Author: Erik Hofmann, MS, MD (EM Resident Physician, LAC + USC Medical Center) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF)

Case Presentation

A 56 year-old female with a past medical history of recurrent urinary tract infections and hyperlipidemia presents with 1 week of suprapubic pain and fever. The patient states that she has been having progressively worsening suprapubic pain, sharp, constant, and radiating to the right flank. She has had subjective fever over the past 3 days and burning with urination for the past week. The patient states that the burning with urination is similar to her prior episodes of UTI, but that she has never had pain like this. The patient took ibuprofen 400 mg PO Q4 hours but it only provided temporary relief. Vital signs include a temperature of 101.2, HR 100, BP 132/80, RR 16, and SaO2 100% on room air. Positive physical exam findings include CVT. Blood cultures, lactate, CBC, urine analysis, urine culture and chem 7 are drawn within 3 hours of presenting to the ED. Significant laboratory results include WBC 15K and a lactate of 3.0 mmol/L. Urinalysis demonstrates pyuria, moderate blood, and positive leukocyte esterase. The patient is started on ceftriaxone 1g IV Q24 hours and 2L of crystalloid. A second lactate drawn within 6 hours of presenting to the ED is 2.55 mmol/L.

Question: Where should you send this patient?

Lactate Metabolism

Most of our pyruvate and lactate is generated via a redox-coupled interconversion catalyzed by lactate dehydrogenase (LDH) during anaerobic glycolysis. NADH is oxidized to NAD when pyruvate is converted to lactate producing protons in the process. LDH is a tetramer with five isoforms that is composed of various combinations of LDHA and LDHB subunits.1 There is a higher concentration of LDHA subunits in tissues that favors the reduction of pyruvate to lactate due to LDHA’s higher affinity for pyruvate.1 The normal concentration of serum lactate to pyruvate is in a 10:1 ratio that increases significantly with increasing concentrations of NADH:NAD.1

The human body normally produces 20 mmol/kg of lactate daily.1 Skeletal muscle, which contains a higher concentration of LDHA, is responsible for a majority of the lactate that is produced on a daily basis during normal metabolism.1 Lactate can be converted to pyruvate in a number of organs and tissues. The Cori cycle is involved in the production of lactate via glycolysis in skeletal muscle producing 2 ATP. Lactate is then transported to the liver and converted to glucose via gluconeogenesis using ATP generated from fatty acid metabolism. Lactate is also transported into mitochondrial cells via the monocarboxylic acid transporter and converted to pyruvate via LDH producing NADH. The pyruvate is decarboxylated via pyruvate dehydrogenase to acetyl-CoA. Acetyl-CoA enters the TCA cycle which produces additional NADH used in the production of ATP, CO2, and H2O through a series of reactions in the electron transport chain. The generation of lactate produces 2 ATP and 2 protons which is normally balanced by the consumption of these products through the re-conversion to pyruvate and NADH.

Causes of Lactic Acidosis

The cause of lactic acidosis can be categorized into either type A or type B. Type A includes disorders associated with impaired tissue oxygenation while type B is associated with causes other than impaired tissue oxygenation.1 Most cases of type A lactic acidosis can be attributed to tissue hypoperfusion due to either cardiogenic shock, hypovolemic shock, cardiac failure, severe trauma, or sepsis.1 However, there is considerable overlap between type A and type B lactic acidosis in a number of disease states.1

The true source of hyperlactemia is multifactorial and likely includes a combination of global tissue hypoxia, microcirculatory dysfunction, enzymatic dysfunction, and a metabolic stress response. Hyperlactemia occurs when there is an imbalance in the consumption or production of lactate ions and its equivalent protons. Glucose utilization during tissue hypoxia results in the production of lactate and ATP thus causing a net increase in lactate during anaerobic metabolism. There have been a number of studies that demonstrate the relationship between lactic acidosis and tissue hypoxia due to either a decrease in oxygen saturation, cardiac output, or blood volume causing decreased clearance. An extensive review of lactic acidosis by Madias et al. demonstrates that there is a decrease in lactate uptake by the liver with graded increases in hypoxia of the liver parenchyma converting the liver from a net consumer of lactic acid to a net producer.2 One in vivo animal study shows that a reduction of oxygen tension to a mean of 47 mmHg or more decreases hepatic uptake of lactic acid2. Decreases in blood flow of 30% or more to the liver causes a decrease in lactate utilization and a net increase in lactic acidosis.2 A phenomenon called microcirculatory and mitochondrial distress syndrome also plays a key role in organ dysfunction during sepsis. The auto-regulatory mechanism in the microcirculation is severely affected due to the heterogeneous expression of iNOS during sepsis3. Organs become under-perfused and red blood cells become less deformable as a result of decreases in NO-induced vasodilation.3 A sepsis induced inflammatory response activates leukocytes which release reactive oxygen species thereby disrupting the microcirculatory barrier leading to tissue edema and a worsening oxygen extraction deficit.3 Revelly et al. describes how glucose turnover increases during septic shock causing a commensurate increase in lactate production.4 This effect is largely due to a combination of increased glycolysis and increased insulin resistance secondary to inflammatory mediators during septic shock.4

A number of studies in the 1980s found that improved outcome from septic shock and cardiogenic shock was dependent on lactate clearance as well as overproduction.5 A single center prospective study by Levraut et al. in 1998 found that mild hyperlactemia in stable septic patients was due to altered lactate utilization rather than overproduction due to tissue hypoxia during sepsis.6 They found that the hyperlactemic group had a lower lactate clearance than the normal lactate group while both groups had a similar lactate production. The hyperlactemic group had a lactate clearance of 437 ml/kg/h whereas those with normal lactate had a clearance of 1002 ml/kg/hr. They concluded that hyperlactemia is likely due to a disturbance in lactate metabolism rather than a defect in cellular oxygenation alone. There are a number of mechanisms at play that can affect lactate clearance during severe sepsis and septic shock. Lactate consumers under normal basal conditions include the liver, renal cortex and heart.2 Lactate usage by the liver and kidneys for gluconeogenesis increases during hyperlactemia in addition to increased renal excrection.2 Pyruvate dehydrogenase is inactivated through dephosphorylation during sepsis thereby increasing the conversion of pyruvate to lactate.6 However, one study by Revelly et al. found that there was no significant difference in lactate clearance between critically ill patients and healthy subjects with the administration of exogenous lactate.4

Hyperlactemia can also occur as a result of endotoxemia during sepsis despite normal systemic perfusion, blood pressure, and oxygen delivery.7 A study by Michaeli et al. found that lipopolysaccharide (LPS) administration in healthy volunteers increased net lactate production.8 Another study by Traves et al. found that LPS induced immune cell activation during sepsis increased glucose consumption and lactate production by macrophages through an ERK1/2-dependent mechanism.8

There is a competing theory to the traditional concept that hyperlactemia is induced by tissue hypoxia called aerobic glycolysis. Studies have shown that there is an increased release of epinephrine during sepsis that is triggered by neuroendocrine and cardiovascular stimuli.9 Epinephrine in turn increases the activity of the Na, K-ATPase pump in a number of well oxygenated tissues including erythrocytes, vascular smooth muscle, neurons, and glia.9 Increased Na, K-ATPase activity generates ADP which stimulates phosphofructokinase (PFK).9 PFK, and then up-regulates membrane glycolytic pathways that are in close proximity to the Na, K-ATPase pumps.9 Cyclic AMP is also increased by epinephrine in skeletal muscle cells stimulating both Na, K-ATPase activity and glycogenolysis.9 Overall, these processes produce a large, rapid supply of glucose during a hyper-dynamic state that outpaces lactate utilization thereby causing hyperlactemia. Marik et al. argues that activation of the evolutionary stress response is the main source of hyperlactemia and hyperglycemia during sepsis.5 He points out that the heart normally oxidizes free fatty acids for a majority of its bioenergetic need.5 However, the heart shifts its substrate utilization during shock and starts metabolizing lactate at a higher rate.5 The brain also increases lactate oxidation for its bioenergetic needs during episodes of acute stress.5 This is supported by two randomized control trials that demonstrated an increase in mortality in patients who failed to increase lactate and glucose in response to epinephrine during septic shock.5 He concludes that the fall in lactate concentration during sepsis resuscitation is most likely due to a blunting of the stress response and can actually be harmful to cardiovascular and brain function.5

The Evidence for Lactate Clearance

There have been a number of studies that have demonstrated an association between hyperlactemia, multi-system organ failure (MSOF), and mortality in severe sepsis and septic shock. Bakker et al. in 1996 found that the duration of lactic acidosis was a significant predictor of multi-system organ failure and death in septic shock patients.10 The duration of lactic acidosis or “lactime” was defined as the time during which blood lactate was ≥ 2.0 mmol/L. This “lactime” was found to be the only significant marker of organ failure in their study. The study also found a significant difference in the decrease in blood lactate levels during the first 24 hours between survivors and non-survivors. However, the study failed to demonstrate statistical significance in initial lactate levels between survivors and non-survivors.

In 2001, Rivers et al. examined whether early goal directed therapy before admission to an ICU decreased multi-organ dysfunction, mortality, and the use of hospital resources.11 They found that early goal directed therapy was associated with a 15% decrease in in-hospital mortality over standard therapy at the time. Serum lactate concentration was measured at 0, 3, 6, 12, 24, 36 , 48, 60 and 72 hours in order to calculate the acute physiology and chronic health evaluation (APACHE II) score, the simplified acute physiology score II (SAPS II) and the multiple organ dysfunction score (MODS). They found that there was a statistically significant decrease in serum lactate of 3.0 mmol/L versus 3.9 mmol/L in survivors versus non-survivors respectively. Although serum lactate was only used in this study as a means to calculate MOSF, it did provide evidence that end goal directed therapy was associated with a decrease in mortality in patients who had a lower lactate level after resuscitation.

McNelis et al. in 2001 examined the correlation between the time to normalization of lactate and outcome in post-operative SICU patients.12 They found that prolonged lactate clearance correlated with mortality. Patients that failed to clear their lactate during their hospital course had a 100% mortality rate. The mortality rate at 24, 48, and 96 hours was 3.9%, 13.3%, and 42.5% respectively.

Levraut et al. in 2003 looked at the prognostic value of lactate clearance and lactate production in severe sepsis and septic shock patients with initial lactate levels < 3.0 mmol/L. Percent lactate clearance was defined as lactate at hour 0 minus lactate at hour 6 divided by lactate at ED presentation multiplied by 100.13 There was no difference in initial blood lactate level between survivors and non-survivors. Lactate clearance was significantly lower and production was significantly higher in non-survivors. They concluded that decreased lactate clearance was a significant independent predictor of increased mortality, and proposed that tracking lactate clearance could be used as an early predictor of increased mortality.

Nguyen et al. in 2004 studied the clinical utility of lactate clearance in the emergency department as an indicator of MSOF and 60-day in-hospital mortality for patients presenting with severe sepsis and septic shock.14 Survivors had a lactate clearance of 38% versus 12% in non-survivors within the first 6 hours. There was an 11% decrease in likelihood of mortality for each 10% increase in lactate clearance. Overall, patients with a lactate clearance of ≥ 10% had a lower 60-day mortality rate. They argued that serial lactate measurements within the first 6 hours was a better prognostic indicator of organ failure and mortality than a single lactate measurement.

Arnold et al. in 2009 studied the clinical utility of using serial lactate measurements, in a protocoled resuscitation bundle, as a predictor of in-hospital mortality in patients presenting to the ED with severe sepsis.15 Lactate clearance was defined as a repeat lactate decrease of 10% or greater at 6 hours, or both initial lactate and repeat levels < 2.0 mmol/L. In-hospital mortality was 60% for non-lactate clearance versus 19% for lactate clearance, and they found that lactate non-clearance was a significant independent predictor of death.

Jansen et al. in 2010 presented a multi-center open-label randomized control study investigating whether patients with elevated lactate levels ≥ 3.0 mEq/L on ICU admission would benefit from serial lactate monitoring and protocoled therapy directed at decreasing lactate levels.16 Patients with a lactate level ≥ 3.0 mEq/L were given more fluids and more vasodilators during an 8 hour treatment period. Treatment was aimed at decreasing lactate levels by 20% every 2 hours during an 8 hour treatment period. They found that the lactate group was given significantly more fluids and vasodilators during the 8 hour treatment period. There was a significant decrease in in-hospital mortality in the lactate group when the authors adjusted for predefined risk factors. They also found a significant decrease in length of stay, organ failure, ventilation time, and inotrope use in the lactate group. However, they did not find a difference in the rate of lactate reduction between the control group and the lactate group despite a more aggressive resuscitation strategy. It should be noted that the patients in this study also received a comprehensive resuscitation strategy including ScvO2.17

Puskarich et al. in 2012 presented a multi-center ED prospective randomized control trial studying the prognostic value of achieving a “lactate clearance goal” on in-hospital mortality in septic shock patients using goal directed therapy.17 Lactate clearance goal was defined as a decrease of ≥ 10% from an initial lactate of ≥ 2.0 mM, or both initial and repeat lactate levels < 2.0mM. Serum lactate was measured every 2 hours until the lactate goal was achieved or at hour 6 of the resuscitation period. They found that the lactate clearance only group was associated with a lower mortality than the ScvO2 only group. The authors concluded that failure to achieve a lactate clearance of ≥ 10% was associated with a worse prognosis than failure to achieve a ScvO2 of 70%.

Marty et al. in 2013 presented a prospective observational case series investigating the prognostic value of serial lactate measurements and lactate clearance on 28 day in-hospital mortality in the ICU after initial resuscitation in the ED.18 The mean time between a diagnosis of severe sepsis and ICU admission was 8 hours. The goals of management were dictated by the international guidelines for sepsis management in the first 24 hours. Mean serum lactate concentrations at time H0, H6, H12, and H24 were significantly lower in survivors than non-survivors. Lactate clearance was significantly higher in survivors than non-survivors for the H0-H6 time period and the H0-H24 time period as well. They found that lactate clearance for the H0-H24 time period was the best predictor of mortality at day 28, and lactate clearance at H0-H24 was independently correlated to survival status. The authors concluded that lactate concentration and lactate clearance were both predictive of 28-day in-hospital mortality.

Puskarich et al. in 2013 presented a preplanned analysis of his previous multi-center ED-based randomized control trial looking at the association between whole blood lactate kinetics and survival in patients with septic shock receiving a protocoled resuscitation bundle.19 Normalization of lactate (decline to < 2.0 mM), absolute clearance (initial minus delayed value), relative clearance (absolute divided by initial multiplied by 100), and clearance rate (relative clearance divided by clearance time) were calculated. Relative lactate clearance ≥ 50% after excluding for vasopressor administration and lactate normalization at 6 hours were the only statistically significant predictors of in-hospital survival. Interestingly, lactate clearance ≥ 10%, absolute clearance, and relative clearance were not significantly associated with in-hospital survival.

Surviving Sepsis Campaign Guidelines and Lactic Acidosis

Phase I of the surviving sepsis campaign was presented with the Barcelona Declaration in October 2002 in order to improve survival in severe sepsis. Phase II of the SSC introduced by Dellinger et al. in 2004 represented the culmination of a multi-organizational effort by experts in critical care and infectious disease in the development and publication of guidelines for the management of severe sepsis and septic shock.20 Lactate clearance was not included in the initial 6 hour bundle because it lacked “precision as a measure of tissue metabolic status.”20 In 2010 Levy et al. presented data from phase III of the SSC which included guideline implementation, behavior change and data collection.21 They found that the mortality rate for septic patients who had both hypotension and a lactate ≥ 4 mmol/L was 46.1% while the mortality rate was 30% for patients who initially presented with a lactate of ≥ 4.0 mmol/L. The third edition of the SSC guidelines in 2013 by Dellinger et al. recommended protocoled quantitative resuscitation of patients with sepsis-induced tissue hypo-perfusion.22 They suggested “targeting resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypo-perfusion.”22 They cited a number of observational studies in addition to the 2001 Rivers et al. study and the SSC study by Levy et al. in 2010 as their rationale for using a lactate target of ≥ 4 mmol/L and targeting resuscitation to normalize lactate. However, they noted that some hospitals had “lowered the lactate threshold for triggering quantitative resuscitation in the patient with severe sepsis but that these thresholds had not been subjected to randomized trials.” The revised SSC guidelines also emphasized the utility of following lactate in association with ScvO2.22 They stated that lactate normalization was an appropriate alternative for assessing resuscitation if ScvO2 was not available. Their rationale for following lactate normalization included two randomized trials. One of the studies by Jones et al. found that a lactate clearance ≥ 10% was non-inferior to using ScvO2 ≥ 70% as a way to measure early quantitative resuscitation. The other study that they cited as evidence was the 2010 study Jansen et al. A number of changes were made to the SSC guidelines in April of 2015 which included the exclusion of measuring ScvO2 in the event of persistent hypotension despite volume resuscitation.23 The current guidelines still included measuring a lactate level and administering 30 ml/kg of crystalloid for a lactate of ≥ 4 mmol/L within 3 hours of declaration and remeasuring lactate within 6 hours if the initial lactate was elevated.

The utility of using lactate clearance as a marker of inadequate oxygen delivery and a measure of resuscitation in the updated SSC bundle remains controversial. A 2011 study by Nguyen et al. set out to examine the effectiveness of the phase III SSC resuscitation bundle with the addition of lactate clearance.24 Lactate clearance in this study was defined as any decrease in lactate within 12 hours from baseline or an initial lactate of < 2.0 mmol/L. Patients with lactate clearance had a lower APACHE II score and baseline lactate. The lactate group also had lower CVP and MAP but higher ScvO2 at baseline compared with the group who did not clear lactate. Overall they found that there was a 23% decrease in mortality in the lactate clearance group, and lactate clearance was independently associated with a decreased mortality. However, as Napoli et al notes global perfusion markers including CVP, MAP, and ScvO2 were near normal at baseline regardless of whether the bundle did or did not include lactate clearance as a marker of resuscitation.25 They also note that baseline hemodynamics, vasopressor use, and the amount of fluids given were the same for both lactate clearance and non-lactate clearance groups in the revised SSC bundle.25 These findings indicated that the mechanism of lactate clearance was unrelated to traditional hemodynamic markers.

Clinical Bottom Line

It is hard to deny the overwhelming evidence demonstrating an association between lactate clearance and mortality. Despite the ongoing controversy regarding the optimal endpoints of early sepsis resuscitation and the source of hyperlactemia, lactate remains the best non-invasive marker of illness severity. Given the current data, a ≥ 10% lactate clearance at 6 hours is an appropriate marker to follow when resuscitating a septic patient. However, recent research by Puskarich et al. showed that lactate normalization to < 2.0 mmol/L within the first 6 hours of resuscitation is superior to the rate of clearance.19 The best approach to current SSC guidelines when encountering a patient with systemic inflammatory response syndrome (SIRS) is to measure a lactate level and obtain blood cultures prior to giving antibiotics. If the MAP is ≥ 65 mmHG and initial lactate is < 2.0 mmol/L, all available data suggest that this patient has a low risk for MOSF and inpatient mortality and can go to the ward or an observation unit depending on other comorbidities. 26 If the MAP is ≥ 65 mmHg and the initial lactate is 2.0 to 3.9 mmol/L, provide 2 L of crystalloid and start source specific antibiotics.26 Remeasure the lactate within 6 hours and if there is a ≥ 10% decrease in lactate clearance, admit to either the ward or the observation unit.26 If the lactate clearance is < 10% after 2L of crystalloid, provide an additional 1L of crystalloid, and admit to the ICU.26 If the MAP is ≥ 65 mmHg and initial lactate is ≥ 4.0 mmol/L, provide either 3L or 4L of crystalloid within the first 6 hours depending on volume status and other comorbidities and admit to the ICU.26 If the patient presents with a MAP of < 65mmHg, begin fluid resuscitation, start source specific antibiotics, start norepinephrine targeted at a MAP ≥ 65 mmHg, and admit to the ICU.26

References/Further Reading

Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014 Dec 11;371(24):2309-19. Madias NE. Lactic acidosis. Kidney Int. 1986 Mar;29(3):752-74. Ince C. The microcirculation is the motor of sepsis. Crit Care. 2005;9 Suppl 4:S13-9. Revelly JP, Tappy L, Martinez A, Bollmann M, Cayeux MC, Berger MM, Chioléro RL. Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med. 2005 Oct;33(10):2235-40. Marik PE, Bellomo R, Demla V. Lactate clearance as a target of therapy in sepsis: a flawed paradigm. OA Critical Care 2013 Mar 01;1(1):3. Levraut J, Ciebiera JP, Chave S, Rabary O, Jambou P, Carles M, Grimaud D. Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproduction. Am J Respir Crit Care Med. 1998 Apr;157(4 Pt 1):1021-6. Chertoff J, Chisum M, Garcia B, Lascano J. Lactate kinetics in sepsis and septic shock: a review of the literature and rationale for further research. J Intensive Care. 2015 Oct 6;3:39. Gibot S. On the origins of lactate during sepsis. Crit Care. 2012 Sep 10;16(5):151. James JH, Luchette FA, McCarter FD, Fischer JE. Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. Lancet. 1999 Aug 7;354(9177):505-8. Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg. 1996 Feb;171(2):221-6. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. McNelis J, Marini CP, Jurkiewicz A, Szomstein S, Simms HH, Ritter G, Nathan IM. Prolonged lactate clearance is associated with increased mortality in the surgical intensive care unit. Am J Surg. 2001 Nov;182(5):481-5. Levraut J, Ichai C, Petit I, Ciebiera JP, Perus O, Grimaud D. Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients. Crit Care Med. 2003 Mar;31(3):705-10. Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, Tomlanovich MC. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med. 2004 Aug;32(8):1637-42. Arnold RC, Shapiro NI, Jones AE, Schorr C, Pope J, Casner E, Parrillo JE, Dellinger RP, Trzeciak S; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock. 2009 Jul;32(1):35-9. Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J; LACTATE study group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010 Sep 15;182(6):752-61. Puskarich MA, Trzeciak S, Shapiro NI, Arnold RC, Heffner AC, Kline JA, Jones AE; Emergency Medicine Shock Research Network (EMSHOCKNET). Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation. Acad Emerg Med. 2012 Mar;19(3):252-8. Marty P, Roquilly A, Vallée F, Luzi A, Ferré F, Fourcade O, Asehnoune K, Minville V. Lactate clearance for death prediction in severe sepsis or septic shock patients during the first 24 hours in Intensive Care Unit: an observational study. Ann Intensive Care. 2013 Feb 12;3(1):3. Puskarich MA, Trzeciak S, Shapiro NI, Albers AB, Heffner AC, Kline JA, Jones AE. Whole blood lactate kinetics in patients undergoing quantitative resuscitation for severe sepsis and septic shock. Chest. 2013 Jun;143(6):1548-53. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM; Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004 Mar;32(3):858-73. Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, Schorr C, Artigas A, Ramsay G, Beale R, Parker MM, Gerlach H, Reinhart K, Silva E, Harvey M, Regan S, Angus DC. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med. 2010 Feb;36(2):222-31. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. Updated Bundles in Response to New Evidence (n.d.): n. pag. Surviving Sepsis Campaign. Apr. 2015. Web. 15 Dec. 2015. Nguyen HB, Kuan WS, Batech M, Shrikhande P, Mahadevan M, Li CH, Ray S, Dengel A; ATLAS (Asia Network to Regulate Sepsis care) Investigators. Outcome effectiveness of the severe sepsis resuscitation bundle with addition of lactate clearance as a bundle item: a multi-national evaluation. Crit Care. 2011;15(5):R229. Napoli AM, Seigel TA. The role of lactate clearance in the resuscitation bundle. Crit Care. 2011;15(5):199. doi: 10.1186/cc10478. Epub 2011 Oct 24. “Quality Review Gets Septic.” Review. Audio blog post. EM:RAP. Cameron Berg, MD FAAEM and Rob Orman, MD. Aug. 2015. Web. 15 Dec. 2015.