management Bundles

The sepsis management bundle consists of: (i) administer low dose steroids as standard policy; (ii) administer rhAPC as standard policy; (iii) maintain tight glycemic control; and (iv) lung protective strategy-prevent excessive inspiratory plateau pressure.

RATIONALE BEHIND SEVERE SEPSIS BUNDLES Sepsis Resuscitation Bundle

Serum lactate levels. Hyperlactataemia in pateints

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and intra-abdominal infectons are the major sources of infection in severe sepsis or shock and other sources accounting less than five percent of cases. 24 The prevalence of pneumonia as a cause of sepsis lends support to the case for treating severe sepsis with early antibiotic administration. In a recent study6 of ventilator associated pneumonia, pateints with severe sepsis who received delayed antibiotics had far greater ICU mortality and hospital mortality. Antibiotics selection should be guided by the susceptibility of likely pathogens in the community and the hospital. Other factors, like drug intolerance and associated diseases may influence choice and doses of antibiotics. The antibiotics should cover all likely pathogens as there is little margin for error in critically ill patients. Specific antibiotic with narrower spectrum should be initiated after identifying the causative organism and its susceptibility for minimising the development of resistant pathogens and containing costs. Initiation of broad-spectrum antibiotics is recommended within one hour of observation of sepsis. 11 Treatment of hypotension and/or elevated lactate. All patients with severe sepsis who either have suspected hypovolaemia or serum lactate greater than 4 mmol/dL (36mg/dL) should be given a fluid challenge which consists of 20 mL/kg of fluid over 30 minutes. As a resuscitation bundle, this is minimum amount of fluid, and additional fluid can also be given. Crystalloid and colloid fluids are equally effective as resuscitative fluids. 25 Saline vs albumin fluid evaluation (SAFE) study 25 showed no significant differences between the two groups in the primary outcome measures: mortality days spent in the ICU, days spent in the hospital, days of mechanical ventilation, or days of renal replacement therapy. In the same study sub-group analysis of patients with sepsis revealed a trend toward improved mortality in the group of patients treated with albumin. For the selection of fluid, clinicians will need to include cost considerations and specific clinical scenario in their decision making process to select the appropriate type of fluid for resuscitating patients with sepsis. The end-point of fluid resuscitation is to achieve central venous pressure (CVP) of 8-10 mmHg.11,26 Vasopressor therapy is required when an appropriate fluid challenge fails to restore a mean arterial pressure (MAP) to 65 mmHg or more and organ perfusion remains inadequate. In the case of life-threatening hypotension, vasopressor therapy may be required simultaneously with fluid challenge to sustain life and maintain perfusion, even when hypovolaemia has not been resolved. Norepinephrine or dopamine shuold be used as first-line agents to correct hypotension in pateints with sepsis. As other vasopressors have disadvantages like tachycardia

and reduced splanchnic blood flow (epinephrine), and decreased stroke volume (phenylnephrine), in patients who do not respond to initial vasopressors, epinephrine and phenylnephrine are recommended. Finally, vasopressin is not recommended as a firstline agent and can be used, as hormone replacement, in cases refractory to other vasopressor at low doses (0.01-0.04 U/min) 24 hours after the onset of shock. 27,28 Low dose dopamine is not recommended for the purpose of renal protection. 11 Target is to achieve MAP to 65 mmHg or more.11 The pateints with sepsis-induced tissue hypoperfusion with a haematocrit below 30% despite achieving a CVP above 8 mmHg and a MAP above 65 mmHg, should receive blood transfusion. Blood transfusion may serve dual purposes; first it increases ScvO2 due to increased oxygen delivery to ischaemic tissue beds, and secondly, by increasing CVP that will correct hypovolaemia for longer periods than fluids alone. Rivers et al29 showed that blood transfusion was associated with significant improvement in mortality in these pateints. Critical evaluation of outcomes based on different haemoglobin thresholds for transfusion in a general population of critically ill patients have suggested that keeping haemoglobin level above 10 g/dL offered no benefits when compared with a more conservative target of 7g/dL.30 A group of pateints such as those with myocardial ischaemia or severe hypoxaemia may require higher haemoglobin levels, though the effectiveness of transfusion in these pateints is inadequately characterised.31,32 Recommended target of haemoglobin is 7-9 g/dL in pateints with sepsis, recognising that some pateints with altered oxygen transport are likely to benefit from blood transfusions targeted at achieving a ScvO2 of 70% or more.11

Sepsis Management Bundle

Administer low dose steroids as standard policy. The stress response to infection and the anti- inflammatory effects of steroids in sepsis is the rationale behind use of glucocorticoids in sepsis trials. Use of corticosteroids in sepsis has been a point of controversy for decades.34-47 Various doses have been tried with inconsistent results. Randomised controlled trials (Table 2) using high-dose glucocorticoids (30 mg/kg methylprednisolone or equivalent) have failed to improve outcome and may even worsen the outcome.33-41 However, recent randomised, controlled trials with low doses of hydrocortisone (200-300mg of hydrocortisone or equivalent) administered for five to seven days or longer in septic shock showed improved outcome, in the form of reduced vasopressor requirement and mortality (Table 2).42-46 Some authors argue ACTH stimulation test to identify survivors, i.e., responders of septic shock,44,47 but treatment with corticosteroids was ineffective in

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Table 2. Major trials of corticosteroids in sepsis Author, Year [Reference] Treatment Study Design Number of Patients (Deaths) Steroid Control Group Group 9 6 (54) 4 6 (24) 8 6 (9) 9 8 (32) 3 9 (22) 8 6 (33) Relative Survival Benefit (95% CI) 0.65 (0.50-0.84) 1.10 (0.69-1.75) 1.45 (0.69-1.73)

Bennett et al, 1963 33 Klastersky et al, 1971 34 Schumer, 1976 35

Hydrocortisone, 300 mg 1, then decrease by 50 mg per day Betamethasone, 1 mg/kg of body weight per d 3 days Dexamethasone 3 mg/kg, or methylprednisolone, 30 mg/kg, may be repeated 1 Methylprednisolone, 30 mg/kg 1, and then repeated upto 3 times within 24 h if in shock Dexamethasone 2 mg/kg bolus, followed by 2 mg/kg per day in first 48 h Methylprednisolone, 30 mg/kg or Dexamethasone 6 mg/kg; repeat 1 at 4 h if patient still in shock Methylprednisolone, 30 mg/kg 4 doses Methylprednisolone, 30 mg/kg bolus followed by 5 mg/kg per h for 9 h Methylprednisolone, 30 mg/kg 4 doses over 24 h Hydrocortisone, 100 mg every 8 h for 5 days, then taper over 6 days Hydrocortisone, 100 mg 1, then 0.18 mg/kg/h until the patient is no longer on vasopressors, then 6 days taper Hydrocortisone, 100 mg every 8 h for 3 days, then taper over 4 days Prednisolone, 5 mg every morning and 2.5 mg every night 10 days Hydrocortisone, 100 mg every 6 h, and fludrocortisone, 50 g/d7 days

Double blind Double blind Double blind

Thompson et al, 1976 36 Lucas and Ledgerwood, 1984 37 Sprung et al, 1984 38 Bone et al, 1987 39 Veterans administration, 1987 40 Luce et al, 198841 Bollaert et al, 1998 42 Briegel et al, 1999 43 Chawla et al, 1999 44 Yildiz et al, 2002 45 Annanne et al, 2002 46

Double blind

2 8 (22)

3 2 (55)

0.98 (0.37-2.59)

Open label

2 3 (5)

2 5 (5)

0.98 (0.73-1.31)

Open label

4 3 (33)

1 6 (11)

0.74 (0.29-1.89)

Double blind Double blind

191 (65) 112 (23)

190 (48) 111 (24)

0.88 (0.78-1.01) 1.01 (0.89-1.16)

Double blind Double blind Double blind

3 8 (22) 2 2 (7) 2 0 (3)

3 7 (20) 1 9 (12) 2 0 (4)

0.92 (0.55-1.53) 1.85 (1.01-3.40) 1.06 (0.80-1.42)

Double blind Double blind Double blind

NA NA 2 0 (8) 150 (82)

NA 2 0 (12) 149 (91) 1.50 (0.79-2.83) 1.17 (0.89-1.52)

NA = not available; CI = confidence interval.

responders. 43 It is recommended that clinicians should not wait for ACTH stimulation results to administer corticosteroids in patients with septic shock.11 Hydrocortisone is preferred as it is a synthetic equivalent to cortisol and does not require metabolic transformation; has mineralo-corticoid activity (methylprednisolone or dexamethasone does not). Most of the published experience with low-dose corticosteroid treatment in septic shock has been with the use of hydrocortisone. 42-44, 46 Intravenous corticosteroids are recommended in pateints with septic shock who, despite fluid therapy require vasopressors. The dose is 200-300 mg/day of hydrocortisone in three to four divided doses or as continuous infusion for seven days.11

Administer rhAPC (drotrecogin alfa) as standard policy. Development of rhAPC is considered as a major breakthrough in the management of sepsis. Sepsis is characterised by alteration of the procoagulant-anticoagulant balance, with an increase in pro-coagulant factors (Va and VIIIa) and a decrease in anti-coagulant factors (protein C, protein S, antithrombin III and tissue-factor pathway inhibitors). 48 Furthermore, the proinflammatory and pro-coagulant responses can be amplified by secondary ischaemia (shock) and hypoxia (lung injury).49 Therapies targeting pro-coagulant and anticoagulant pathways, other than protein C, either have not evaluated or showed negative results.50-53 In severe sepsis, therapy with rhAPC 24 g/kg/h for 96 hours) has been shown to decrease mortality and to

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ameliorate organ dysfunction.54-55 The mechanism of action by which activated protein C improves the clinical outcome is unknown. Activated protein C was shown to increase protein C and decrease markers of thrombin generation, though it has little effect on coagulation in a human intravenous endotoxin model of sepsis 56,57 suggesting that coagulation pathway may not be the primary mechanism of benefit. Perhaps the beneficial effects are because of its complex anti-inflammatory, 58 antiapoptotic, and anti-coagulant actions.59 Pateints with severe sepsis and an increased risk of death as indicated by an Acute Physiology and Chronic Health Evaluation (APACHE II) score greater than or equal to 25 or dysfunction of two or more organs had the greatest benefit from this therapy, 11 with absolute decrease in the mortality rate of 13 percent. 60 However, early enthusiasm about administration of activated rhAPC was hampered by subsequent studies, which showed lack of effectiveness in low risk adult patients and also in pediatric patients with sepsis. 61,62 Major trials with rhAPC are shown in table 3.54,61-63 Bleeding (up to 3.5%) is the most frequent and serious adverse event that may be induced by rhAPC treatment. 55,63 So, patients with high risk of serious bleeding like, recent trauma or surgery (within 12 hours), active haemorrhage, concurrent therapeutic anti-coagulation, thrombocytopenia (platelet count of less than 30.000/mm 3) and recent stroke should not be given this therapy. Maintain tight glycemic control. Hyperglycaemia is a
Table 3. Major trials of recombinant human activated protein C Patients Study/ Author PROWESS Bernard et al54 Number of Patients 1690

common finding in patients with severe sepsis probably, caused by insulin resistance in the liver and muscle, and is considered an adaptive response, providing glucose for the brain, red cells, and wound healing. Generally, hyperglycaemia is considered as beneficial and hypoglycaemia as dangerous. Hyperglycaemia is only treated when blood glucose increases to greater than 215 mg/dL (>12 mmol/L). This concept has been challenged recently in the management of sepsis, and controlling blood glucose levels by intensive insulin therapy (Table 4) in surgical critically ill patients with decreased moratility and morbidity.64-68 Van den Berghe et al, 64 in a large single-center study involving post-operative surgical patients demonstrated that controlling blood glucose levels, between 80 and 110 mg/dL (4.4-6.1 mmol/L), by intensive insulin therapy significantly decreased mortality and morbidity in critically ill patients. Reduced blood stream infections, requirement of dialysis or haemofiltration, critical illness polyneuropathy and transfusion requirements were the other benefits observed in this study. 64 This study 64 also showed that the best results were obtained when blood glucose is maintained between 80 and 110 mg/ dL (4.4-6.1 mmol/L). However, achieving a level less than 150 mg/dL (8.3 mmol/L) also improve outcome and may reduce the risk of hypoglycaemia. Benefits of insulin therapy seem multifactorial, besides treating hyperglycaemia insulin has anti-inflammatory effects, 69 favourable effects on coagulation and fibrinolysis 70,71 and on macrophage function 72 which

Intervention Group Cases Control Subjects rhAPC Placebo

Mortality (%) Cases Control Subjects 25 31

Conclusions

Patients with severe sepsis and septic shock Patients with severe sepsis and septic shock, at increased risk of death

Treatment with rhAPC significantly reduces mortality in patients with severe sepsis Treatment with rhAPC significantly reduces mortality in patients with severe sepsis at high of death Treatment with rhAPC is not beneficial in patients with severe sepsis who are at low risk of death Treatment with rhAPC in patients with severe sepsis is effective and safe Treatment with rhAPC is not effective in children with sepsis

PROWESS Bernard et al54

817

rhAPC

Placebo

31

44

Patients with severe ADRESS sepsis and with low Abraham et al 61 risk of death

2613

rhAPC

Placebo

17

18.5

Patients with severe ENHANCE-US sepsis Bernard et al62

273

rhAPC

Placebo

26.4

32.9

Children with severe sepsis

RESOLVE Nadal et al63

477

rhAPC

Placebo

17.15

17.45

rhAPC = recombinant human activated protein C, drotrecogin alfa.

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Table 4. Major trials of glycemic control in sepsis Study Design and Author, Patient Year Population (No.) [Reference] Intervention Group Control Cases Subjects Conventional therapy IIT Major Results Conventional Therapy IIT Mortality (%) Other Mortality (%) Effects (%) 8 4.6 p Value Other Effects (%) <0.04

RCT, patients Van den admitted in surgical Berghe et al, ICU (1548) 2001 64 Observational study (531) Finney et al, 2003 65

Conventional therapy

IIT

Higher blood glucose and less exposure to insulin was associated with less mortality OR < 1.0 21.9 and 32.8 at 28 and 90 days, respectively Overall (40) > 3 days stay in ICU (52.5) (a) In ICU ITT group (16.2) long stayer (27.8) (b) In hospital IIT group (23.6) long stayer (37.9) Hypoglyc aemia* (2.1) ARF* (12.3) ARF (7.7)

Blood glucose of 111-144 mg/dL was positively associated with ICU mortality OR 1.02 (95% CI=1.01-1.04)

NA

RCT, admitted in ICU (488)

VISEP trial66

Conventional therapy Conventional therapy Conventional therapy

IIT

21.6 and 29.5 at Hypoglyc28 and 90 days, aemia respectively (12.1) Overall (37) > 3 days saty in ICU (43) (a) In ICU ITT group (13.2) long stayer (21.7) (b) In hospital IIT group (16.2) long stayer (30.1) ARF (8.6)

0.43

RCT, patients in Van den medical ICU (1200) Berghe et al, 2006 67 RCT, intention to treat, mixed surgical/medical ICU (2748) Van den Berghe et al, 2006 68

IIT

0.33 0.009

IIT

ARF (4.5) 0.02 0.009

0.04 0.002

No. = number of patients; RCT = randomised control trial; IIT = intensive insulin therapy; ITT = intention to treat; ICU = intensive care unit; ARF = acute renal failure; OR = odds ratio; CI = confidence intervals; NA = not available. * = Statistically significant (p-value not shown); = long stayers defined as at least 3 days of ICU stay. Table 5. Major trials ventilatory strategy for acute lung injury and acute respiratory distress syndrome (ARDS) Authors Number of Patients Low VT Control Subjects 29 58 60 26 432 50 24 58 60 26 429 45 Tidal Volume (VT) (mL/kg) Low VT Control Subjects 6.1 7.2 7.2 7.3 6.3 7.2 0.2 0.2 0.8 0.1 0.1 0.8 11.9 10.4 10.6 10.2 11.7 10.0 0.5 0.2 0.2 0.1 0.1 1.1 Mortality (%) Low VT Control Subjects 38 47 50 50 31 32 71 38 47 46 40 53.3 Reported Mortality Differences (p value) <0.001 0.38 0.72 0.60 0.007 0.040

Amato et al76 Brochard et al77 Stewart et al78 Brower et al79 ARDS Net trial group80 Villar et al81

could also contribute to the well-documented benefits of treating hyperglycaemia to reduce infection. Till date, studies showed variable results and last word is still not out. Hopefully the role of glucose control in sepsis will be better understood after results of two large, controlled trials (Glucontrol Study and NICEGlucose study) are published.73,74 Although the last word is not out, monitoring blood glucose under 150 mg/dL (8.3 mmol/L) is recommended for the management of patients with severe sepsis. 15

Lung protective strategy: prevent excessive inspiratory plateau pressure. Respiratory failure is a common finding in patients with severe sepsis/ septic shock. 75 About half of these patients develop acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) requiring endotracheal intubation and mechanical ventilation (MV).76 Ventilatory strategies are to avoid high tidal volumes and high plateau pressures n ALI/ARDS. Clinicians should use as a starting point a reduction in tidal volumes over one

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to two hours to a "low" tidal volume (6 mL/kg lean body weight) as a goal in conjunction with the goal of maintaining end-inspiratory plateau pressures of to 30 cm H2O or less. Various trials (Table 5)76-81 with low tidal volume showed mixed results. The largest trial of a volume and pressure-limited strategy showed a 9% decrease in the all-cause mortality in patients ventilated with tidal volumes of 6 mL/kg of estimated lean body weight (as opposed to 12 mL/kg) while aiming for a plateau pressure of lelss than 30 cm H2O.80 Recently, Villar et al,81 showed that MV strategy with a peak end expiratory pressure (PEEP) level set on day 1 above lower inflection point (Pflex) and a low tidal volume compared with a strategy with a higher tidal volume and relatively low PEEP has a beneficial impact on outcome in patients with severe and persistent ARDS. Permissive hypercapnea, in conjunction with limiting tidal volume and minute ventilation has been demonstrated to be safe and useful intervention in small studies. 82-84 Other strategies like semi-recumbent position ventilation and minimal PEEP to prevent lung collapse at end expiration and to maintain adequate oxygenation, i.e., a pulse oximetric saturation of 90% or more and fraction of inspired oxygen less than 0.60 were also shown to be useful.85,86 Each intervention, thus, seems rational and more or, less efficacious and are recommended by SSC guidelines though, the evidence for individual intervention is not so strong.11 These interventions are recommended in early phase of sepsis, i.e., within six hours and twenty-four hours for sepsis resuscitation bundle and sepsis management bundle, respectively. Data on efficacy of this early intervention is limited. Rivers et al29 showed that in-hospital mortality was 30.5% in the group assigned to early goal directed therapy as compared with 46.5% in the group assigned to standard therapy (p=0.009). The patients assigned to early goal-directed therapy had a significantly higher mean (SD) central venous oxygen saturation (70.410.07% vs 65.311.4%), a lower lactate concentration (3.04.4 vs 3.94.4 mmol/ L), a lower base deficit (2.06.6 vs 5.16.7 mmol/L), and a higher pH (7.400.12 vs 7.360.12) than the pateints assigned to standard therapy (p 0.02 for all comparisons) during the interval from seven to seventy-two hours. Severe organ dysfunction, as indicated by mean APACHE II scores, were significantly lower in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.06.3 vs 15.96.4, p<0.001).29 Compliance to the recommendation is variable at present. Gao at al 87 found that the compliance with the six-hour sepsis bundle was 52% and with the 24hour sepsis bundle was achieved in only 30% (21/69) of the eligible candidates. In this study, 87 sources of infection were sought and confirmed in 87 of 101

patients. The chest was the most common source (50%), followed by the abdomen (22%). Compared with the compliant group, the non-compliant group had a more than two-fold increase in hospital mortality [49% vs 23%; relative risk (RR) 2.12, 95% confidence intervals (CI) 1.20 to 3.76, p=0.01] despite similar age and severity of sepsis. Hospital mortality was increased in the non-compliant group from 29% to 50%, with a 76% increase in risk for death, although the difference did not reach statistical significance (RR 1.76; 95% CI 0.84 to 3.64, p=0.16). The number needed to treat to save one life was approximately four.87 Despite the fact that individual strategy for the management of sepsis have been used by various workers, the evidence favouring the benefits are not robust. It is agreed by most workers that when these recommendations are combined, in the form of bundles, will lead to improvement of outcome of severe sepsis, although no large randomised controlled trial is available to favour this. It is also true that recommendations for the management of sepsis will keep on changing and improving with future research. In India, critical care is advancing at rapid pace, although same is not widely available in all settings due to economic reasons and lack of trained manpower. However, in hospitals where well equipped ICU and emergency room (ER) facilities are available, sepsis bundles can easily be used. The strategies of measurement of pH, blood culture, early antibiotic therapy, fluid resuscitation, administration of steroid and lung protective ventilation are easy to implement. Awareness of benefit of these bundles is of paramount importance. Health care providers in ERs and ICUs should be well versed with benefit of these interventions. There may be difficulty in maintaining tight glycemic control in critically ill patients as it requires resources and manpower. The risk of hypoglycaemic episodes is definitely there for which frequent monitoring is required. Availability of glucometers and constant volume infusion pumps are must to implement tight glycemic control in these patients. In conclusion, sepsis bundles are strategies which can be easily implemented even in resourceconstrained settings, like India.

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