Severe sepsis is one of the most common fatal conditions with a mortality rate of 20% to 50%. Although the mortality rate is in decline, the incidence of sepsis has been increasing steadily for several decades (1–4).
A subset of patients with severe sepsis suffers from global tissue hypoxia despite normal hemodynamic indices, which is referred to as cryptic shock (CS) (5–7) or occult hypoperfusion (8). In CS, lactate production at the cellular level is increased because of anaerobic metabolism, whereas the clearance of lactate is decreased as a result of sepsis. Despite this, multiple compensatory mechanisms maintain normal hemodynamic parameters (8). Therefore, several studies have used elevated serum lactate concentrations (≥4 mmol/L) as objective evidence of tissue hypoxia or CS, regardless of the presence of evident hypotension (7, 9, 10).
Among sepsis patients, CS is common and mortality is high (8, 11–13). Deceptively normal hemodynamic parameters are a barrier to early recognition and resuscitation (14–16). Even if patients with CS are managed with a quantitative protocol–based resuscitation, CS is as dangerous as overt shock (OS) and carries a similar mortality risk (11). In particular, we also noticed that a significant number of hemodynamically stable patients with CS may deteriorate to OS; these patients underwent invasive interventions during the early phase of treatment in the ED. We therefore performed this study to evaluate the clinical characteristics and outcomes of patients who presented with CS without hemodynamic deterioration, CS progressing to OS (COS) during initial treatment, and OS on ED arrival. We also investigated risk factors for progression to OS in patients who initially manifested with CS.
This was a single-center retrospective cohort study of patients presenting to the ED of Samsung Medical Center, a tertiary teaching hospital located in an urban area and receiving 70,000 visits per year. The institutional review board approved this study, and informed consent was waived because of the retrospective nature that required no intervention.
Patient inclusion criteria
We included patients aged 18 years or older who initially presented with septic shock or severe sepsis with serum lactate concentrations of 4 mmol/L or greater. We excluded patients with terminal malignancy or a previously signed “Do Not Resuscitate” order, as well as patients who refused early goal-directed therapy.
“Sepsis” was defined as suspected or confirmed infection in the presence of two or more systemic inflammatory response syndrome criteria. “Systemic inflammatory response syndrome” was defined by two or more of the following conditions: 1) a body temperature greater than 38°C or less than 36°C; 2) a heart rate greater than 90 beats/min; 3) a respiratory rate greater than 20 breaths/min or PaCO2 of less than 32 mmHg; and 4) white blood cell count greater than 12,000/mm3, less than 4,000/mm3, or the presence of more than 10% immature neutrophils (“bands”) (17). “Severe sepsis” was defined as sepsis associated with acute organ dysfunction. “Septic shock” was defined as sepsis that presented with hypotension (systolic blood pressure, <90 mmHg; mean arterial pressure [MAP], <60 mmHg; or a reduction in systolic blood pressure, >40 mmHg from baseline), despite adequate fluid resuscitation, in the absence of other causes of hypotension (18). “Cryptic shock” was defined as severe sepsis with serum lactate concentrations of 4 mmol/L or greater and normal blood pressure. “Cryptic shock progressing to OS” was defined as CS at the time of ED presentation that progressed to septic shock within 72 h (19). “Overt shock” was defined as septic shock diagnosed at the time of ED arrival. We classified patients into a CS group, a COS group, and an OS group. Patients with CS who did not progress to hypotension were assigned to the CS group. A Sequential Organ Failure Assessment (SOFA) score of 2 or greater for each target organ was defined as organ failure (respiratory failure, nervous system failure, hepatic failure, coagulation failure, or renal failure) (20).
We analyzed the sepsis registry, which has been prospectively collected since August 2008 for relevant patients presenting to the ED (16). During the study period, protocol-based resuscitation was performed for patients with severe sepsis or septic shock based on the protocol by Rivers et al. (7) and the 2008 Surviving Sepsis Campaign guidelines (21).
The data included detailed patient characteristics, comorbidities, vital signs, sites of infection, laboratory data, and the time to diagnosis of each type of shock. Data about sepsis interventions such as fluid administration, use of vasopressors, central line insertion, mechanical ventilation, and resuscitation bundle compliance were also recorded (12). The resuscitation bundle was categorized by seven interventions (12, 22, 23): 1) serum lactate measurement, 2) blood culture before antibiotic administration, 3) broad-spectrum antibiotics administered within 3 h from the time of presentation if the patient was hypotensive and/or had a lactate level of 4 mmol/L or greater, 4) delivery of an initial minimum volume of 20 mL/kg crystalloid (or colloid) in the event of persistent hypotension despite fluid resuscitation and/or lactate of 4 mmol/L or greater, 5) achievement and maintenance of MAP of 65 mmHg or greater, 6) achievement of central venous pressure (CVP) 8 mmHg or greater, and 7) achievement of central venous oxygen saturation (ScvO2) of 70% or greater. The SOFA scores were calculated at the time of diagnosis of severe sepsis or septic shock, and the Acute Physiology and Chronic Health Evaluation (APACHE) II score was also evaluated (24).
In-hospital mortality was the primary end point of this study. Secondary end points were in-hospital length of stay (LOS) and compliance with the protocol for sepsis interventions (21).
Data are presented as medians with interquartile ranges (IQRs) for numeric data and numbers with percentages for categorical data. The Kruskal-Wallis test was used for non-normally distributed variables, and the chi-square test was used for categorical variables. Multiple comparisons were performed to compare each group using Wilcoxon rank sum tests, and Bonferroni corrections were used to determine if multiple comparisons were significant. A multivariable logistic regression model was developed to assess variables related to in-hospital mortality. Adjusted factors were age, sex, APACHE II score, source of infection, initial serum lactate, and sepsis interventions. A multivariable Cox regression model was also used to evaluate predictive factors for progression to OS in patients who initially showed cryptic shock (the CS and COS groups). In this model, variables that could be initially assessed in the ED were included (age, sex, vital signs, and the presence of organ failure). The results were described as adjusted odds ratios (ORs) or hazard ratios (HRs) with a 95% confidence interval (CI). A value of P < 0.05 was considered significant. STATA 11.0 (STATA Corporation, College Station, Tex) was used for statistical analysis.
We analyzed 591 patients who met the inclusion criteria. Of the eligible patients, we assigned 187 patients to the CS group, 157 patients to the COS group, and 247 patients to the OS group (Fig. 1). The median time to diagnosis was 1.1 h (IQR, 0.8 – 1.6 h) in the CS group, 4.9 h (IQR, 1.8 – 10.6 h) in the COS group, and 0.9 h (IQR, 0.6 – 1.5 h) in the OS group.
Baseline characteristics of each group are described in Table 1. Age, sex, and comorbidities were not related to the type of shock. Patients with intra-abdominal infections presented more frequently in the COS group than in the OS group. Initial serum lactate concentration was the highest in the COS group, followed by the CS and then the OS group. The initial SOFA score and APACHE II score were lower in the CS group compared with the COS and OS groups. Compared with the COS group, the OS group showed significantly lower values in MAP, body temperature, and serum lactate concentration. On the other hand, the OS group showed higher values for C-reactive protein, blood urea nitrogen, creatinine, and SOFA scores than the COS group.
Comparison of sepsis interventions
A comparison of sepsis interventions is shown in Table 2. Compared with the CS and COS groups, the OS group had a significantly higher total fluid volume within 6 h, as well as more central line insertions. In addition, more patients in this group received vasopressors. The overall compliance with resuscitation bundles and compliance with each intervention, including timely lactate measurement, timely antibiotic use, fluid challenge, achievement of CVP goal, and achievement of ScvO2 goal, were highest in the OS group, followed by the COS and the CS groups.
Comparison of outcomes
Overall in-hospital mortality was 18.6% (Table 3). The in-hospital mortality of patients with CS (CS group and COS group) at the time of ED administration was not different from that of the OS group (16.3% vs. 21.9%, respectively; P = 0.09); however, the CS group showed significantly lower in-hospital mortality than the OS group (7.0% vs. 21.9%; P < 0.01). The COS group showed a higher in-hospital mortality than the OS group (27.4% vs. 21.9%; P = 0.62), but the difference was not statistically significant.
In-hospital LOS was not significantly different among the three groups.
Multivariable regression analysis
The unadjusted OR for in-hospital mortality was 0.28 (95% CI, 0.14 – 0.51; P < 0.001) in the CS group and 1.35 (95% CI, 0.85 – 2.14; P = 0.21) in the COS group compared with the OS group. In multivariable logistic regression analysis, the adjusted OR for in-hospital mortality was 0.17 (95% CI, 0.07 – 0.40; P < 0.01) in the CS group and 0.83 (95% CI, 0.46 – 1.49; P = 0.54) in the COS group when compared with the OS group (Table 4).
Among patients who initially showed CS (the CS and COS groups), a higher blood lactate concentration (adjusted HR, 1.16; 95% CI, 1.09 – 1.24; P < 0.01) and respiratory failure (adjusted HR, 2.22; 95% CI, 1.56 – 3.15; P < 0.01) were significant risk factors for progression to OS (Table 5).
We found that the mortality of CS that progresses to apparent hypotension is comparable to the mortality from OS; however, CS without the development of hypotension during initial treatment has a significantly lower mortality rate than OS. In addition, elevated serum lactate concentrations and respiratory failure were significant factors that predicted the development of hypotension in CS patients that did not respond to initial fluid resuscitation.
Cryptic shock is known to be associated with high mortality. Puskarich et al. (11) reported that normotensive patients with severe sepsis and elevated lactate (CS) had a mortality rate that was not significantly different from those who presented with OS. Levy et al. (12) demonstrated that the mortality rate of severe sepsis with an elevated lactate concentration greater than 4 mmol/L was 29.9% compared with 36.7% for severe sepsis with vasopressor use only and 46.1% in severe sepsis with elevated serum lactate and vasopressor use.
In this study, we differentiated the COS group from patients who initially presented with CS only. About half of the CS patients in this study deteriorated to hypotension, and the mortality of the COS group was not significantly different from that of the OS group. This would explain in part the high mortality of CS. Our data support the importance of early detection and proper management of CS or occult tissue hypoperfusion to prevent the development of hypotension and to improve survival (8). Although it is not a new observation, it is a clinically crucial point to be reemphasized. The finding suggests that further research to develop an effective strategy to prevent overt hypotension in patients who initially present with CS is warranted.
Our study suggests that some independent risk factors should be evaluated as soon as patients with suspected sepsis arrive to the ED, such as blood lactate concentration and respiratory failure. These variables may help the physician to identify a patient likely to progress from CS to OS during initial treatment of sepsis. We think that early bedside screening using a point-of-care lactate measurement and blood gas analysis is a promising tool to decrease the time to detection of high-risk CS (25, 26).
In our study, the overall resuscitation bundle compliance was similar to previous studies (12, 13, 27), but the CS group showed a better survival rate despite lower compliance compared with the COS and OS groups. There are multiple possible explanations for these results. First, patients in the CS group might have relatively well-preserved organ function despite elevated serum lactate concentration because the initial SOFA score was significantly lower in this group. Second, physicians tended to manage patients less aggressively because their signs of organ failure were not evident (14) and they did not regard the situation as seriously. For example, a central line may not have been inserted if serum lactate elevation was the only abnormal finding. In future studies, patients who do not require invasive interventions should be identified and treated accordingly.
This study has some limitations that should be considered. First, it was conducted at a single center; therefore, our findings may not be generalizable to other settings. Second, the serum lactate level of the CS and COS groups should be greater than 4 mmol/L by definition; however, hyperlactatemia was not essential according to the current definition of septic shock (18, 28). Therefore, the OS group in this study was mixed with patients with hyperlactatemia and normolactatemia, which could influence in-hospital mortality (29). Third, therapeutic interventions were not consistently provided to all included patients. Clinicians tended to provide more aggressive interventions to patients in the OS group, which may affect the outcome (30). Lastly, our study did not show specific causes of deterioration during the initial treatment for sepsis. We did not prospectively control or prevent CS patients from developing hypotension. Our data could not show that low compliance with sepsis interventions was one of the causes of progression to OS because we could not fully adjust for disease severity and some patients deteriorated before intervention was achieved.
In conclusion, patients with CS without deterioration to hypotension during initial treatment showed significantly lower mortality than patients with OS. The mortality of CS that progressed to apparent hypotension, however, was comparable to the mortality of OS. A higher blood lactate concentration and respiratory failure were significant risk factors for progression to OS during initial treatment of sepsis.
1. Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Lepoutre A, Mercier JC, Offenstadt G, Regnier B: Incidence, risk factors, and outcome of severe sepsis
and septic shock
in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis
274: 968–974, 1995.
2. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP: The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA
273: 117–123, 1995.
3. Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis
in the United States from 1979 through 2000. N Engl J Med
348: 1546–1554, 2003.
4. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis
in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med
29: 1303–1310, 2001.
5. Otero RM, Nguyen HB, Huang DT, Gaieski DF, Goyal M, Gunnerson KJ, Trzeciak S, Sherwin R, Holthaus CV, Osborn T, et al.: Early goal-directed therapy in severe sepsis
and septic shock
revisited: concepts, controversies, and contemporary findings. Chest
130: 1579–1595, 2006.
6. Marchick MR, Kline JA, Jones AE: The significance of non-sustained hypotension in emergency department patients with sepsis
. Intensive Care Med
35: 1261–1264, 2009.
7. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M: Early goal-directed therapy in the treatment of severe sepsis
and septic shock
. N Engl J Med
345: 1368–1377, 2001.
8. Howell MD, Donnino M, Clardy P, Talmor D, Shapiro NI: Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med
33: 1892–1899, 2007.
9. 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
32: 1637–1642, 2004.
10. Shapiro NI, Howell MD, Talmor D, Nathanson LA, Lisbon A, Wolfe RE, Weiss JW: Serum lactate
as a predictor of mortality in emergency department patients with infection. Ann Emerg Med
45: 524–528, 2005.
11. Puskarich MA, Trzeciak S, Shapiro NI, Heffner AC, Kline JA, Jones AE: Outcomes
of patients undergoing early sepsis
resuscitation for cryptic shock compared with overt shock. Resuscitation
82: 1289–1293, 2011.
12. Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, Schorr C, Artigas A, Ramsay G, Beale R, et al.: The Surviving Sepsis
Campaign: results of an international guideline-based performance improvement program targeting severe sepsis
. Intensive Care Med
36: 222–231, 2010.
13. Levy MM, Artigas A, Phillips GS, Rhodes A, Beale R, Osborn T, Vincent JL, Townsend S, Lemeshow S, Dellinger RP: Outcomes
of the Surviving Sepsis
Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis
12: 919–924, 2012.
14. Kakebeeke D, Vis A, de Deckere ER, Sandel MH, de Groot B: Lack of clinically evident signs of organ failure affects ED treatment of patients with severe sepsis
. Int J Emerg Med
6: 4, 2013.
15. Carlbom DJ, Rubenfeld GD: Barriers to implementing protocol-based sepsis
resuscitation in the emergency department—results of a national survey. Crit Care Med
35: 2525–2532, 2007.
16. Kang MJ, Shin TG, Jo IJ, Jeon K, Suh GY, Sim MS, Lim SY, Song KJ, Jeong YK: Factors influencing compliance with early resuscitation bundle in the management of severe sepsis
and septic shock
38: 474–479, 2012.
17. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ: Definitions for sepsis
and organ failure and guidelines for the use of innovative therapies in sepsis
. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest
101: 1644–1655, 1992.
18. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis
Definitions Conference. Crit Care Med
31: 1250–1256, 2003.
19. Glickman SW, Cairns CB, Otero RM, Woods CW, Tsalik EL, Langley RJ, van Velkinburgh JC, Park LP, Glickman LT, Fowler VG Jr, et al.: Disease progression in hemodynamically stable patients presenting to the emergency department with sepsis
. Acad Emerg Med
17: 383–390, 2010.
20. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG: The SOFA (Sepsis
-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis
-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med
22: 707–710, 1996.
21. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, et al.: Surviving Sepsis
Campaign: international guidelines for management of severe sepsis
and septic shock
: 2008. Crit Care Med
36: 296–327, 2008.
22. Castellanos-Ortega A, Suberviola B, Garcia-Astudillo LA, Holanda MS, Ortiz F, Llorca J, Delgado-Rodriguez M: Impact of the Surviving Sepsis
Campaign protocols on hospital length of stay and mortality in septic shock
patients: results of a three-year follow-up quasi-experimental study. Crit Care Med
38: 1036–1043, 2010.
23. Castellanos-Ortega A, Suberviola B, Garcia-Astudillo LA, Ortiz F, Llorca J, Delgado-Rodriguez M: Late compliance with the sepsis
resuscitation bundle: impact on mortality. Shock
36: 542–547, 2011.
24. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med
13: 818–829, 1985.
25. Goyal M, Pines JM, Drumheller BC, Gaieski DF: Point-of-care testing at triage decreases time to lactate
level in septic patients. J Emerg Med
38: 578–581, 2010.
26. Shapiro NI, Fisher C, Donnino M, Cataldo L, Tang A, Trzeciak S, Horowitz G, Wolfe RE: The feasibility and accuracy of point-of-care lactate
measurement in emergency department patients with suspected infection. J Emerg Med
39: 89–94, 2010.
27. Ferrer R, Artigas A, Levy MM, Blanco J, Gonzalez-Diaz G, Garnacho-Montero J, Ibanez J, Palencia E, Quintana M, de la Torre-Prados MV: Improvement in process of care and outcome after a multicenter severe sepsis
educational program in Spain. JAMA
299: 2294–2303, 2008.
28. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al.: Surviving sepsis
campaign: international guidelines for management of severe sepsis
and septic shock
: 2012. Crit Care Med
41: 580–637, 2013.
29. Hernandez G, Castro R, Romero C, de la Hoz C, Angulo D, Aranguiz I, Larrondo J, Bujes A, Bruhn A: Persistent sepsis
-induced hypotension without hyperlactatemia: is it really septic shock
? J Crit Care
26: 435.e9–e14, 2011.
30. Donnino MW, Nguyen B, Jacobsen G, Tomlanovich M, Rivers E: Cryptic septic shock
: a subanalysis of early, goal-directed therapy. Chest
124: 90S, 2003.