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Can We Improve Survival in Sepsis?

The presentation of sepsis varies and so does the understanding of this disease process by medical professionals

"Mortality is highest in immune compromised patients and in those patients who have been referred late to the ICU, after losing advantage of initial six to 24 hours" - Dr Prachee Sathe Director, ICU Ruby Hall Clinic Pune

Severe Sepsis and septicaemic shock are the syndromes of overwhelming response of the body to severe infections. At times, it can be protective to body but at times it can lead to sequential multi-organ failure leading to death. The incidence of sepsis is increasing and it is as high as the incidence of myocardial infarctions (heart attacks).

Scope of the Problem

Sepsis is a significant problem. The mortality rate among patients with severe sepsis has been reported at 20 per cent to 50 per cent. A study of National Hospital Discharge Survey (NHDS) data identified organ failure in 19.1 per cent of sepsis patients from 1979 to 1989 and 30.2 per cent from 1990 to 2000. Comparing data from the five-year time frame between 1979 and 1984 with a span from 1995 to 2000, the number of patients who had dysfunctional organs more than doubled (2.7 per cent to 7.1 per cent), and the number of patients who had at least three dysfunctional organs more than tripled (0.5 per cent to 1.9 per cent). Though we do not have exact statistics from India, the incidence and mortality from sepsis could be worse in India. Indian statistics shows much higher incidence of infections needing ICU admissions as compared to Australian ICUs. The worldwide campaign to reduce mortality (death rates) of sepsis has been launched as 'Surviving Sepsis Campaign' (SSC) since 2002. The SSC has generated the following six-point action plan to reduce global mortality from severe sepsis by 25 per cent by 2009.

• Build awareness of sepsis.
• Improve early and accurate diagnosis.
• Increase the use of appropriate treatments and interventions.
• Educate staff about sepsis diagnosis, treatment and management.
• Improve access to post-ICU care for sepsis patients.
• Develop global standards of care.

Classification

The presentation of sepsis varies and so does the understanding of this disease process by medical professionals. The most important step towards improving survival is to identify the signs of sepsis very early. Sepsis is defined as 'documented or suspected infection' with one or more of the following:

General variables:

• Fever (core temperature >38.30 C).
• Hypothermia (core temperature <360 C).
• Heart rate>90 beats /min or >2 Standard Deviations (SD) above normal range for age.
• Tachpnea (fast respiratory rate).
• Altered mental status.
• Significant edema or positive fluid balance (>20 ml/kg over 24 hours).
• Hyperglycemia (plasma glucose >120 mg/dL or 7.7mmol/L) in the absence of diabetes.

Inflammatory variables:

• Leukocytosis (white blood cell [WBC] count >12,000/ mL).
• Leukopenia (WBC count <4000/ mL).
• Normal WBC count with >10 per centimetre forms.
• Plasma C-reactive protein >2 SD above normal value.
• Plasma procalcitonin (PCT) >2 SD above normal value.

Organ dysfunction variables:

Severe sepsis is defined as sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Because of disparity between oxygen supply to the tissues and oxygen demands by the tissues various organs in the body start failing their function and organ dysfunction variables can be monitored as below:

• Arterial hypoxemia (low oxygen levels: partial pressure of arterial oxygen/ fraction of inspired oxygen [PaO2/ FIO2 ] <300).
• Acute oliguria (Low urine output): Urine output <.5 mL/Kg/h or 45 mmol/L for at least two hours).
• Creatinine >2.0 mg/ dL.
• Coagulation abnormalities: International Normalised Ratio [INR] >1.5 or activated partial thromboplastin time [aPTT]> 60 seconds).
• Thrombocytopenia (platelet count <100,000/ mL).
• Hyperbilirunemia (plasma total bilirubin>2.0 mg/ dL or 35 mmol/ L).

Tissue perfusion variables:

• Blood lactate levels should be measured
• Hyperlactatemia (>2mmol/L)
• Decreased capillary refill or mottling

Haemodynamic variables:

Arterial hypotension, Systolic Blood Pressure [SBP] <90 mm Hg, Mean Arterial Blood Pressure [MAP] <65 mm Hg, or SBP decrease >40 mm Hg.

Diagnosis

Septic shock is defined as acute circulatory failure unexplained by other causes.

Acute circulatory failure is indicated by persistent arterial hypo-tension (low BP) despite adequate IV fluids for volume resuscitation. Diagnostic criteria for sepsis in the paediatric population are signs and symptoms of inflammation plus infection with hyper or hypothermia (rectal temperature >38.50 or <350 C), tachycardia (may be absent in hypothermic patients), and at least one of the following indications of altered organ dysfunction- altered mental status, hypoxemia, increased serum lactate level, bounding pulses.

Once the identification is done, rapid implementation of protocolised care is most important. Like in a heart attack, where initial treatment of re-canalisation has to be given within first six hours or in brain stroke within three hours and in severe accidental trauma first hour is called 'golden hour', in sepsis too, first six hours and first 24 hours carry significant importance to implement certain treatment guidelines. These treatment guidelines have been proven by evidence to increase the chance of survival.

The guidelines consider various topics relevant to managing severe sepsis and septic shock. Topics directly relevant to the management of severe sepsis and septic shock include:

• Initial resuscitation.
• Infection diagnosis.
• Antibiotic therapy.
• Infection source control.
• Fluid therapy.
• Vasopressors.
• Inotropic therapy.
• Corticosteroids.
• Recombinant human activated protein C (rhAPC).
• Blood product administration.

Supportive Therapy

• Mechanical ventilation of sepsis -induced Acute Lung Infection (ALI)/ Acute Respiratory Distress Syndrome (ARDS).
• Sedation, analgesia, and neuromuscular blocked in sepsis.
• Glucose control.
• Renal replacement.
• Bicarbonate therapy.
• Deep vein thrombosis prophylaxis.
• Stress ulcer prophylaxis.
• Selective digestive tract decontamination.
• Consideration for limitation of support.

The ultimate determinant of survival in sepsis and reversal of organ failure is supplying adequate oxygen to the tissues. All the interventions, including improving blood pressure/ haemodynamic, supporting artificial ventilation, blood transfusion to increase haemoglobin work ultimately for better oxygen delivery to the tissues.

Early Severity Assessment and Timely Intervention

This aids in optimising management of severe sepsis and septic shock.

Importance of early identification and treatment: Several lines of evidence indicate that early identification and treatment of severe sepsis and septic shock improve outcomes. Early initiation of hemodynamic resuscitation with specified treatment endpoints, also referred to as Early Goal Directed Therapy (EGDT), consistently has improved mortality rates in numerous clinical trials. Prior to a seminal study by Rivers and colleagues, trials of haemodynamic resuscitation as an intervention for patients who had septic shock allowed patient enrollment for upto 72 hours after ICU admission and produced negative intervention. Participants in the study by Rivers and colleagues were assigned to receive goal directed or standard resuscitation therapy. Patient in the goal directed therapy group were resuscitated according to the EGDT protocol for at least six hours immediately following arrival in the ED. In hospital, 28-day and 60-day mortality rates for the EGDT group were 30.5 per cent, 33.3 per cent and 44.3 per cent, respectively, compared with 46.5 per cent, 49.2 per cent, and 56.9 per cent in the standard therapy group.

Because rapid and appropriate treatment is likely to improve outcomes, early recognition of severe sepsis and septic shock is important.

Some predisposing factors can worsen the severity of sepsis making outcome also worse.

These should be treated more aggressively:

• Diabetes Mellitus: With meticulous blood sugar control.
• Surgery through invasive procedures: Be careful not to have infection through surgical interventions.
• Immuno compromised status: AIDS, cancer chemotherapy, alcoholism are predisposing factors for severe sepsis.
• Malnutrition: Can increase severity and mortality with serious infections.

Advances in Identifying Source of Infection

The laboratories have much improved and much faster techniques to grow bacteria in the lab and check their sensitivity to antibiotics.

Infection identification and source control: According to recommendations in the SSC guidelines, cultures to identify causative organisms should be drawn before starting anti-microbial therapy, as long as sampling does not delay antibiotic administration significantly. Sampling before antibiotic therapy is important, because sterilisation of blood culture can occur within a few hours of the first dose. Identification of causative organisms facilitates adjustment of antibiotic therapy. At least two blood cultures should be drawn, and atleast one should be percutaneous. Do not miss early signs of sepsis. May it be any tropical fever like malaria, typhoid or any bacterial infection like pneumonia, perforated appendix or may it be any post operative infection. Always assess for following signs:

• Temperature greater than 38.2 c[r1]
• Heart rate greater than 120 beats/ min.
• SBP less than 110 mm Hg.
• Platelet counts less than 150 X 10 9/ L.
• Leukocyte count less than 4 X 10 9 / L.
• Sodium greater than 145 mmol/ L.
• Bilirubin greater than 30 mmol/ L.
• Urea greater than 15 mmol/ L.

Organ Dysfunction Signs

Severe sepsis is defined as sepsis accompanied by organ dysfunction, hypoperfusion, or hypotension. Epidemiologic data indicate that the percentage of sepsis patients who have organ dysfunction is increasing and the mortality increases accordingly.

It is important to recognise that,

• Organ dysfunction occurs on a progressive continuum.
• Recognition of early organ abnormalities can facilitate treatment at earlier stages of MODS or Multi- Organ Dysfunction Syndrome.
• Measures of organ dysfunction over time provide a better indication of disease course than individual measurements.
• Organ dysfunction can be affected by many factors, including those that are host and intervention related.

Mortality doubles as the number of dysfunctional organs increases from one to two, and it increases three - to fourfold as the number of dysfunctional organs increases from one to four, or more. Because early recognition of severe sepsis facilities timely intervention, it increases opportunities to maintain tissue perfusion and oxygenation and limit additional organ dysfunction. Unfortunately, clinicians do not always recognise that dysfunction in one organ, along with indications of sepsis, qualifies the patient as having severe sepsis. Concurrent signs of infection and SIRS should motivate clinicians to seek signs of organ dysfunction and hypoperfusion, even in the absence of hypotension. Because, indications of organ dysfunction can be attributable to several causes other than sepsis (eg. surgical procedures, acute myocardial infarction, drug therapies or underlying disease states) clinicians should work to identify or eliminate other easily identifiable causes.

Organ dysfunction in sepsis is observed most commonly in the respiratory, cardiovascular, renal, haematologic, central nervous and hepatic systems. The signs of these have already been mentioned earlier.

Current Tools

The highest priority tasks that should be performed within six hours of a severe sepsis diagnosis focus on

• Hemodynamic stabilisation/ resuscitation.
• Restoring tissue oxygenation.
• Infection identification.
• Infection control (antibiotic therapy / source control).

Monitoring Haemodynamics, Perfusion and Tissue Oxygenation

Once severe sepsis shock has been identified, the highest management priorities are establishing vascular access and initiating fluid resuscitation to improve tissue perfusion. Maintenance of tissue perfusion is critical, because global tissue hypoxia is a key step toward multiple organ failure. Fluid resuscitation recommendations have been updated in the 2008 aSSC guidelines but remain based on the demonstrated effectiveness of EGDT in managing septic shock. Readers are encouraged to consult the 2008 SSC guidelines for more comprehensive information regarding initial resuscitation recommendations.

Haemodynamic monitoring is essential to resuscitation efforts based on attaining specified targets for BP and oxygen saturation. BP measurements, CVP in particular, are readily available targets for directing fluid resuscitation. BP measurements, however do not necessarily reflect bold flow and oxygenation. Even when resuscitation goals for CVP and MAP have been achieved, additional measurements of venous oxygenation and lactate may reveal inadequate oxygenation and tissue perfusion and indicate that additional resuscitation efforts are required. Therefore, measurements of tissue perfusion and oxygenation are necessary to determine whether the ultimate goal of resuscitation, an adequate oxygen supply to tissue, has been attained.

Antibiotics

Antibiotics are greatest tools in combating the attack of micro-organisms, provided they are used wisely and timely. But remember, antibiotic alone are not the magic bullets which will revert sepsis syndrome.

They have to be used expeditiously along with other early interventions for sepsis.

Antimicrobial Therapy

The importance of timely antimicrobial treatment has been mentioned. Delaying empiric antibiotic treatment to await culture results has negative consequences. Clinicians should be aware that blood cultures will be negative in more than 50 per cent of severe sepsis/ septic shock cases. Furthermore, restricting use of antibiotics to limit development of resistance or reduce cost is not appropriate in this patient population. Broad-spectrum therapy is warranted until information (causative agent, antibiotic susceptibilities) is available for therapeutic adjustment. Selection of an appropriate antimicrobial agent, often in the absence of microbiologic confirmation, requires consideration of patient-related characteristics such as drug intolerances, recently used antibiotics previous infections, underlying disease and clinical syndrome. Awareness of the prevalence of infections caused by specific organisms can provide clinicians with insight into appropriate empiric antimicrobial therapy. Pathogen resistance patterns in the hospital and community, along with hospital protocols to limit antibiotic resistance, also should be considered. Along with Gram negative bacteria, Gram positive or fungal infections also have to be considered in the Indian scenario.

New Biomarkers

New tools and techniques are emerging that may assist clinicians in assessing patient risk of sepsis progression, in minimally invasive measurement of tissue levels, and in diagnosis of infection. These advances should allow clinicians to provide appropriate interventions more quickly. Studies have been performed to identify biomarkers for use in the early identification of patients at risk of developing severe sepsis and septic shock. Many recent studies, however, have documented the benefits of PCT measurements for sepsis evaluation in critically ill patients and in guiding antimicrobial therapy.

Summary

Because sepsis-related mortality is unacceptably high, the SSC has set a quality improvement goal to reduce mortality caused by severe sepsis and septic shock by 25 per cent by 2009. Clearer definitions of sepsis, severe sepsis, and septic shock will help in achieving this goal, as well as recently updated evidence-based management guidelines for severe sepsis and septic shock. To be effective, these definitions and guidelines need to be applied to the early identification and aggressive treatment of patients who have severe sepsis or septic shock. Early goal-directed therapy to achieve haemodynamic stabilisation has been demonstrated to decrease mortality in patients who have septic shock. Currently, clinicians must rely on clues to sepsis progression in the patient's medical history, vital signs, haemodynamic monitoring, lactate levels and indications of organ dysfunction, all in the context of infection- to identify patients who have severe sepsis. Of these, haemodynamic monitoring, lactate levels, and indications of organ dysfunction may be most useful in indicating the patient's stage of sepsis. In the future, less-invasive measures of haemodynamics and blood flow, molecular techniques for identifying infectious agents, refined scoring systems, biomarkers and genetic screening may aid clinicians in identifying patients who have severe sepsis. Once a patient who has severe sepsis has been identified, timely implementation of guideline recommendations should follow. Resources and tools are available through the SSC and IHI to facilitate the efficient translation of the SSC guideline recommendations into clinical practice.

Drotrecogin alfa (activated) (Xigris, marketed by Eli Lilly and Company) is a recombinant form of human activated protein C that has anti-thrombotic, anti-inflammatory, and profibrinolytic properties. Drotrecogin alpha (activated) belongs to the class of serine proteases. It is used mainly in intensive care medicine as a treatment for severe sepsis.

We have treated several cases of severe sepsis in our ICU successfully including diabetic foot infection, dog bite, leptospirosis, abdominal sepsis, post-operative sepsis, tetanus etc. leading to multi-organ failure. Mortality varies between 30 to 40 per cent. Mortality is highest in immune-compromised patients and in those patients who have been referred late to ICU after losing advantage of initial six to 24 hours.

Let us be vigilant for early recognition and early definite treatment for best outcome.

prachee.sathe@gmail.com