12 Aug, 2018
Sepsis and Septic shock
Surviving Sepsis Guidelines:  In their own words of wisdom – ” The recommendations in this document are intended to provide guidance for the clinician caring for adult patients with sepsis or septic shock. Recommendations from these guidelines cannot replace the clinician’s decision-making capability when presented with a patient’s unique set of clinical variables. These guidelines are intended to be best practice and not created to represent standard of care”.
 
The clinician may push back from use of recommendations for fear that evidence-based guidelines lead to “cookie cutter” medicine and reflexive behaviors that deemphasize the “art” of medicine.The recommendations are intended for a “typical” septic patient. Patients still benefit from the art of medicine, which includes interpretation of data and individualization of treatment. The recommendations provide much needed general treatment guidance to the bedside decision maker who is busy, pressured to see more patients in less time, and who will use a distillation of the current literature into a coherent set of recommendations suitable for the large majority of septic patients who are “typical”.
 
Definitions:
Sepsis has very many definitions which makes it very confusing. 
 
CMS definition of sepsis ( SIRS + infection): Using this definition, we assume SIRS as an appropriate, not necessarily dysregulated, host response to infection.  Sepsis is defined as presence of infection, which can be proven or suspected, and 2 or more of the following SIRS criteria: 
  • Temp  > 38 C ( 100.4 F) or less than < 36 C (<96.8F) 
  • Tachypnea, RR>20 or PaCO2 <32 
  • Heart rate > 90 
  • WBC > 12,000 or < 4,000 or with >10% “bands” 
Severe sepsis is sepsis with impaired blood flow to body tissues (hypoperfusion) or detectable organ dysfunction. Severe sepsis may occur with or without sepsis-induced hypotension. Signs of organ dysfunction could include lactate > 2 mmol/L, Creatinine >2, urine output less than<0.5 ml/kg/hr for at least 2 hours despite fluid resuscitation, creatinine increase > 0.5 mg/dL , INR > 1.5 or aPTT > 60 seconds , platelet count < 100,000 , total bilirubin > 2 mg/dL , change in mental status. 
 
Septic shock is severe sepsis with sepsis-induced hypotension [SBP < 90 mm Hg or a drop of > 40 mm Hg from baseline or MAP < 65 mm Hg] that persists after adequate fluid resuscitation.  CMS also defines a lactate > 4 as septic shock. 
 
Sepsis 3 Defintion: It is a lifethreatening organ dysfunction caused by dysregulated host reponse to infection. Organ dysfunction can be identified as an acute chnage in SOFA score by more than 2 points consequent to infection. SOFA scores include a range of 0-24 points using P/F ratio, GCS, MAP, Vasopressor needs, creatinine, bilirubin, platelet count. It defines septic shock as a subset of sepsis with circulatory and cellular/metabolic dysfunction. Patients with septic shock can be defined as persistent hypotension requiring vasopressors to maintain a MAP> 65 and having a serum lactate >2 mmol/L, despite adequate volume resuscitation. In ICU patients, SOFA score was a better predictor of mortality than SIRS criteria. 
 
Q-SOFA criteria – Used more for screening of sepsis and doesn’t require any lab tests. A range of 0-3 points using SBP less than 100, RR>20 and alterred mentation. Sepsis is defined in presence of atleast 2 criteria in presence of an infection.
 
LODS score ( Logistic organ dysfunction syndrome) – A range of 0-22 points using P/F ratio, GCS, systolic blood pressure, HR, creatinine, bilirubin, platelet count, WBC, urine output, BUN and INR. 
 
Pathophysiology:
The major pathophysiologic changes in patients with severe sepsis and septic shock include vasoplegic shock (distributive shock), myocardial depression, altered microvascular flow and a diffuse endothelial injury. The widespread endothelial injury results in a microvascular leak, with tissue and organ edema, hypotension, and shock. Increased endothelial permeability is caused by shedding of the endothelial glycocalyx and development of gaps between endothelial cells (paracellular leak). Vasoplegic shock due to the failure of the vascular smooth muscle to constrict, results in arterial and venodilatation. Venodilatation decreases venous return and compounds the intravascular volume deficit caused by the vascular leak. Chest. 2014 Jun;145(6):1407-18,  N Engl J Med 2001; 345:588-595
 
Diagnosis: 
  1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobials.  At least 2 sets of blood cultures (Both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hrs) inserted. Sterilization of cultures can occur within minutes to hours after first dose of antibiotics. All cultures can be drawn at the same time. Blood culture yield has not been shown to be improved with sequential draws or timing to temperature spikes. 
  2. Use of the 1,3 beta-D-glucan assay (grade 2B), mannan and anti-mannan antibody assays (2C), if available, and invasive candidiasis is in differential diagnosis of cause of infection.   
  3. Imaging studies performed promptly to confirm a potential source of infection (UG).  
  4. If blood cultures from vascular device are positive earlier then peripheral cultures, vascular device is likely the source of infection. 
  5. The volume of blood drawn with each culture tube should be ≥ 10 mL 
 
Early Goal-Directed Therapy for Severe Sepsis/Septic Shock
 
Old Guidelines: The goals during the first 6 hours of resuscitation should be (Grade 1C): 
  1. Mean arterial pressure (MAP) ≥ 65 mm Hg
  2. Central venous pressure (CVP) 8-12 mm Hg (12-15 mm Hg in patients receiving mechanical ventilation or with known preexisting decreased ventricular compliance). However, CVP has been proven to be unreliable indicator of fluid status and can’t be used soley to drive fluid resuscitation. Chest. 2008 Jul;134(1):172-8 , Crit Care Med. 2013 Jul;41(7):1774-81. An excellent article on the usefulness of CVP can be found here. In a study reviewing the outcomes of patients enrolled in the Surviving Sepsis Campaign database, the attainment of a CVP of >8 mm Hg and Scvo2 of > 70% did not influence survival in patients with septic shock. Emerg Med J. 2011 Jan;28(1):3-4
  3. Central venous oxygen saturation (from the superior vena cava) SCVO2 ≥ 70%, or mixed venous oxygen saturation (from a pulmonary artery catheter) ≥ 65%. Patients who are septic may have a normal or increased Scvo2 caused by reduced oxygen extraction. Infact, higher ScVO2 may indicate very sick tissues and may lead to worse mortality rates. Ann Emerg Med. 2010 Jan;55(1):40-46.e1 ( Lactate clearance of 25% has been found to be equivalent to ScVo2 measurements and hence, it is falling out of favour) Crit Care Med. 2004 Aug;32(8):1637-42
  4. Urine output ≥ 0.5 mL/kg/hr 
  5. Lactate clearance: An elevated lactate concentration is a consequence of increased aerobic glycolysis as part of the stress response and that titrating therapy to the rate of decline in lactate concentration is a potentially harmful endeavour. Furthermore, an increased lactate concentration may be an important adaptive survival response during critical illness. OA Critical Care, 1 (1) (2013), p. 3
​CMS core measures for severe sepsis and septic shock ( SEP-1 bundle )
0-3 hours
  • Initial lactate level measurement
  • Broad spectrum or other antibiotics administered within an hour
  • Blood cultures drawn prior to antibiotics
  • Fluid bolus of 30cc/kg if SBP less than 90 or MAP 40mm Hg less than baseline or lactate >4. ( Can use IBW in case of obesity). 

​0-6 hours

  • Repeat lactate measurement if intial lactate is elevated. 
  • Vasopressors infusion if hypotension persists after fluid bolus
  • Repeat volume status and tissue perfusion assessment by one of the following, if hypotensive or lactate > 4 after fluid bolus-
    1. ​​Option 1: Document a focused physical exam including all of : Vital signs, cardiopulmonary exam, capillary refill evaluation, peripheral pulse evaluation, and skin examination 
    2. Option 2: Document two of the following: CVP measurement, ScVO2 measurement, Bedside cardiovascular ultrasound, Passive leg raise or fluid challenge
SEP1 bundle was found not only non evidence based and useless. No high- or moderate-level evidence shows that SEP-1 or its hemodynamic interventions improve survival in adults with sepsis. Ann Intern Med. 2018;168(8):558-568. SEP-1 bundle could actualluy be harmful. Anaesthesiol Intensive Ther. 2017;49(5):323-328.  Please be part of this campaign to retract SSC guidelines and lets provide the best care for the patient, not the check the boxes type of care. Also, in patients admitted to ICU with a diagnosis of sepsis, only one third of patients had a confirmed infection. Upon post-hoc analysis, 13 % had an infection likelihood of “none” ,  30 % had an infection likelihood of possible, whereas slightly more than half scored a higher infection likelihood (25 % probable and 33 % definite).  Crit Care. 2015 Sep 7;19:319.  So, we do inappropriate things to 2/3rd of patients because of some stupid SEP-1 bundled care. 
 
New guidelines proposed by SCCM ( 1 hour bundle by SCCM ) – Time zero starts at triage. 
  1. Measure lactate and remeasure within 2–4 hours if level is >2 mmol/L. 
  2. Obtain at least two sets of blood cultures (aerobic and anaerobic) prior to administration of antibiotics. Do not withhold antibiotics pending blood cultures.
  3. Administer broad-spectrum iv antibiotics
  4. Initiate a bolus of 30 mL/kg of IV crystalloid for hypotension or lactate >4. This bolus should be completed within 3 hours. Colloid is not recommended.
  5. Use vasopressors to maintain mean arterial pressure (MAP) above 65 mm Hg during or after fluid resuscitation.
Goals of resuscitation:
  • Crystalloid is recommended for initial fluid resuscitation for severe sepsis and septic shock. A minimum of 30 ml/kg of crystalloids be given in the first 3 hours and additional fluids can be given as long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables.  
  • Surviving sepsis guidelines recommend to consider albumin fluid resuscitation if large volumes of crystalloid are required to maintain intravascular volume. ( ?If large volumes of crystalloid are needed to maintain intravascular volume, patient may actually not be fluid responsive and actually need vasopressors instead of more fluids or albumin). Metaanalysis of all studies that compared albumin vs crystalloids showed some mortality benefit with albumin in septic shock, especially when given less than 6 hours from identification of septic shock. 
  • Vasopressors should be begun within 6 hours for patients with hypotension despite aggressive initial fluid resuscitation (i.e., septic shock), to maintain a mean arterial pressure ≥ 65 mm Hg. Recent data indicate that vasopressors started even within the first hour while fluid resuscitation is being carried out tend to have better outcomes. The goal is to never allow drop in MAP thereby preventing end organ damage in the early phases of resuscitation. Crit Care. 2014 Oct 3;18(5):532 , Crit Care. 2014; 18(6): 691 
  •  The goal of attaining a mean arterial pressure (MAP) of ≥ 65 mm Hg for patients receiving vasopressors for septic shock is based on very limited evidence. Accordingly, the Surviving Sepsis Guidelines advise that “the optimal MAP should be individualized” during treatment of septic shock — perhaps higher than 65 mm Hg in a patient with hypertension and known atherosclerosis; perhaps lower than 65 mm Hg in a young healthy patient with a baseline normal blood pressure — and that other markers of perfusion such as serum lactate, skin appearance and temperature, urine output, and mental status should supplement the use of mean arterial pressure in all patients. 
  • Transfusion of packed red blood cells to a hematocrit of 30% and/or dobutamine infusion in patients with low ScVO2, despite volume resuscitation,  have not been proven to be beneficial and use of them is strongly discouraged. 
  • Lactic acidosis in sepsis: SSC recommends serial measurent of lactate until normalization of lactate level. They also recommend that in patients whose blood pressure has been restored to normal after fluid resuscitation, but still have lactate elevations ≥ 4 mmol/L , goal-directed therapy with serial measurements of CVP, ScVO2 and lactate should continue until these parameters improve. The rationale is that an elevated lactate is a consequence of tissue hypoxia and inadequate oxygen delivery. However, multiple studies have demonstrated that the increased blood lactate concentration in sepsis is not caused by tissue hypoxia but is rather produced aerobically as part of the metabolic stress response. A high lactate concentration should be interpreted as a marker of disease, portending a bad outcome. The presence of hyperlactataemia in resuscitated septic patients should not be taken as proof of oxygen debt needing increases in systemic or regional oxygen transport to supranormal values. Lactate, instead of being regarded only as a marker of hypoxia, might be an important metabolic signal. Lancet. 1999 Aug 7;354(9177):505-8 , Lancet. 2005 Mar 5-11;365(9462):871-5 , Lancet Diabetes Endocrinol. 2014 Apr;2(4):339-47, J Intensive Care. 2015; 3: 39.
 
Studies on usefulness of Early goal directed therapy
  1. Early goal directed therapy (Rivers study):  Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy.  
Of note, at baseline, EGDT group have lower CVP, lower MAP, lower SVO2, higher lactate, higher APACHE II score, higher SAPS II score, and higher MODS. At 7-72 hour mark, the patients assigned to early goal directed therapy had significantly higher central venous oxygen saturation, a lower lactate, a lower base deficit, and a higher pH than the patients assigned to standard therapy.  
 
The protocol was as follows: A 500-ml bolus of crystalloid was given every 30 minutes to achieve a central venous pressure of 8 to 12 mm Hg. If the mean arterial pressure was less than 65 mm Hg, vasopressors were given to maintain a mean arterial pressure of at least 65 mm Hg. If the central venous oxygen saturation was less than 70 percent, red cells were transfused to achieve a hematocrit of at least 30 %. After the central venous pressure, mean arterial pressure, and hematocrit were thus optimized, if the central venous oxygen saturation was less than 70 percent, dobutamine administration was started. N Engl J Med 2001; 345:1368-1377 
 
  1. PROCESS trial (Protocol based care in septic shock ): Protocol-based resuscitation (EGDT) of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. There was no difference in 60 day mortality in protocol based EGDT, protocol based standard care or physician led standard care. The need for RRT was higher in protocol based standard care 
The key aspects in protocol for standard therapy are use of peripheral 18G IV’s, fluid bolus of 2 litres within 1 hour with first 500-1000ml in 20 mins, no dobutamine, use of vasopressors if SBP<100 or shock index>0.8 ( Heart rate/SBP) after being fluid replete and no need for SVO2.  It also strongly discouraged CVP and SVO2 measurements. Of note, vasopressors were started immediately once patient is fluid replete.  N Engl J Med. 2014 Mar 18. 
 
  1.  ARISE Trial ( EGDT vs Usual Care):  In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days ( 18.6% EGDT vs. 18.8% usual care group ). There was also no difference in Hospital & ICU LOS. N Engl J Med 2014; 370:1683-1693. 
Key pointers: 
  • Compared with Process trial, the vasopressors requirements in both groups at baseline are the same. 
  • Volume of fluid administered during the first 6 hours was EGDT 1.9 liters vs. Usual-care group 1.7 liters . ​
  • Between 6 and 72 hours, the proportion of patients receiving vasopressor infusions was higher in the EGDT group than in the usual-care group (58.8% vs. 51.5%) 
  • IV fluids given were 2.5 litres before randomization, 1.7 to 1.9 litres in first 6 hours and then 4.2 litres between 6-72 hours. 
  • Vasopressor use was significantly less in usual care group in both first 6 hours as well as 6-72 hrs.  ​
  1. Promise Trial : In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome ( 90 day mortality was 29.5% in EGDT vs 29.2% in usual care group). All patients recieved a median of 2 liters before randomization.  ProMISe Trial
  2. PRISM Study : In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics.  PRISM Study
  3. CLASSIC Trial: A protocol restricting resuscitation fluid successfully reduced volumes of resuscitation fluid compared with a standard care protocol in adult ICU patients with septic shock. The patient-centred outcomes including 90 day mortality, ischemic events in ICU and worsening of AKI all pointed towards benefit with fluid restriction. CLASSIC Trial​
  4. FEAST Study: Fluid boluses significantly increased 48-hour mortality in critically ill children with infection and impaired perfusion in these resource-limited settings in Africa. Feast Study​
  5. REFRESH Trial: Finished enrolling to evaluate the efficacy of a fluid restrictive strategy. Due for publication some time this year.  REFRESH Trial​
  6. CLOVERS Trial: RCT to compare the liberal and restrictive fluids strategies, the Crystalloid Liberal or Early vasopressor resuscitation in Sepsis trial.Two competing strategies are emerging: a liberal fluids approach, consisting of a larger volume of initial fluid (50 to 75 mL/kg [4 to 6 L in an 80-kg adult] during the first 6 hours) and later use of vasopressors, vs a restrictive fluids approach, consisting of a smaller volume of initial fluid (≤30 mL/kg [≤2 to 3 L]), with earlier reliance on vasopressor infusions to maintain blood pressure and perfusion. Clovers Trial
 
Initial Antibiotic / Antimicrobial Therapy in Severe Sepsis/Septic Shock: 
 
  • For severe sepsis or septic shock, give antimicrobials “within the first hour” after severe sepsis or septic shock is recognized. Each hour delay in administering antibiotics is associated with increased mortality.  Crit Care Med. 2006 Jun;34(6):1589-96.
  • SSC recommend double gram negative coverage for the intial management of septic shock but not for sepsis without shock. 
  • Antimicrobials should be chosen that cover all the likely causative pathogens — nearly always including bacteria, but sometimes also fungi and/or viruses. 
  • Antimicrobials should be selected that are expected to penetrate into the presumed infected tissues. 
  • For patients at risk for fungal infection as a source for severe sepsis, checking one of the newer assays for invasive candidiasis such as 1,3-beta-D-glucan, mannan, or anti-mannan ELISA antibody testing 
  • Review the antibiotic / antimicrobial regimen daily, and de-escalate therapy whenever appropriate. Strength: Grade 1B (strong recommendation with moderate-quality evidence). 
  • Consider using Procalcitonin to help gain confidence in stopping empiric antibiotics in patients who appeared to have severe sepsis or septic shock at first, but now have a lower suspicion for infection.  Strength: Grade 2C (weak recommendation with low-quality evidence). Viral infections tend to increase the cytokine interferon-gamma, which inhibits procalcitonin release–resulting in lower levels of procalcitonin during viral infection.  
  • Use combination therapy (multiple drugs active against the same organisms, through different mechanisms of action) when appropriate, but for only a limited time (3-5 days). If positive cultures and sensitivity data are available sooner than 3-5 days, narrow antibiotic use as soon as data is available.  
  • Combination therapy is recommended for septic shock or severe sepsis with Neutropenia, MDR bacteria like Pseudomonas, Acinetobacter, et al. or sepsis with respiratory failure.  
  • Use an extended-spectrum beta-lactam and either a fluoroquinolone or aminoglycoside in Pseudomonas aeruginosa bacteremia causing septic shock and respiratory failure  
  • Combine a beta-lactam and a macrolide in Streptococcus pneumoniae with bacteremia and septic shock. 
  • Treat most infections in people with severe sepsis / septic shock for 7-10 days total. Longer treatment might be appropriate for patients who are responding slowly, have abscesses, empyema, or other infectious foci not amenable to drainage, have Staphylococcus aureus bacteremia, have unusual infections (e.g., fungal or viral) or have immune deficiencies (e.g., neutropenia).  Shorter courses are appropriate in some patients, particularly those with rapid clinical resolution following effective source control of intra-abdominal or urinary sepsis and those with anatomically uncomplicated pyelonephritis. 
Source Control  
 
1. A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is made, if feasible (grade 1C).  
2. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established.  
IV fluids:
 
Pathophysiologically, sepsis is characterized by vasoplegia with loss of arterial tone, venodilation with sequestration of blood in the unstressed blood compartment and changes in ventricular function with reduced compliance and reduced preload responsiveness. Sepsis is not a volume-depleted state and recent evidence demonstrates that most septic patients are poorly responsive to fluids. Furthermore, almost all of the administered fluid is sequestered in the tissues, resulting in severe oedema in vital organs and, thereby, increasing the risk of organ dysfunction. Newer data suggest that a physiologic, haemodynamically guided conservative approach to fluid therapy in patients with sepsis would be prudent and would likely reduce the morbidity and improve the outcome of this disease. Br J Anaesth. 2016 Mar;116(3):339-49. An excellent article of resuscitation fluids can be found here. The effect of fluids on micro and macrocirculation can be found here. 
 
Beyond the early administration of antibiotics, aggressive “supportive measures” may be harmful and the “less is more” paradigm appears applicable for the management of patients with severe sepsis. In these highly vulnerable patients, more intensive treatment may promote the chance of unwanted adverse effects and, hence, iatrogenic injury. In a latest prospective study in african children, mortality was higher in people who are fluid resuscitated with iv fluids or albumin compared to those who are not fluid resuscitated at all. The mortality was even higher in people who are resuscitated with both fluids and albumin. FEAST Trial
 
Current teaching suggests that aggressive fluid resuscitation is the best initial approach for the cardiovascular instability of sepsis. Consequently, large volumes of fluid (5-10 L) are often infused in the early stages of sepsis. There is, however, no human data that substantial (> 30 mL/kg) fluid resuscitation reliably improves BP or end-organ perfusion. There is also no controlled data exist that increases in cardiac output due to volume expansion are beneficial or even reliably achieved. Crit Care. 2012 Jan 25;16(1):302 , Crit Care. 2011;15(3):164 , Chest. 1999 Nov;116(5):1354-9.
 
Increased cardiac filling pressures consequent to large-volume resuscitation increase the release of natriuretic peptides. Natriuretic peptides cleave membrane-bound proteoglycans and glycoproteins off the endothelial glycocalyx. The endothelial glycocalyx plays a major role in regulating endothelial permeability, and damage to the glycocalyx plays a major role in increasing tissue edema. Because of the endothelial injury, capillary leak, and increased hydrostatic pressures, < 5% of infused crystalloid remains intravascular within 3 h after infusion, resulting in an increase in EVLW and further tissue edema. 
 
Multiple clinical studies have demonstrated an independent association between an increasingly positive fluid balance and increased mortality in patient with sepsis. FEAST Study, Crit Care Med. 2011 Feb;39(2):259-65,  Crit Care. 2013 Oct 20;17(5):R246,  Respir Med. 2008 Jul;102(7):956-61 ,  Chest. 2000 Jun;117(6):1749-54
 
Even though surviving sepsis guidelines recommend 30cc/kg fluid bolus for everyone on admission to ED, its important to still look at the individual patient factors. If patient is clearly volume overloaded ( CHF, ESRD, Cirrhosis of liver with ascites), its imperative to use clinical judgement and not bombard them with iv fluids, just because guidelines said so. In VASST study, optimal survival occurred with a positive fluid balance of approximately 3 L at 12 h. In ARISE study, 2.2 ± 1.9 L of fluid were given in the first 6 h. The hospital mortality was 23% in the ARISE study compared with 30% in the intervention arm of the EGDT study.
 
In a massive study on 50,000 patients, More rapid completion of a 3-hour bundle of sepsis care and rapid administration of antibiotics, but not rapid completion of an initial bolus of intravenous fluids, were associated with lower risk-adjusted in-hospital mortality. N Engl J Med 2017; 376:2235-2244
 
In volume overloaded patients, the cardiac muscle fibre is already overstretched ( think of frank-starling curve). If we add more volume, we will make the muscle fibre stretch even more with resultant decrease in contractility and thereby a decrease in cardiac output. Infact, in volume overloaded patients, giving careful diuretics when appropriate, may bring the muscle fibre to optimal length and may improve contractility with improved cardiac output. Recent studies also showed that early use of vasopressors rather than waiting for MAP to be stabilized with iv fluids results in better outcomes.  
 
 
 
 
 
 
 
If the primary goal of IV fluids is to restore the volume status, only give just enough fluids to restore euvolemia. 
 
Diastolic pressure is a surrogate marker of vascular tone. If vasodilatory shock, diastolic pressure is low and in hypovolemic shock, diastolic pressure will be normal. It might give a sense of how much shock is due to vasodilation and how much due to volume depletion. 
 
Also, we see quite often that patient becomes septic while admitted on the floor and they are given 30cc/kg fluid bolus for hypotension and possibly, even more. Those patients don’t go from euvolemia to hypovolemia with sepsis alone and all they may need is vasopressors alone, instead of iv fluids. ( We can’t treat vasodilatory shock as hypovolemic shock). Also, its very common in practice to give IV fluids as infusions. Remember, use iv fluids only if you think patient is hypovolemic. If patient is infact hypovolemic, replace all the volume in a much expedited fashion, preferably as boluses. ( Fluid bolus by definition should be pressure bagged and 1 litre should be given within 8 mins, not 999ml/hr).
 
Fluid responsiveness: By giving boluses, we are trying to rapidly restore intravascular volume and improve cardiac output. We have to watch the dynamic variables to see if the patient is fluid responsive. A patient is considered fluid responsive if stroke volume or cardiac output improve by 10-13% after a fluid challenge. Lot of time, improvement in blood pressure is mistaken for fluid responsiveness. However, increase in MAP doesn’t correlate very well with improvement in cardiac output and hence, shouldn’t be used to judge fluid responsiveness.  An excellent article on predicting the fluid responsiveness can be found here. Six guiding priciples of fluid resuscitation can be found here. 
 
Patients who have decreased systolic or diastolic function (on the descending limb of the Frank Starling curve) will not respond to a fluid challenge, even if they are intravascularly depleted. Also, Fluid responsiveness does not equate to the need for fluid boluses. 
 
A patient whose SV/CO significantly increases after a fluid challenge is considered to be a fluid responder and judged to need fluid therapy. However, the currently recommended fluid challenge dose of crystalloid 250–500 mL has little effect on increasing blood volume and is not sufficient to increase the preload of the Starling curve. Especially in septic patients, due to their vascular hyperpermeability, increase in blood volume is even smaller.  For these reasons, fluid responsiveness with small crystalloid challenge is questionable as a clinical indicator of fluid therapy. J Intensive Care. 2017; 5: 34.
 
Sepsis induced cardiomyopathy: Incidence of biventricular failure from sepsis is as high as 60%. Crit Care Med. 2008 Jun;36(6):1701-6. Bedside ECHO might help in evaluating the cardiac function and can help in the optimal dose of iv fluids. Dobutamine or milrinone can be added if there is any evidence of systolic dysfunction. One of the most common reasons for worsening lactate inspite of adequate MAP is sepsis induced cardiomyopathy. If we fail to diagnose it, quite often clinicians tend to give more iv fluids trying to wash out lactate and that could be lethal. 
 

Colloids vs Crystalloids

  1. ALBIOS Study (Albumin vs. Crystalloids): The use of 20% albumin in adults with severe sepsis or septic shock will improve hemodynamic indices, but will not reduce mortality, length of stay, mechanical ventilation, 90 day mortality or other secondary organ dysfunction. Its use is safe but not recommended for routine fluid resuscitation. Targeting a serum albumin of 3g/dl or more does not appear to have a survival advantage. N Engl J Med 2014; 370:1412-1421 
Key pointers: 
20% albumin was administered on a daily basis, to maintain serum albumin equal or greater than 3 g/dL.  This study is little different from SAFE study in that the amount of albumin used in this study is much lower and the goal was to increase albumin level rather than improve hemodynamics as in SAFE study. However, in a post hoc analysis of ALBIOS study, there was some mortality benefit in the sub group of patients with septic shock (43% vs. 50%).  
  1. SAFE Study (Albumin vs. Crystalloids in ICU): In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days,which includes ICU days, vent days, or days on renal replacement therapy or 28 day mortality rates. However, shock was reversed faster in a sub group analysis of septic shock patients. N Engl J Med 2004; 350:2247-2256 
  2. SWIPE Study : Resuscitation with 20% albumin decreased resuscitation fluid requirements, minimized positive early fluid balance and was not associated with any evidence of harm compared with 4-5% albumin. SWIPE Trial
 
Vasopressors in septic shock
 
Optimal time to start a vasopressor agent in patients with sepsis has not been well studied. After receiving 20 to 30 mL/kg of crystalloid, it seems unlikely that additional fluid boluses will result in a sustained increase in mean arterial pressure, even though transient rise in blood pressure could be achieved. Restoration of blood pressure with vasopressors results is recruitment of microvasculature and better tissue oxygenation. 
 
Earlier administration of vasopressor therapy leads to a decrease in the amount of fluids administered over the first 24 hours or more of therapy of septic shock. There is concern that the use of aggressive early fluid resuscitation in septic shock (regardless of whether it is essential for stabilization) leads to potential detrimental increased tissue edema down the road in the patient with septic shock. It may be that this edema is associated with organ dysfunction, need for organ support, and the ability to wean organ support. This could lead to longer days on mechanical ventilation, longer days in the intensive care unit, and the potential for later-stage increases in morbidity and mortality. It is possible that aggressive fluid resuscitation saves lives on the front end but a price is paid on the back end. There likely is a fine balance between the use of vasopressors to maintain MAP versus the use of continued fluid resuscitation in the presence of capillary leak to maintain MAP. 
 
The chief author of SCCM guidelines, Dr.Dellinger, has this to say in his own words – ” Earlier initiation of vasopressor therapy is linked to better knowledge and better management skills for severe sepsis by the treating providers. It may be that earlier vasopressor therapy is a marker of quality of delivered care and this alone would lead to improved outcomes regardless of the impact of the vasopressor alone on outcome”. Critical Care 201418:691
 
Norepinephrine (Levophed), epinephrine, vasopressin, phenylephrine, and dopamine are the most commonly used vasopressors for septic shock. 
  • Vasopressors should be begun initially to target a MAP of 65 mm Hg. 
  • Norepinephrine (Levophed) should be provided as the first-line vasopressor and titrate up to 35-90 µg/min. Norepinephrine increases mean arterial pressure primarily through vasoconstriction ( both venous and arterial ), with little effect on heart rate, stroke volume, and cardiac output.  
  • Vasopressin at 0.03 units/minute is appropriate to use with norephinephrine, either to improve perfusion (increase MAP) or to reduce the required dose of norepinephrine. Vasopressin is not recommended for use as a single vasopressor for septic shock. Vasopressin doses higher than 0.03 – 0.04 units/min are recommended to be reserved only when septic shock is refractory to standard doses of multiple vasopressors (ungraded recommendation). 
  • Epinephrine is considered the next-line agent for septic shock after norepinephrine. When norepinephrine is insufficient to maintain MAP 65 mm Hg, epinephrine at the dose of 20-50 mcg/min should be added to or substituted for norepinephrine. Epinephrine may increase lactate concentrations by stimulating skeletal muscles aerobic metabolism, thereby interfering with the use of lactate as a marker of perfusion during treatment of septic shock. 
  • Dopamine is suggested to not be used as an alternative to norepinephrine in septic shock, except in highly selected patients such as those with inappropriately low heart rates (absolute or relative bradycardia) who are at low risk for tachyarrhythmias. Dopamine is recommended to not be used in low doses in a so-called renal-protective strategy (Grade 1A). 
  • Phenylephrine at a dose of 200-300 mcg/min  can be added when septic shock persists despite the use of 2 or more inotropic/vasopressor agents along with low-dose vasopressin; or cardiac output is known to be high, or norepinephrine is considered to have already caused serious arrhythmias. 
  • An arterial catheter for hemodynamic monitoring should be placed as soon as practical, if resources are available, for all patients requiring vasopressors (ungraded recommendation). 
  • Dobutamine may be tried for patients in septic shock who have low cardiac output with high filling pressures while on vasopressors, or who have persistent evidence of hypoperfusion after attaining an adequate mean arterial pressure and intravascular volume (with or without vasopressors) (Grade 1C). 
  • A dobutamine infusion up to 20 mcg/kg/min can be added to any vasopressor(s) in use. Dobutamine is also an appropriate first-line agent in patients with severe sepsis and low cardiac output, with a preserved mean arterial pressure (i.e., who are not in septic shock) (Grade 1C). 
  • Dobutamine is recommended not to be used to deliberately raise cardiac output to higher than normal levels in an attempt to improve perfusion (Grade 1B). 
  • Dopamine vs. Levophed (SOAP II Trial): Although there was no significant difference in mortality between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events. Dopamine was also associated with more arrhythmias. A sub group analysis revealed that there was increased mortality with dopamine in cardiogenic shock but no difference in septic or hypovolemic shock. We would expect to maintain higher cardiac output with dopamine and lesser mortality but possibly more arrhythmias resulted in increased mortality in cardiogenic shock. N Engl J Med 2010; 362:779-789 
  • Dopamine vs. Levophed: In patients with septic shock, dopamine administration is associated with greater mortality and a higher incidence of arrhythmic events compared to norepinephrine administration. Crit Care Med. 2012 Mar;40(3):725-30 
 
Steroids in septic shock:
 
The use of low-dose corticosteroids in patients with severe sepsis remains controversial. Whilst there are signals for improved cardiovascular parameters, this did not translate to clear mortality benefits.
Corticosteroids may have beneficial effects in sepsis, including increasing adrenergic responsiveness, preserving the endothelial glycocalyx, inhibit inducible form of NO and decrease inflammatory cytokines. No need for cortisol testing or ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone. Random cortisol levels may still be useful for absolute adrenal insufficiency; however, for septic shock patients who suffer from relative adrenal insufficiency or no adequate stress response, random cortisol levels have not been demonstrated to be useful.  Also, steroids are likely to be beneficial early in the course of the disease, especially within 6 hours after onset of septic shock. Crit Care. 2012 Jan 7;16(1):R3 , JAMA. 2009 Jun 10;301(22):2362-75 .
 
  1. CORTICUS Study (Steroids in Septic shock): Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. N Engl J Med 2008; 358:111-124  
  2. Steroids in Septic Shock (Annane Study ): Low dose hydrocortisone and fludrocortisone therapy, when given within 8 hrs,  significantly reduced 28 day mortality in relative adrenal insufficiency (non-responders to Cosyntropin), 53% VS 63%. No significant difference in all patients combined. Also, time for vasopressor withdrawal was better with steroids, 7 days in steroid vs. 9 days with placebo.  Rate of adverse effects were similar including infections and GI bleed.   JAMA. 2002;288(7):862-871. 
Key pointers: 
On subgroup analysis, the 28 day mortality was higher with steroids in responders, 61 in steroids vs. 53 in placebo. Average cortisol level before cosyntropin test in responders is 30 and in non-responders is 18. After Cosyntropin, the cortisol level remained around 20 in non-responders but increased to 55 in responders.  Cortisol level in all patients combined before test is 20 and after test is 28. Is giving steroids to a patient (responders) who already had a cortisol>55 the reason for increased mortality?  The high mortality rates in this study could also be because of delayed administration of antibiotics (5-6 hrs in non-responders vs. 9 hrs in responders). This study found that patients with septic shock and relative adrenal deficiency, who were treated with low dose steroids, had a significantly improved mortality. 
 
In another study, single dose of 50mg hydrocortisone greatly improved vasopressor dose-response relationship in septic shock with relative adrenal insufficiency.  
 
Conclusions : 
In Cosyntropin non responders (Relative adrenal insufficiency), Low dose hydrocortisone and fludrocortisone reduced the risk of death in patients with septic shock (especially if basal cortisol level is less than 20) without increasing adverse events like infections. The median time for vasopressor withdrawal was 7 days in steroid group vs. 10 days in placebo group. Also, within first 28 days, more patients were off vasopressors in steroid group than in placebo group. 
 
In Cosyntropin responders, there was no significant difference between the groups.  The key question is did steroids improve mortality in non responders or did steroids worsen mortality in responders? 
  1. Corticus vs Annane study: There was a clear benefit in mortality rates with steroids in Annane study. However, he used both hydrocortisone and fludrocortisone. Annane study was allowed only within 8 hours after fulfilling entry criteria, as compared with a 72-hour window in our study.  In the results graph, the 28 day mortality benefit curve was significantly better already by 72 hrs and it just continued for 28 days. (? Mortality benefit for steroids may only be present in 1st 72 hrs). Maybe, giving steroids within 8 hours made the difference in mortality. Also, his patients are sicker with higher SAPS 2 scores.  
At baseline, the vasopressor needs in corticus study was around 0.5mcg/kg/min of levophed and in Annane study, it was around 1mcg/kg/min. The severity of shock was lot more in annane group than in corticus group.  Does steroids help only in highly vasopressor dependent states?
 
The duration of the administration of corticosteroids may be pertinent, with the possibility that any gain that was achieved by an earlier reversal of shock was counterbalanced by later complications. In the Annane study, corticosteroid treatment was stopped abruptly after 7 days, whereas in corticu study, therapy was tapered from day 6 to day 12.  
  1. APPROCCHS Study (Again by Annane):  In critically ill patients with septic shock, the addition of hydrocortisone and fludrocortisone bolus compared to placebo was associated with an aboslute risk reduction of 6% in mortality at 90 days ( 43% vs 49%) as well as increase in vasopressor free days. There are several weaknesses to this study though- Trial was conducted using 2008 sepsis guidelines and care has changed since then. Might lack external validity as their population has high use of vasopressors in both groups ( Average of levophed 80mcg/min and epinephrine 125min/min). Also, the trial went for more than 7 years during which our understanding of sepsis changed dramatically. It was also suspended twice and some patients recieved xigress during the early phase of study. The results of this study couldn’t be replicated outside france. Patients in this study were given steroids much sooner than other studies, which could explain the mortality benefit.   APPROCCHS Study
  2. ADRENAL Study: Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. However, there was lower median time to shock reversal with no difference in mortality, incidence of bacteremia or need for RRT. Strengths of the study was popoulation size of more than 3 times the approcchs study, much faster enrollment and involving multiple hospitals across multiple countries.  ADRENAL Study
  3. My take home message: Give steroids upfront and stop steroids as soon as they come off vasopressors. If you want to be ultra conservative, start steroids atleast when you are adding a second vasopressor. Other studies also showed that in septic shock, low doses of hydrocortisone can restore vascular responsiveness to catecholamines. An excellent review on setroids in septic shock can be found here. 
 
Bicarbonate for Lactic acidosis: 
 
Do not use sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH >7.15 (grade 2B). In BICAR-ICU Trial, sodium bicarbonate had no effect on the primary composite outcome of death or presence of atleast one organ failure. However, it did improve mortality and need for RRT in subgroup of patients with AKI. 
 
Vitamin C in septic shock:
 
Vitamin C has strong immunomodulating and antioxidant activity. As such, vitamin C is promoted as adjuvant therapy in conditions characterized by excessive oxidative stress or crippled immunity such as ischemia-reperfusion disorders, trauma, and various inflammatory disease processes. For example, in patients with septic shock and dialysis , vitamin C is substantially cleared by dialysis and at least 50% of ascorbate may be lost during CRRT.
 
Evidence is emerging that parenteral administration of high-dose vitamin C can prevent or restore reactive oxygen radical-induced microcirculatory flow impairment, prevent or restore vascular responsiveness to vasoconstrictors, preserve endothelial barrier and augment antibacterial defense. Critical Care 2014, 18:460,  J Thorac Dis. 2016 Sep; 8(9): E993–E995,  J Res Pharm Pract. 2016 Apr-Jun;5(2):94-100 , J Transl Med. 2014 Jan 31;12:32 ,  Crit Care. 2015 Nov 27;19:418.
 
In a recent trial by Dr.Marik, early use of intravenous vitamin C, together with corticosteroids and thiamine proved to be effective in preventing organ dysfunction including acute kidney injury and reducing the mortality of patients with severe sepsis and septic shock. The hospital mortality was 8.5% in the treatment group compared to 40.4% in the control group (p < 0.001). Mean duration of vasopressors was 18.3 ± 9.8 hours with vitamin C protocol vs. 54.9 ± 28.4 hours in the control group (p<0.001). Chest. 2016 Dec 6. pii: S0012-3692(16)62564-3.
 
His protocol includes:
  • Vit.C 1500mg IV Q6 hrs for 4 days or until ICU discharge
  • Thiamine 200mg IV Q12 hrs for 4 days or until ICU discharge
  • Hydrocortisone 50mg IV Q6 hrs for 7 days or until ICU discharge followed by 3 day taper
A good article on the physiological rationale for the use of Vit.C with thiamine and steroids can be found here. 
 
Cardiac output monitors in ICU:
 
Recently, number of cardiac output monitors came into the market like FLOTRAC, LIDCO, PICCO and NICO monitors. The problem with these devices are that people fail to understand when to use these machines. They are useful when there is ambiguity of giving fluids. In my opinion, these monitors should not be used when the patient is clearly fluid overloaded or already in significant positive fluid balance. Regardless of what these machines say, if a patient is already in significant positive fluid balance ( >5 liters), there is no indication for extra fluids. An excellent review by Dr.Marik on cardiac output monitors can be found here. Also, the error rate can range between 30-70%. So, take the readings from these monitors with some skepticism and don’t follow those numbers blindly. Try to fit those numbers into clinical picture and see if makes some sense. 
 
Transfusion of blood products in Sepsis and Septic Shock 
The Surviving Sepsis Guidelines advocate restricting red blood cell transfusion in adults with severe sepsis/septic shock until hemoglobin falls below 7.0 g/dL, and not transfusing above 9.0 g/dL, if ischemic heart disease, severe hypoxemia, or active bleeding are not present.  
 
For patients with severe sepsis and septic shock, the Surviving Sepsis Guidelines suggest transfusing platelets prophylactically only when platelets fall to 10,000 / mm3, assuming no bleeding is present. In patients considered at significant risk for bleeding, a threshold of 20,000 / mm3 is suggested, and for those with active bleeding or who are undergoing surgery or invasive procedures, transfusing platelets to 50,000 mm3 is suggested.  
 
Mechanical ventilation in Sepsis: 
Low tidal volumes and plateau pressures should not just be used in people with full-blown ARDS, but virtually everyone with sepsis, because observational trials suggest a decreased risk for ARDS when lower tidal volumes are used (Ungraded). 
 
Glucose Control  
1. A protocolized approach should target an upper blood glucose ≤180 mg/dL rather than an upper target blood glucose ≤ 110 mg/dL.  
2. Blood glucose values are monitored every 1–2 hrs until glucose values and insulin infusion rates are stable and then every 4 hrs thereafter.   
3. Glucose levels obtained with point-of-care testing of capillary blood are interpreted with caution; such measurements may not accurately estimate arterial blood or plasma glucose values.  
 
Deep Vein Thrombosis Prophylaxis  
  • Patients with severe sepsis receive daily pharmacoprophylaxis against venous thromboembolism (VTE). This should be accomplished with daily subcutaneous low-molecular weight heparin (LMWH) (grade 1B versus twice daily UFH, grade 2C versus three times daily UFH).  
  • Patients with severe sepsis are treated with a combination of pharmacologic therapy and intermittent pneumatic compression devices whenever possible.  

 Stress Ulcer Prophylaxis

  • Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor is given to patients with severe sepsis/septic shock who have bleeding risk factors (grade 1B). ​
  • When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA  
 
Nutrition  
  • Administer oral or enteral feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock (grade 2C).  
  • Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (eg, up to 500 calories per day), advancing only as tolerated (grade 2B).   
  • Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock (grade 2B).  
 
Unresolved Sepsis: 
Could be due to non-infectious cause like drug fever, source still present like infected lines, MDR pathogens, inappropriate antibiotics, unusual sources like meningitis, sinusitis, cavernous sinus thrombosis, DVT, thrombophlebitis, C.Diff, Prosthetic devices or tumor fever. 
 
Renal Replacement therapies: 
Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure. However, all those studies are done on patients who are hemodynamically stable. 
 
Deresuscitation:
With the advent of newer literature and protocols, we have become quite good in resuscitation, or even little bit overzealous resuscitation. In that process, patients often end up with significant fluid overload. Multiple studies have shown that fluid overload is significantly associated with increased mortality. We pay such a poor attention to deresuscitation. An excellent slide delineating the side effects of fluid overload is shown below. 
Image from Manu et al, 2014
 
Image from Malbrain et al, 2014
De-resuscitation specifically refers to Late Goal Directed Fluid Removal (LGFR), which involves “aggressive and active fluid removal by means of diuretics and renal replacement therapy with net ultrafiltration. An excellent method of resuscitation and deresuscitation involves a ROSE approach ( resuscitation, optimization, stabilization and evacuation phases of fluid resuscitation). It includes a goal of a zero to negative fluid balance by day 3 and to keep the cumulative fluid balance on day 7 as low as possible. Anaesthesiol Intensive Ther. 2014 Nov-Dec;46(5):361-80 ,
 
ROSE approach for resuscitation and deresuscitation:
  1. Resuscitation phase (R): Early phase of treatment with fluid boluses. The goal is early adequate goal directed fluid management to achieve a MAP > 65 mm Hg, CI > 2.5 L min-1m-2, PPV < 12%, LVEDAI > 8 cm m-2.
  2. Optimisation phase (O): Occurs within hours and leads to reperfusion. Degree of positive fluid balance may be marker of severity in this phase. Unstable, compensated shock state requires titrating of fluids to cardiac output.
  3. Stabilisation phase (S): Evolves over days. Fluid therapy only for normal maintenance and replacement. Monitor daily body weight, fluid balance and organ function and target for a neutral or negative fluid balance
  4. Evacuation phase (E): Patients who do not transition from the ‘ebb’ phase of shock to the ‘flow’ phase after the ‘2nd hit’ develop global increased permeability syndrome (GIPS). Requires late goal directed fluid removal (“de-resuscitation”) to achieve negative fluid balance. Need to avoid over enthusiastic fluid removal resulting in hypovolaemia​

An excellent paper on how to avoid fluid overload can be found here and here.

 
Clinical Trials: 
  1. Does CVP predict fluid responsiveness ( by Paul Marik) : There is a very poor relationship between CVP and blood volume as well as the inability of CVP/ΔCVP to predict the hemodynamic response to a fluid challenge. CVP should not be used to make clinical decisions regarding fluid management. Chest. 2008;134(1):172-178,   Crit Care Med. 2013 Jul;41(7):1774-81
  2. SEPSISPAM Study (Higher MAP vs Lower MAP target in septic shock):  Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. N Engl J Med 2014; 370:1583-1593 

Key pointers:

  1. New onset A.fib is significantly higher in high MAP group.
  2. In patients with chronic hypertension, the doubling of creatinine as well as need for RRT in first week is significantly lower in high MAP group.  
Note: In other studies as well, the benefit is lost once the MAP is above 65.  
 
In a study, the perfused vessel density increased when MAP’s are raised from 65 to 75 and then to 85. This indicates that by increasing MAP from 65 to 85, there may be improvement is microcirculation. Crit Care. 2011;15(5):R222  
 
In another study, there was no significant benefit in raising the MAP from 65 to 85 in patients who had low basal perfused capillary density. Crit care 2009, 13 R:92 
 
Note: Higher MAP’s may be indicated in patients with chronic hypertension, low basal perfused capillary density and in patients with elevated abdominal pressure.  
  1.  Etomidate in sepsis: Etomidate was associated with increased mortality among septic patients, possibly due to adrenal suppression, even though there was no direct evidence. Crit Care Med 2012; vol 40(11):2945-53. 
 
 
PEARLS: 
  • Causes of hyperlactatemia in sepsis include endogenous catecholamine release, hypoxia and hypotension, beta agonist mediated, inhibition of pyruvate dehydrogenase and thereby decreased lactate clearance in liver. 
  • Lactate is a marker of hypoperfusion and results from anaerobic metabolism is a misconception. Lactate is also produced from beta agonist effects of catecholamines released from stress but not from anaerobic metabolism. In sick states, the body changes its energy substrate to lactate from glucose. Hence, more lactic acid is produced. It just indicates how sick you are. By trying to clear lactate with increased perfusion, there is no benefit and we are depriving the body of lactate. Also, supra physiological doses of oxygen delivery is harmful. In a study, infusion of sodium lactate improved cardiac function. Maybe, this will convince to use RL instead of NS. 
  • SSC guidelines suggested against the use of sodium bicarbonate therapy to improve hemodynamics or to reduce vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH ≥ 7.15.
  • Mean arterial pressure vs Systolic blood pressure: Quite often we see clinicians targetting a systolic blood pressure of 90 or whatever makes them comfortable. However, body doesn’t just perfuse during systole only. Hence, MAP rather than systolic blood pressure is the preferred metric in the ICU to guide therapy. Crit Care Med. 2013 Jan; 41(1): 34–40
  • All isotonic solutions get distributed throughout the extracellular space but not intracellular space. So, for each litre of NS infused, only 1/4th stays intravascularly and 3/4th goes into interstitial component. 
 
Infections