The Treatment Approach to Sepsis.
We believe that sepsis is a treatable and “curable” disease and that if the disease is diagnosed early and treated according the evidence-based approach outlined below patients will not develop progressive organ failure or die from sepsis. It is however important to emphasize that patients with a rapidly fatal and/or incurable underlying disease who become septic may develop organ failure and die because of their underlying disease; i.e. our approach “cures” sepsis but does not cure advanced malignancy, dementia, end-stage heart failure, etc. Furthermore, the earlier that the patient is treated the greater the likelihood of a good outcome. In addition, it is critical to appreciate that all the steps below must be followed (see the “Steps to the cure” below). Many individuals erroneously believe that our “metabolic resuscitation protocol” by itself will cure sepsis; this is incorrect, this protocol will likely prevent progressive organ failure and death when used as an adjunct to the essential evidence-based components of the entire treatment strategy. Adequate and appropriate antimicrobial therapy and source control are essential if the patients are to be cured from sepsis; failure to achieve these goals will results in progressive organ failure and death. The “steps to the cure” are outlined below and will be briefly reviewed. We have previously reviewed our approach to sepsis, the reader is encouraged to review these publications.[1-5]
Empiric Broad Spectrum Antibiotics
Empiric intravenous antibiotic therapy should be started as soon as possible after appropriate cultures have been obtained. While the tight window as suggested by the Surviving Sepsis Campaign is not supported by scientific evidence, common sense would dictate that delaying the administration of antibiotics serves no useful purpose. The choice of antibiotics is largely determined by the source or focus of infection, the patient’s immunologic status, whether the patient has risk factors for a drug resistant pathogen (DRP) as well as knowledge of the local microbiology and sensitivity patterns. Initial empirical anti-infective therapy should include one or more drugs that have activity against the likely pathogens. Because the identity of the infecting pathogen(s) and its sensitivity pattern(s) are unknown at the time of initiation of antibiotics, for patients with severe sepsis and septic shock the initial regimen should include two or more antibiotics or an extended spectrum ?-lactam antibiotic.
It has been known for centuries that, unless the source of the infection is controlled, the patient will not be cured of his/her infective process and that death will eventually ensue. It is important that specific diagnoses of infection that require emergent source control be made in a timely manner (eg, necrotizing soft tissue infection, peritonitis, cholangitis, cholecystis, urinary tract obstruction, intestinal infarction) and surgical consultation be immediately obtained.[7,8] When source control is required for a severely septic patient, the effective intervention associated with the least physiological insult should be used (eg, percutaneous rather than surgical drainage of an abscess).[7,9] It is important to emphasize that patients who do not demonstrate the typical exponential fall in serum procalcitonin (PCT) levels (reviewed in the section on diagnosis), as well as a persistently increased WBC and lactate, that inadequate source control or a new inadequately treated infection should be strongly suspected.
A restrictive, physiologically guided fluid strategy
It is important to stress, that in general sepsis is not a volume depleted state and that patients in septic shock are generally poorly responsive to fluids. Patients with sepsis have not lost liters of fluid and the aggressive approach to fluid replacement inherent in the Early Goal Directed Therapy (EGDT) approach to sepsis management and further perpetuated and encouraged by the Surviving Sepsis Campaign Guidelines are without scientific support and extremely dangerous.[6,7,10-12] This is not a new concept and was elegantly demonstrated in a series of studies performed at the NIH by Frederick Ognibene, Margaret Parker and colleagues in the late 80’s. These authors demonstrated that patients in septic shock were unable to increase left ventricular end-diastolic volume (LVEDV) and stroke volume in response to a fluid challenge.[13,14] It is important to emphasize that some patients with sepsis are dehydrated (due to poor oral intake, etc.) and may respond to SMALL boluses of fluid. However, the recommendation of the Surviving Sepsis Campaign to rapidly infuse a 30 ml/kg bolus of fluid is unsupported by the scientific literature and will likely lead to “salt water drowning.” Furthermore, it is essential to make the distinction between dehydration and intravascular volume depletion; these are not the same condition and are treated differently. The following concepts are vitally important to understand when formulating an approach to fluid and vasopressor resuscitation in patients with sepsis:[16-19]
- The only reason to give a patient a fluid bolus is to cause an increase in the stroke volume (of at least 10%); this underlies the concept of fluid responsiveness. In patients who are fluid non-responders, fluid boluses are likely to be harmful.
- It has been clearly established (and is now indisputable) that only about 50% of hemodynamically unstable patients are fluid responders. It is likely that the less than 40% of patients with severe sepsis/septic shock are fluid responders.
- The fact that a patient is a fluid responder does not equate with the need for a fluid bolus. Fluid boluses are potentially harmful (cause tissue and organ edema) and the risk/benefit ratio should be determined prior to each fluid bolus.
- The optimal volume of a fluid bolus is 500cc. A smaller volume is likely to cause an insignificant increase in the mean circulating filling pressure (MSFP) which is required to ensure increased venous return.  Large fluid boluses (30ml/kg) as enforced by the Surviving Sepsis Campaign [6,7,11,12] are without a physiologic basis, will cause a large increase in filling pressures (with the consequent release of atrial-natiuretic peptides) and are likely to lead to severe tissue edema.
- The hemodynamic response to each and every fluid bolus should be evaluated; failure to do so represents a severe breach of the physician’s responsibility to uphold the Hippocratic principle of “Primum Non Nocere”. This should include the change in blood pressure, heart rate, respiratory rate, and arterial saturation and ideally the stroke volume (as determined by minimally invasive nor non-invasive cardiac output monitors). Blindly giving fluid boluses without regard to its hemodynamic effect (benefit/harm) is an extremely dangerous.
- It should be recognized that the hemodynamic response to a fluid challenge is usually small and short lived. In healthy persons, less than 20% of a crystalloid bolus remains intravascular 2 hours following the infusion; in patients with sepsis this percentage is likely to be less than 10%. Consequently, the hemodynamic benefit (increased stoke volume and blood pressure) following a fluid bolus in critically ill patients has been demonstrated to be short lived, lasting only 15-30 minutes. The net effect of large fluid boluses (> 500mls) is to expand the extravascular, extracellular compartment resulting in severe tissue edema; the fluid goes directly from the infusion bag into the tissues.
- Clinical signs, the chest radiograph, central venous pressure (CVP) and ultrasonography cannot be used to determine fluid responsiveness.
- The passive leg raising maneuver (PLR) or a fluid challenge coupled with real-time stroke volume (SV) monitoring are the only accurate methods for determining fluid responsiveness.
- A high CVP is a major factor compromising organ perfusion. Titrating fluid to achieve a CVP > 8 mmHg as directed by EGDT and recommended by the Surviving Sepsis Campaign [6,7,10-12] will predictably increase the risk of kidney failure, impaired hepatic and gastro-intestinal function and DEATH. 
- Lactated Ringers solution (LR) is the crystalloid of choice for volume expansion. Normal saline (NS) is an un-physiologic solution that is associated with a hyperchloremic metabolic acidosis, a reduction in glomerular filtration as well as a coagulopathy and is pro-inflammatory.
- A continuous infusion of a 20-25% albumin solution (at 10-20 ml/hr) should be considered in patients with a serum albumin less than 30 g/dl. In addition to increasing the colloid osmotic pressure, albumin may restore the endothelial glycocalyx which is damaged in patients with sepsis. While this approach is SAFE,  its effects on organ failure and survival are unclear.
- The approach to resuscitation of each patients should be individualized according to each patient’s unique clinical presentation, co-morbidities and hemodynamic profile; this concept is called precision medicine. Simplistic non-adaptive flowcharts are designed for stupid people who should not be providing care to the sickest of patients.
Hemodynamically unstable septic patients should receive fluid boluses of no greater than 500 ml best guided by an assessment of fluid responsiveness. A 30ml/kg bolus of fluid is without scientific foundation, is reckless and exceedingly dangerous. Patients who have not achieved the hemodynamic goals (see below) despite 1000 to 1500 ml of crystalloid and in those who are fluid non-responsive an infusion of norepinephrine should be started and titrated to achieve the desired hemodynamic goals.
- MAP > 65 mmHg
- HR < 100/min
- Adequate tissue perfusion as assessed by clinical examination
- CI > 2.2 l/min/m2
- CVP < 8 mmHg
A bedside echocardiogram performed by the critical care team is essential to guide hemodynamic management. An echocardiogram allows for the early detection of severe systolic dysfunction which may influence the treatment strategy i.e, use of low dose dobutamine or milrinone.
The Failure of EGDT and the Surviving Sepsis Campaign 6-hour “Resuscitation Bundle”.
Even though the treatment strategy as advocated by EGDT  was clearly absurd and lacking in any scientific basis and that the reported results were implausible and contradictory (see accompanying U-tube Videos by Dr. Nathanson and Dr. Marik) this bogus study was the foundation on which the 2004, 2008, 2012 and 2016 (except SmvO2) Surviving Sepsis Campaign 6-hour resuscitation bundle was based. [6,7,11,12] It is remarkable that a group or seemingly intelligent individuals (now more than 35) could have been so badly misled by this obviously bogus study. Astonishingly, many of the current authors of the Surviving Sepsis Campaign still believe in the myths perpetuated by this study. Bewilderingly, because the bogus EGDT study was endorsed and promoted by the Surviving Sepsis Campaign, EGDT became regarded as the standard of care for the management of sepsis around the world. Many of the treatment elements of EGDT have been so deeply ingrained in the management of patients around the world that they are difficult to reverse; the failure to de-adopt a recognized therapy which is subsequently shown to be non-beneficial or harmful is a serious medical issue. [22-25] Indeed, the control arms of the Process, ARISE and Promise studies were so severely influenced by EGDT that these studies essentially compared two similar treatment strategies. [26-28] It is important to recognize that all the elements of EGDT and by inference the Surviving Sepsis Campaign 6-hour bundle have now been demonstrated to be wrong and NONE are supported by the medical literature. The era of EGDT and the SSC Guidelines are now dead; the metabolic resuscitation protocol together with a conservative physiologic guided fluid strategy has risen from the ashes of this bogus approach to the management of sepsis.
- Marik P, Bellomo R. A rational apprach to fluid therapy in sepsis. Br J Anaesth 2016; 116:339-49.
- Marik PE. Early management of severe sepsis: Current concepts and controversies. Chest 2014; 145:1407-18.
- Marik PE. Surviving sepsis: going beyond the guidelines. Ann Intensive Care 2011; 1:17.
- Marik PE, Varon J. Precision medicine and the Federal sepsis initiative! Crit Care Shock 2016; 19:1-3.
- Marik PE. The demise of early goal-directed therapy for severe sepsis and septic shock. Acta Anaesthesiol Scand 2015; 59:561-67.
- Rhodes A, Evans L, Alhazzani W et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock:2016. Crit Care Med 2017; 45:486-552.
- Dellinger RP, Levy MM, Rhodes A et al. Surviving Sepsis Campaign: International Guielines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med 2013; 41:580-637.
- Boyer A, Vargas F, Coste F et al. Influence of surgical treatment timing on mortality from necrotizing soft tissue infections requiring intensive care management. Intensive Care Med 2009; 35:847-53.
- Bufalari A, Giustozzi G, Moggi L. Postoperative intraabdominal abscesses: percutaneous versus surgical treatment. Acta Chir Belg 1996; 96:197-200.
- Rivers E, Nguyen B, Havstad S et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-77.
- Dellinger RP, Carlet JM, Masur H et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32:858-73.
- Dellinger RP, Levy MM, Carlet JM et al. Surviving sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296-327.
- Ognibene FP, Parker MM, Natanson C et al. Depressed left ventricular performance: response to volume infusion in patients with sepsis and septic shock. Chest 1988; 93:903-10.
- Parker MM, Suffredini AF, Natanson C et al. Response of left ventricular function in survivors and nonsurvivors of septic shock. J Crit Care 1989; 4:19-25.
- Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care 2014; 4:21.
- Marik PE. Fluid responsiveness and the six guiding principles of fluid resuscitation. Crit Care Med 2016; 44:1920-1922.
- Monnet X, Marik PE, Teboul JL. Prediction of fluid responsiveness: an update. Ann Intensive Care 2016; 6:111.
- Marik PE. The physiology of volume resuscitation. Curr Anesthesiol Rep 2014; 4:353-59.
- Aya HD, Rhodes A, Ster IC et al. Haemodynamic effect of different doses of fluids for a fluid challenge: a quasi-randomised controlled study. Crit Care Med 2017; 45:e161-e168.
- Chowdhury AH, Cox EF, Francis S et al. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012; 256:18-24.
- Finfer S, Bellomo R, Boyce N et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247-56.
- Prasad V, Cifu A, Ioannidis JP. Reversal of established medical practices. Evidence to abandon ship. JAMA 2012; 307:37-38.
- Prasad V, Vandross A, Toomey C et al. A decade of reversal: An analysis of 146 contradicted medical practices. Mayo Clin Proc 2013; 88:790-798.
- Niven DJ, Rubenfeld GD, Kramer AA et al. Effect of published scientific evidence on glycemic control in adult intensive care units. JAMA Intern Med 2015; 175:801-9.
- Davidoff F. On the undiffusion of established practices. JAMA Intern Med 2015; 175:809-11.
- Yealy DM, Kellum JA, Huang DT et al. A Randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370:1683-93.
- Peake SL, Delasney A, Bailey M et al. Goal-directed resuscitation for patients with Early Septic Shock. N Engl J Med 2014; 371:1496-506.
- Mouncey PR, Osborn TM, Power S et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015; 372:1301-11.
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