Role of central venous oxygen saturation in prognostication of patients with severe sepsis and septic shock in emergency medical services.

INTRODUCTION: All the components of early goal-directed therapy, especially central venous oxygen saturation (ScvO2) as one of the endpoints of resuscitation, may not have mortality benefit, more so after results of the Australasian Resuscitation of Sepsis Evaluation, A Randomized Trial of Protocol-Based Care for Early Septic Shock, and The Protocolised Management in Sepsis trials. However, extrapolating results from trials undertaken in the developed world may not be entirely appropriate.
MATERIALS AND METHODS: In this prospective observational study conducted in the emergency medical services, we aimed to find out the mean baseline ScvO2 in a cohort of 200 patients presenting with severe sepsis/septic shock and its prognostic significance. The measurement of ScvO2 was performed by sampling blood from the superior vena cava through the central venous catheter.
RESULTS: The mean age of patients was 46.70 ± 17.64 years. The mean ScvO2 at baseline of the study cohort was 65.95 ± 20.70%. Based on initial ScvO2 values, 104 (52%) patients had a lower ScvO2 level, a priori classified as the hypoxic group. Sixty-five (32.5%) patients had an initial ScvO2 level in between 70 and 89%, categorized as normoxic group, and the remaining 31 (15.5%) patients had high ScvO2, leveled as the hyperoxic group. Sixty-six (33%) patients had hospital mortality. Of 104 hypoxemic patients, 28 (26.9%) had hospital mortality. In this group, the mean ScvO2 value in 28 nonsurvivors at baseline and after 6 h of resuscitation was 46.21 ±16.66% and 48.82 ±18.81%, respectively. Twenty-five (38.5%) patients had hospital mortality among 65 patients with baseline ScvO2 value in the normoxic range. Hospital mortality figure stood at 13 (41.9%) patients in the hyperoxic group. Among patients in the hyperoxic group, the mean serum lactate value at baseline in nonsurvivors was 4.52 ± 2.95 mmol/L, significantly higher as compared to the mean value of 2.89 ± 1.55 mmol/L in survivors. The hyperoxia group had higher hospital mortality though it was not statistically significant.
CONCLUSION: The mean baseline ScvO2 was lower in our study cohort. In the hypoxic group, patients with hospital mortality had persistently lower ScvO2 level during the first 6 h of resuscitation. Importantly, higher mortality in the hyperoxic group with high serum lactate emphasizes the point that ScvO2 value should be analyzed along with serum lactate levels as complimentary resuscitation endpoints. Copyright:

INTRODUCTION

Sepsis is among the most common causes of mortality and morbidity in emergency medical services. Mortality due to sepsis continues to remain high in the range of 10–60% despite great advances in medicine.[123456] The search for a specific management protocol for the complicated problem of severe sepsis and septic shock started with the Rivers' study in 2001, which introduced the early goal-directed therapy (EGDT). EGDT produced a significant reduction in mortality in patients with severe sepsis and septic shock. The EGDT, thus, introduced a new hemodynamic parameter: central venous oxygen saturation (ScvO2).[7] As the central line was an essential part of the EGDT, to measure central venous pressure (CVP), ScvO2 was easy to measure in all patients. Because ScvO2 is the oxygen saturation of venous blood returning to the heart, it represents the balance of systemic oxygen delivery and oxygen consumption by tissue. A low ScvO2 reflects either decreased oxygen delivery or increased oxygen extraction or both. A normal ScvO2 means that the body is able to compensate for the increased oxygen demand by increasing the cardiac output and the respiratory rate. A high ScvO2 reflects either oxygen delivery above demand or decreased oxygen extraction due to blockage in the capillaries (microclotting in sepsis) or mitochondrial dysfunction.

Three recently published large randomized studies, including Australasian Resuscitation of Sepsis Evaluation (ARISE), A Randomized Trial of Protocol-Based Care for Early Septic Shock (ProCESS), and The Protocolised Management in Sepsis (PROMISE) trial, have challenged the benefit of EGDT approach in improving survival in severe sepsis and septic shock and suggest that some interventions carried out during EGDT algorithm may not have mortality benefit (central venous catheter [CVC] insertion, ScvO2 monitoring, dobutamine, and transfusion triggers for hematocrit <30%).[8910] These findings have brought in focus the utility of targeting a predefined value of ScvO2 in the management of severe sepsis/septic shock. However, there is an important caveat in interpreting the result of these trials as there is a significant difference in the mean baseline ScvO2 value in patients recruited in Rivers' trial as compared to patients recruited in these three trials. The mean initial ScvO2 reported by Rivers et al. was 49%, which is lower than that documented at baseline in these trials.[78910] Extrapolating results from these trials undertaken in the developed world would not be entirely appropriate. It would therefore be pertinent to find out the mean baseline ScvO2, the prevalence of abnormal ScvO2, both low and high at presentation, and their prognostic significance in a cohort of patients presenting with severe sepsis/septic shock in our emergency medical services in developing world.

MATERIALS AND METHODS

This single-center prospective observational study was conducted in the emergency medical services of a tertiary care institution in North-Western India. Two hundred adult (≥18 years old) medical patients admitted to the emergency medical services for more than 24 h with an admission diagnosis of severe sepsis and/or septic shock fulfilling all inclusion and exclusion criteria were included in the study.[11] Exclusion criteria were patients <18 years old, pregnant females, patients with primary admitting diagnosis of acute pulmonary edema, acute myocardial infarction, cerebrovascular event, asthma exacerbation, major cardiac arrhythmia, seizure, drug overdose, injury from burn or trauma, active gastrointestinal hemorrhage leading to hemodynamic instability, requirement for immediate surgery, do-not-attempt-resuscitation status, contraindication to central venous catheterization, contraindication to blood transfusion and transferred from another in-hospital setting with duration of stay of more than 24 h. Sociodemographic details, baseline clinical and laboratory parameters were recorded in a predesigned instrument. Arterial blood gas (Model: Cobas b 121, Manufacturer: Roche) was measured at presentation and as and when required from the peripheral artery and central venous line. Line insertion involved a CVC, inserted either into subclavian or internal jugular vein. The CVC was inserted using standard techniques for central access. Guidelines of the CVC care bundle were followed for insertion and day to day care. A blood sample was taken as soon as possible after CVC insertion from the superior vena cava through the CVC for the measurement of ScvO2 by a standard blood gas analyzer. The ScvO2 levels were stratified into three groups of hypoxia (ScvO20–69%), normoxia (ScvO270–89%), and hyperoxia (ScvO290–100%).[12] These thresholds have been selected a priori. The severity of illness was assessed by sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE II) score from the data collected during the first 24 h following admission. All patients were followed up throughout their hospital stay, and requirement of any kind of organ support, e.g., renal replacement therapy, mechanical ventilation, and the vasoactive agents were also recorded in a predesigned proforma. The immediate cause of death in the case of hospital mortality was noted. The institute ethics committee approved the study. Informed consent was obtained from the patient or next of kin. We have scrupulously followed all the checklists contained in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline during reporting the index study.

Statistical analyses

The data were expressed as percentages (%), mean ± SD, or median and 25% to 75% interquartile range (IQR), as appropriate. Patients were divided into hospital survivors and nonsurvivors; also based on ScvO2 levels at baseline, patients were stratified into three groups: hypoxia (ScvO20–69%), normoxia (ScvO270–89%), and hyperoxia (ScvO290–100%). Between groups of survivors and nonsurvivors, continuous and categorical characteristics were analyzed. Continuous, normally distributed variables were compared with the t-test, and for nonnormally distributed, Mann–Whitney U-test was used. Categorical variables were compared utilizing the Chi-square test. To determine the univariate relationship between hypoxia, hyperoxia, and normoxia groups, categorical variables between these groups were compared using the Chi-square test. For normally distributed continuous variables between these three groups, the analysis of variance test was used. For nonnormally distributed continuous variables, Kruskal–Wallis test was used. For further characterization of significant P values found on the Kruskal–Wallis test, Mann–Whitney test was applied taking two out of three groups in different combinations. We also carried out multivariate logistic regression analysis to find out variables independently associated with hospital mortality. Variables with P < 0.1 on univariate analysis were included in multivariate logistic regression analysis. Statistical analysis was performed using the statistical software SPSS version 22.0 (SPSS Inc., Chicago, IL, USA). All tests were two-tailed. P < 0.05 was considered statistically significant.

RESULTS AND OBSERVATIONS

In this single-center prospective observational study, we analyzed 200 patients with severe sepsis and septic shock admitted in the emergency medical services attached to the department of internal medicine in the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, a tertiary care institution in North-West India. The mean age of patients was 46.7 ± 17.6 years. The male preponderance (114 [57%]) was noted. Hypertension was the most common comorbidity noted in 61 (30.5%) patients. The most common identifiable source of infection at presentation was pulmonary system infections in 78 (39%) patients. Based on initial ScvO2 data, out of 200 patients, 104 (52%) patients had a low ScvO2 level, also leveled as the hypoxic group. Sixty-five (32.5%) patients had an initial ScvO2 level in between 70 and 89%, apriori classified as the normoxic group, and the remaining 31 (15.5%) patients had high ScvO2, leveled as the hyperoxic group. The mean ScvO2 of study cohort at baseline was 65.9 ±20.7%. The mean SOFA score of study cohort at hospital admission was 9.7 ± 3.7, whereas the mean APACHE II score was 24.8 ± 7.1. The mean APACHE II score of the hypoxic group was 24.7 ± 6.9, of the normoxic group was 24.7 ± 7.5, and of the hyperoxic group was 25.1 ± 7.1. Similarly, the mean SOFA score of the hypoxic group was 9.9 ± 3.7, of the normoxic group was 9.6 ± 3.7, and of the hyperoxic group was 10.0 ± 3.9. The median lactate level at baseline was 2.98 mmol/l (IQR = 2.05–4.42). The median lactate levels in the hypoxia, normoxia, and hyperoxia groups were 3.10 (2.30–4.41), 2.65 (2.00–5.30), and 2.92 (2.00–4.06) mmol/l, respectively. Of the 200 patients with severe sepsis and septic shock, acute renal failure was noted in 179 (89.5%) patients, acute respiratory failure in 146 (73%), acute cardiovascular failure in 121 (60.5%), central nervous system failure in 106 (53%) patients, and gastrointestinal failure in 98 (49.5%) patients. Inotrope usage was documented in 123 (61.5%) patients. The median duration of inotrope use was 50.00 (IQR – 30.00–96.00) hours. The refractory septic shock was documented in 50 (25%) patients. Eighty-eight (44%) patients required invasive mechanical ventilation. The median duration of mechanical ventilation was 3.00 (2.00–8.00) days. Forty-seven (23.5%) patients required renal replacement therapy, of which 35 were diagnosed cases of chronic kidney disease (CKD). The median duration of hospital stay was 9.00 (IQR – 4–14) days. The median duration of hospital stay was 9.00 (5.00–14.00) days for hypoxia group, 9.00 (5.00–13.50) days for normoxia group, and 8.00 (3.00–18.00) days for hyperoxia group. Sixty-six (33%) patients had hospital mortality. Further details of various parameters of the whole study cohort are summarized in Tables 1 and 2.

Table 1

Demographic and clinical parameters of 200 patients with severe sepsis/septic shock admitted in emergency medical services

Characteristics	Value
Age (years), mean±SD	46.70±17.64
Male gender, n (%)	114 (57)
Patient comorbidity, n (%)
Hypertension	61 (30.5)
Diabetes mellitus	55 (27.5)
Chronic kidney disease	35 (17.5)
Coronary artery disease	27 (13.5)
Chronic liver disease	23 (11.5)
Malignancy	21 (10.5)
Cerebrovascular accident	11 (5.5)
Tuberculosis	11 (5.5)
Epilepsy	9 (4.5)
Chronic obstructive pulmonary disease	8 (4)
Bronchial asthma	2 (1)
Risk factors, n (%)
Smoking	100 (50)
Alcoholism	42 (21)
Steroid use	35 (17.5)
Immunosuppression	34 (17)
Neutropenia	16 (8)
Recent surgery	14 (7)
Source of infection, n (%)
Respiratory system	78 (39)
Abdomen	72 (36)
Genitourinary	56 (28)
Skin/soft tissue	29 (14.5)
Central nervous system	14 (7)
Heart	4 (2)
Organ failures, n (%)
Renal	179 (89.5)
Pulmonary	146 (73)
Cardiovascular	121 (60.5)
Central nervous system	106 (53)
Gastrointestinal	98 (49)
Refractory septic shock	50 (25)
Physiologic variables at baseline, mean±SD
Mean arterial pressure (mmHg)	77.58±19.98
Pulse rate (/min)	112.51±18.81
SpO2 (%)	90.76±8.63
Respiratory rate (/min)	29.88±5.68
Lactate (mmol/l), median (IQR)	2.98 (2.05-4.42)
SOFA, mean±SD	9.71±3.68
APACHE II, mean±SD	24.77±7.06
Inotrope duration (h), median (IQR)	50.00 (30.00-96.00)
Mechanical ventilation (days), median (IQR)	3.00 (2.00-8.00)
Hospital stay (days), median (IQR)	9.00 (4.00-14.00)
Hospital mortality, n (%)	66 (33)

SD: Standard deviation, SpO2: Oxygen saturation on pulse oximeter, IQR: Interquartile range, SOFA: Sequential organ failure assessment score, APACHE II: Acute physiology and chronic health evaluation score

Table 2

Baseline laboratory parameters of 200 patients with severe sepsis/septic shock admitted in emergency medical services

Laboratory variables at admission, mean±SD	Value
Hb (g/dl)	9.44±2.45
RDW (%)	18.18±3.67
Na (mEq/l)	134.84±8.50
Serum urea (mg/dl), median (IQR)	69.00 (44.00-119.00)
Serum creatinine (mg/dl), median (IQR)	2.70 (1.62-4.17)
Serum protein (g/dl)	6.01±0.93
Serum albumin (g/dl)	2.70±0.84
Serum globulin (g/dl)	3.27±0.78
Corrected Ca (mg/dl)	8.28±1.16
Serum Mg (mg/dl)	2.01±0.49
pH	7.29±0.16
PaCO2 (mmHg)	29.97±8.59
SpO2 (%)	92.48±7.56
Pressure of arterial oxygen/fraction of inspired oxygen ratio	226.35±63.49
PT (s), median (IQR)	19.00 (17.75-22.00)
INR, median (IQR)	1.32 (1.25-1.50)
aPTT (s), median (IQR)	29.50 (27.00-33.50)

Hb: Hemoglobin; RDW: Red cell distribution width, Na: Sodium, IQR: Interquartile range, Ca: Calcium, Mg: Magnesium, PaCO2: Partial pressure of carbon dioxide in arterial blood, SpO2: Oxygen saturation on pulse oximeter, PT: Prothrombin time, INR: International normalized ratio, aPTT: Activated partial thromboplastin time, SD: Standard deviation

Demographic and clinical parameters of 200 patients with severe sepsis/septic shock admitted in emergency medical services

SD: Standard deviation, SpO2: Oxygen saturation on pulse oximeter, IQR: Interquartile range, SOFA: Sequential organ failure assessment score, APACHE II: Acute physiology and chronic health evaluation score

Baseline laboratory parameters of 200 patients with severe sepsis/septic shock admitted in emergency medical services

Hb: Hemoglobin; RDW: Red cell distribution width, Na: Sodium, IQR: Interquartile range, Ca: Calcium, Mg: Magnesium, PaCO2: Partial pressure of carbon dioxide in arterial blood, SpO2: Oxygen saturation on pulse oximeter, PT: Prothrombin time, INR: International normalized ratio, aPTT: Activated partial thromboplastin time, SD: Standard deviation

Various sociodemographic, clinical, and laboratory parameters; the severity of illness scores; and hospital outcome variables were compared between nonsurvivors and survivors. APACHE II score at admission was significantly higher in nonsurvivors as compared to survivors ([27.58 ± 7.56 vs. 23.38 ± 6.41], P ≤ 0.001). SOFA score at admission was also significantly higher in nonsurvivors as compared to survivors ([11.82 ± 2.80 vs. 8.68 ± 3.62], P ≤ 0.001). The mean serum lactate level at baseline was significantly higher in nonsurvivors ([4.84 ± 3.37 vs. 3.16 ± 1.83 mmol/l], P ≤ 0.001) as well. Nonsurvivors had significantly higher incidence of cardiovascular ([86.40% vs. 47.80%], P ≤ 0.001) and central nervous system failure ([77.30% vs. 41.00%], P ≤ 0.001). The incidence of refractory septic shock was also significantly higher in the nonsurvivor group. The mean values of ScvO2 at baseline were also compared among survivors and nonsurvivors, but the differences were not statistically significant. Further elaboration of univariate analysis of various sociodemographic, clinical, laboratory, organ failure assessment, and hospital outcome parameters among survivors and nonsurvivors is shown in Tables 3 and 4. We also carried out multivariate logistic regression analysis to find out the variables independently associated with hospital mortality. Age, serum lactate, and SOFA score at baseline were found to be independently associated with hospital mortality [Table 5].

Table 3

Comparison of various characteristics among survivors and nonsurvivors in a study cohort of 200 patients with severe sepsis and septic shock admitted in emergency medical services

Characteristics	Survivors (n=134)	Nonsurvivors (n=66)	P
Age (years), mean±SD	43.98±17.13	52.23±17.51	0.002
Male, n (%)	65 (48.50)	41 (62.10)	0.073
Patient comorbidity, n (%)
Diabetes mellitus	31 (23.1)	24 (36.4)	0.062
Hypertension	38 (28.4)	23 (34.8)	0.331
Malignancy	10 (7.5)	11 (16.7)	0.052
Coronary artery disease	12 (8.9)	15 (22.7)	0.014
Chronic kidney disease	20 (14.9)	15 (37.9)	0.171
Chronic obstructivepulmonary disease	5 (3.7)	3 (4.6)	0.719
Cerebrovascular accident	6 (4.5)	5 (7.6)	0.510
Human immunodeficiencyvirus infection	7 (5.2)	3 (4.6)	1.000
Tuberculosis	6 (4.5)	5 (7.6)	0.510
Chronic liver disease	13 (9.7)	10 (15.2)	0.248
Epilepsy	6 (4.5)	3 (4.6)	1.000
Source of infection, n (%)
Respiratory	47 (35.1)	31 (46.9)	0.121
Intra-abdominal	49 (36.6)	23 (34.9)	0.485
Central nervous	11 (8.2)	3 (4.6)	0.266
Skin/soft tissue	17 (12.7)	12 (18.2)	0.197
Genitourinary tract	41 (30.6)	15 (22.7)	0.543
Heart	3 (2.2)	1 (1.5)	0.602
Organ failure, n (%)
Cardiovascular system	64 (47.8)	57 (86.4)	<0.001
Gastrointestinal system	67 (50.0)	31 (47.0)	0.734
Pulmonary system	94 (70.1)	52 (78.8)	0.237
Renal system	120 (89.6)	59 (89.4)	1.000
Central nervous system	55 (41.0)	51 (77.3)	<0.001
Refractory septic shock	3 (2.2)	47 (71.2)	<0.001
Physiologic variables at baseline, mean±SD
Respiratory rate, (/min)	30.03±6.02	29.58±4.89	0.597
Pulse oximeter oxygensaturation, (%)	89.73±13.90	85.98±20.87	0.133
Pulse rate, (/min)	113.75±17.27	109.98±21.55	0.184
Mean arterypressure, (mmHg)	77.45±21.55	74.32±22.83	0.355
Central venousoxygen saturation at admission, (%)	64.47±19.20	68.95±23.32	0.151
Number of patients categorized as hypoxic based on baseline ScvO2, n (%)	76 (56.7)	28 (42.4)	0.071
Number of patients categorized as normoxic based on baseline ScvO2, n (%)	40 (29.9)	25 (37.9)	0.265
Number of patients categorized as hyperoxic based on baseline ScvO2, n (%)	18 (13.4)	13 (19.7)	0.299
Sequential organ failure assessment score, mean±SD	8.68±3.62	11.82±2.80	<0.001
Acute physiology and chronic health evaluation score, mean±SD	23.38±6.41	27.58±7.56	<0.001
Inotrope duration (h), mean±SD)	30.61±45.63	78.55±89.42	<0.001
Hospital stay (days), mean±SD	11.95±7.95	7.29±6.49	<0.001

SD: Standard deviation, ScvO2: Central venous oxygen saturation

Table 4

Comparison of various baseline laboratory characteristics among survivors and nonsurvivors in a study cohort of 200 patients with severe sepsis and septic shock admitted in emergency medical services

Laboratory variables at admission, mean±SD	Survivors (n=134)	Nonsurvivors (n=66)	P
Hb (g/dL)	9.72±2.86	9.49±2.53	0.569
Total leukocyte count (/µL)	17596.19±9346.62	21856.21±8906.21	0.231
Platelet count (×103/µL)	205.24±139.26	215.06±146.72	0.645
Serum Na (mEq/L)	135.28±7.78	133.92±10.37	0.029
Serum chloride (mEq/L)	102.82±8.09	102.39±9.22	0.301
Urea (mg/dL)	88.44±66.73	92.17±60.72	0.703
Creatinine (mg/dL)	3.00±2.91	2.71±2.45	0.481
Serum protein (g/dL)	5.74±2.13	5.28±2.22	0.071
Serum albumin (g/dL)	2.65±1.15	2.36±1.15	0.051
Serum Mg (mg/dL)	1.70±0.80	1.51±0.92	0.692
pH	7.36±0.13	7.37±0.12	0.028
PaCO2 (mmHg)	32.24±12.84	31.29±7.34	0.023
Pressure of arterial oxygen/fraction of inspired oxygen ratio	314.69±91.98	296.24±104.98	0.003
PT (s)	17.69±7.93	19.92±11.59	0.163
aPTT (s)	29.68±12.29	33.73±20.23	0.081
Serum lactate (mmol/L)	3.16±1.83	4.84±3.37	<0.001

SD: Standard deviation, PaCO2: Partial pressure of carbon dioxide in arterial blood, Hb: Hemoglobin, Mg: Magnesium, PT: Prothrombin time, aPTT: Activated partial thromboplastin time, Na: Sodium

Table 5

Multivariate logistic regression analysis of variables associated with hospital mortality in a cohort of 200 patients with severe sepsis and septic shock admitted in emergency medical services

Variable	Regression coefficient	OR	95% CI	P
Age	0.026	1.026	1.007-1.046	0.010
SOFA score at baseline	0.258	1.295	1.165-1.439	<0.001
Serum lactate at baseline	0.228	1.256	1.089-1.450	0.002

OR: Odds ratio, CI: Confidence interval, SOFA: Sequential organ failure assessment score

Comparison of various characteristics among survivors and nonsurvivors in a study cohort of 200 patients with severe sepsis and septic shock admitted in emergency medical services

SD: Standard deviation, ScvO2: Central venous oxygen saturation

Comparison of various baseline laboratory characteristics among survivors and nonsurvivors in a study cohort of 200 patients with severe sepsis and septic shock admitted in emergency medical services

SD: Standard deviation, PaCO2: Partial pressure of carbon dioxide in arterial blood, Hb: Hemoglobin, Mg: Magnesium, PT: Prothrombin time, aPTT: Activated partial thromboplastin time, Na: Sodium

Multivariate logistic regression analysis of variables associated with hospital mortality in a cohort of 200 patients with severe sepsis and septic shock admitted in emergency medical services

OR: Odds ratio, CI: Confidence interval, SOFA: Sequential organ failure assessment score

We similarly compared various sociodemographic, clinical, laboratory, the severity of illness scores, and hospital outcome variables among groups with hypoxia, hyperoxia, and normoxia categorized based on baseline ScvO2. We found no significant difference in APACHE II, SOFA score, and hospital mortality among the three groups on univariate analysis. The details are provided in Tables 6 and 7.

Table 6

Comparison of various characteristics among hypoxia, hyperoxia, and normoxia groups categorized on the basis of baseline ScvO2 level in a study cohort of 200 patients with severe sepsis and septic shock admitted in emergency medical services

Characteristics	Hypoxia (n=104)	Normoxia (n=65)	Hyperoxia (n=31)	P
Age (years), mean±SD	47.34±17.70	46.38±17.98	45.23±17.15	0.831
Male gender, n (%)	54 (52)	36 (55.4)	16 (51.6)	0.896
Comorbidity, n (%)
Hypertension	30 (28.8)	20 (30.8)	11 (35.5)	0.779
Diabetes mellitus	29 (27.9)	21 (32.3)	5 (16.1)	0.250
Chronic kidney disease	22 (21.2)	8 (12.3)	5 (16.1)	0.330
Coronary artery disease	17 (16.3)	8 (12.3)	3 (9.7)	0.574
Chronic liver disease	10 (9.6)	5 (7.7)	8 (25.8)	0.023
Malignancy	10 (9.6)	8 (12.3)	3 (9.7)	0.846
Tuberculosis	8 (7.7)	3 (4.6)	0	0.239
Cerebrovascular accident	7 (6.7)	1 (1.5)	3 (9.7)	0.191
Human immune deficiency infection	7 (6.7)	0	3 (9.7)	0.064
Chronic obstructive pulmonary disease	6 (5.8)	2 (3.1)	0	0.319
Epilepsy	3 (2.9)	2 (3.1)	4 (12.9)	0.049
Source of infection, n (%)
Respiratory system	43 (41.3)	20 (30.8)	15 (48.4)	0.198
Abdomen	35 (33.7)	26 (40)	11 (35.5)	0.703
Genitourinary tract	30 (28.8)	19 (29.2)	9 (29)	0.999
Skin/soft tissue	17 (16.3)	8 (12.3)	4 (12.9)	0.740
Central nervous system	7 (6.7)	4 (6.2)	3 (9.7)	0.809
Organ failure, n (%)
Renal system	90 (86.5)	59 (90.8)	30 (96.8)	0.243
Respiratory system	73 (70.2)	47 (72.3)	26 (83.9)	0.318
Cardiovascular system	62 (59.6)	42 (64.6)	17 (54.8)	0.634
Central nervous system	59 (56.7)	30 (46.2)	17 (54.8)	0.397
Gastrointestinal system	48 (46.2)	34 (52.3)	16 (51.6)	0.703
Refractory septic shock	20 (19.2)	21 (32.3)	9 (29)	0.138
Physiologic variables at baseline, mean±SD
Mean arterial pressure, (mmHg)	76.12±22.59	74.28±16.52	81.90±28.74	0.278
Pulse rate, (/min)	112.14±20.15	113.88±15.66	110.84±20.58	0.733
Pulse oximeter oxygen saturation, (%)	86.34±19.45	91.2±13.34	90.45±10.39	0.157
Respiratory rate, (/min)	29.57±4.95	29.72±5.26	31.26±8.30	0.337
Serum lactate (mmol/l), median (IQR)	3.10 (2.30-4.41),	2.65 (2.00-5.30)	2.92 (2.00-4.06)	0.806
SOFA, mean±SD	9.89±3.65	9.69±3.73	10.02±3.98	0.623
APACHE II, mean±SD	24.72±6.88	24.66±7.48	25.13±7.08	0.952
Inotrope duration (h), median (IQR)	50.00 (12.00-72.00)	60.00 (48.00-96.00)	42.00 (16.00-80.00)	0.384
Mechanical ventilation (days), median (IQR)	2.00 (1.00-5.50)	6.00 (1.00-13.50)	4.00 (2.00-14.00)	0.754
Hospital stay (days), median (IQR)	9.00 (5.00-14.00)	9.00 (5.00-13.50)	8.00 (3.00-18.00)	0.844
Hospital mortality, n (%)	28 (26.9)	25 (38.5)	13 (41.9)	0.155

SD: Standard deviation, IQR: Interquartile range, SOFA: Sequential organ failure assessment score, APACHE II: Acute physiology and chronic health evaluation score

Table 7

Comparison of various baseline laboratory characteristics among groups with hypoxia, hyperoxia, and normoxia in a study cohort of 200 patients with severe sepsis and septic shock admitted in emergency medical services

Laboratory variables at admission, mean±SD	Hypoxia (n=104)	Normoxia (n=65)	Hyperoxia (n=31)	P
Hb (g/dL)	9.72±2.85	9.63±2.76	9.45±2.45	0.883
RDW (%)	17.63±3.01	18.39±4.28	18.18±3.67	0.500
Serum Na (mEq/L)	134.20±8.61	136.32±9.35	133.84±7.50	0.128
Serum urea (mg/dL), median (IQR)	83.00 (37.25-126.25)	79.00 (39.00-105.00)	69.00 (44.00-119.00)	0.098
Serum creatinine (mg/dL), Median (IQR)	2.30 (0.92-3.70)	2.20 (0.95-4.40)	2.70 (1.62-4.17)	0.562
Serum protein (g/dL)	5.34±1.07	6.20±1.09	6.01±0.93	0.317
Serum albumin (g/dL)	2.89±0.77	2.86±0.80	2.70±0.84	0.521
Serum globulin (g/dL)	3.40±1.02	3.35±0.73	3.27±0.78	0.774
Serum Ca (mg/dl)	8.24±0.71	8.33±0.94	8.28±1.16	0.789
Serum Mg (mg/dl)	1.96±0.46	1.98±0.41	2.01±0.49	0.872
pH	7.37±0.13	7.37±0.12	7.34±0.15	0.468
PaCO2 (mmHg)	33.16±13.54	30.88±8.28	29.97±8.59	0.264
PT (s), median (IQR)	18.00 (16.00-21.00)	18.00 (16.00-22.25)	19.00 (17.75-22.00)	0.419
International normalized ratio, Median (IQR)	1.10 (1.28-1.53)	1.29 (1.08-1.65)	1.32 (1.25-1.50)	0.440
aPTT (s), median (IQR)	30.00 (27.00-35.00)	30.00 (27.00-36.25)	29.50 (27.00-33.50)	0.954

IQR: Interquartile range, PaCO2: Partial pressure of carbon dioxide in arterial blood, SD: Standard deviation, Hb: Hemoglobin, RDW: Red cell distribution width, PT: Prothrombin time, aPTT: Activated partial thromboplastin time, Na: Sodium, Ca: Calcium

Comparison of various characteristics among hypoxia, hyperoxia, and normoxia groups categorized on the basis of baseline ScvO2 level in a study cohort of 200 patients with severe sepsis and septic shock admitted in emergency medical services

SD: Standard deviation, IQR: Interquartile range, SOFA: Sequential organ failure assessment score, APACHE II: Acute physiology and chronic health evaluation score

Comparison of various baseline laboratory characteristics among groups with hypoxia, hyperoxia, and normoxia in a study cohort of 200 patients with severe sepsis and septic shock admitted in emergency medical services

IQR: Interquartile range, PaCO2: Partial pressure of carbon dioxide in arterial blood, SD: Standard deviation, Hb: Hemoglobin, RDW: Red cell distribution width, PT: Prothrombin time, aPTT: Activated partial thromboplastin time, Na: Sodium, Ca: Calcium

The mean ScvO2 at the presentation in the hypoxic group was 49.22 ± 13.19%. The normoxic group had a mean ScvO2 value of 79.48 ± 5.25% and this value for the hyperoxic group was 93.71 ± 4.88%. Out of 104 hypoxemic patients, 28 (26.9%) had hospital mortality. The mean ScvO2 value in 28 nonsurvivors at baseline and after 6 h of resuscitation was 46.21 ± 16.66% and 48.82 ± 18.81%, respectively. Among 76 survivors, the initial mean baseline ScvO2 value was 50.53 ± 11.60%, which improved to 63.68 ± 15.39% after 6 h of resuscitation. Baseline serum lactate level and severity/organ dysfunction score both APACHE II and SOFA at admission were statistically significantly higher in nonsurvivors. Twenty-five (38.50%) patients had hospital mortality among 65 patients with baseline ScvO2 value in the normoxic range. The baseline ScvO2 level was 80.80 ± 5.90%. Among survivors in the normoxic group, the mean ScvO2 level at baseline was 78.65 ± 4.67%. Baseline serum lactate level was significantly higher in nonsurvivors. APACHE II and SOFA score at admission were also significantly higher in nonsurvivors. Hospital mortality figure stood at 13 (41.90%) patients in the hyperoxic group, categorized based on the baseline ScvO2 level. The nonsurvivor group had mean baseline ScvO2 value of 95.15 ± 3.02%, whereas in survivors the corresponding value was 93.89 ± 3.19%. The mean serum lactate value at baseline in the nonsurvivor group was 4.52 ± 2.95 mmol/l, significantly higher as compared to the mean value of 2.89 ± 1.55 mmol/l in the survivor group. Markers of the severity of illness and organ dysfunction, both APACHE II and SOFA score, were significantly higher in nonsurvivors as compared to survivors indicating greater severity of illness among them. The hyperoxia group categorized on the basis of baseline ScvO2 had higher hospital mortality (hyperoxic group = 13/31 [41.90%] vs. hypoxic group = 28/104 [26.90%] vs. normoxic group = 25/65 [38.50%]; P = 0.155) though it was not statistically significant.

DISCUSSION

This single-center prospective observational study analyzed 200 patients with severe sepsis and septic shock admitted in the emergency medical services attached to the Department of Internal Medicine at PGIMER, Chandigarh, India, a tertiary care institution in North-West India. The mean value of the baseline ScvO2 was 65.95 ± 20.70%. The prevalence of patients with ScvO2< 70% (Hypoxic group) at presentation was 52.00% (104/200) and 15.50% (31/200) of patients had ScvO2≥90% at presentation (hyperoxic group). The hyperoxia group categorized based on the baseline ScvO2 had higher hospital mortality though it was not statistically significant.

The mean age of patients recruited in the study cohort was 46.70 ± 17.64 years, much lower than population recruited in three large randomized trials – ARISE, PROCESS, and PROMISE.[8910] In Rivers' trial, as well, the median age of the recruited study cohort was 66 years.[7] The mean SOFA score of study cohort at hospital admission was 9.71 ± 3.68, whereas the mean APACHE II score was 24.77 ± 7.06 in the index study. In Rivers' trial, APACHE II at enrolment in the EGDT group was 21.4 ± 6.90 and in the control group was 20.4 ± 7.4.[7] APACHE II score in PROCESS trial in the EGDT group was 20.8 ± 8.1, in protocol-based therapy was 20.6 ± 7.4, and in usual care group was 20.6 ± 7.4.[8] In ARISE severity of illness score, APACHE II was 15.4 in the EGDT group, whereas it was 15.8 in the control group.[9] Analyzing these data, it is evident that in our index study, patients enrolled had a much higher severity of illness at presentation, even higher than patients recruited in the Rivers' trial. Possible reasons could be the tertiary care referral nature of our institute, type of illnesses, socioeconomic milieu of the patient population, and late presentation.

One of the main objectives of our study was to find out the mean ScvO2 and prevalence of abnormal ScvO2 at presentation. We found that the mean ScvO2 at the presentation of the whole cohort was 65.95 ± 20.7%. In a seminal study, Rivers et al. introduced the EGDT concept to which we alluded to previously. In this study, the mean ScvO2 of the group receiving standard therapy was 49.2 ± 13.3% at baseline, whereas for EGDT group, it was 48.6 ± 11.2%. At the end of 6 h, the mean ScvO2 was still below the 70% mark at 66.0 ± 15.5% in the control group. The group receiving EGDT showed marked improvement in ScvO2 at the end of the 6-h bundle; it was 77.3 ± 10.0% (P< 0.001). The main difference between standard therapy and EGDT in this trial was a time-bound achievement of resuscitation endpoints, especially the ScvO2 level of >70%.[7] However, as time progressed, clinicians started questioning the importance of each element of EGDT. To answer these questions, three large RCTs, PROMISE, PROCESS, and ARISE, were conceptualized and undertaken in various parts of the world. The results of these studies suggest that few interventions of the EGDT therapy (central line insertion, monitoring of ScvO2, inotropes infusion, and blood transfusions to maintain hematocrit >30%) might not have morbidity and mortality benefit. However, on closer analysis of data of these trials, we find that in all of them, baseline ScvO2 was more than 70% (71% in PROCESS, 72.7% in ARISE, and 70.1% in PROMISE trial).[8910] Our index study showed lower ScvO2 as compared to these studies at baseline. As one of the important resuscitation endpoints in previous surviving sepsis campaign (SSC) guidelines was the attainment of ScvO2 to more than 70% by various interventions; however, importantly in these three RCTs, the baseline ScvO2 was more than 70%, the desired level recommended in SSC guidelines. Furthermore, on critically analyzing these trial data, we find that SOFA and APACHE II scores were much lower and the mean lactate levels were also lower as compared to Rivers' trial and our index study. It can, therefore, be inferred that patients recruited in all three trials were less sick and probably they were recruited at the earlier phase of their septic illness as compared to patients recruited in Rivers' and our index study. Therefore, extrapolating the data of these trials done primarily in the developed world in sepsis patients with lesser severity of illness would be tad premature. We suggest that multicentric trials on similar lines should be undertaken in the developing world as well before abandoning ScvO2 measurement and its optimization in managing such patients.

In the index study, the prevalence of hypoxia at presentation in terms of baseline ScvO2 was 52% (104/200). Normoxia was documented in 32.50% (65/200) and hyperoxia in 15.50% (31/200) of patients. The hospital mortality was 26.92% (28/104) in the hypoxic group. It is quite evident that nonsurvivors continued to have lower ScvO2 levels even after 6 h of protocolized endpoint-guided interventions, whereas survivors had shown marked improvement in ScvO2 level after 6 h of resuscitative efforts. Hypoxia or low ScvO2 in these sepsis/septic shock patients is most likely due to macrocirculatory failure. In a prospective multicenter observational study, 363 patients with septic shock admitted in intensive care units (ICUs) were analyzed. One hundred and eleven patients had low initial ScvO2. 28-day mortality was significantly higher in patients with low ScvO2as compared to the group with initial ScvO2≥70% (37.8% vs. 27.4%).[13] In another observational study, it was found that patients with ScvO2< 60% at baseline during ICU admission was associated with increased mortality.[14]

A hyperoxic group is an intriguing group of patients. High ScvO2could be simply due to the delivery of oxygen, which is more than tissue requirements. However, more worryingly, it could be an indicator of decreased cellular consumption of oxygen either due to microcirculatory or mitochondrial failure. Hospital mortality should have been much lower if it was secondary to just the higher delivery of oxygen, which is more than what is required at the cellular level for various metabolic processes, and serum lactate in this scenario should have been lower or normal. Hospital mortality in the hyperoxic group was 41.93% (13/31) in the index study. Interestingly, the mean serum lactate value at baseline was much higher (4.52 ± 2.95 mmol/l) in the group of patients who had hospital mortality as compared to survivors (2.89 ± 1.55 mmol/l) in this hyperoxic group. These findings are indicative of either microcirculatory or mitochondrial dysfunction in this group of patients with hyperoxia. Markers of the severity of illness and organ dysfunction, both APACHE II and SOFA score, were significantly higher in nonsurvivors as compared to survivors, indicating greater severity of illness among them. All these parameters indicate that in this group especially in patients who had hospital mortality, many patients had either a microcirculatory or mitochondrial failure. In a multicentric retrospectively analyzed prospective observational study, Pope et al. analyzed 619 patients in the emergency department with a suspected diagnosis of sepsis. This study aimed to find out whether abnormal (both low and high) ScvO2is associated with increased mortality. Hospital mortality was highest in the group of patients with hyperoxia (31%).[12] In a study undertaken by Textoris et al., a retrospective analysis of 152 patients of septic shock admitted in ICU was done to find out the relation between maximal ScvO2levels (ScvO2max) and survival. The mortality rate in a group of patients with ScvO2max <80% was 30%, and in patients with ScvO2over 80%, the mortality rate was 48%.[15] The association between maximum ScvO2and mortality persisted in a multivariate analysis adjusted for other variables. Patients with hyperoxia based on ScvO2value are thus an important subset of patients, who require closer scrutiny. The microcirculation and mitochondrial function should be monitored in real-time with devices such as orthogonal polarization spectral imaging, sidestream dark-field imaging, and near-infrared spectroscopy. Prognostic importance of hyperoxia provides a possible avenue for future research in this field to find a therapeutic target. Possible therapies which could be researched might be a unique form of resuscitative interventions to normalize microcirculatory flow in real-time using video microscopy and using novel therapies to recruit microcirculatory blood flow. Another therapeutic target could be mitochondrial activity and improve the same by use of novel factors.

Our study has many strengths. It was a prospective observational study of patients with a confirmed diagnosis of severe sepsis and septic shock. All patients were managed under similar settings with a uniform institutional management protocol based on SSC guidelines. We included patients having a wide range of comorbidities and a variety of illnesses.

However, the present study also had certain limitations. As it is a single-center study, conducted in a tertiary care institution, the results may not be generalizable to other health-care institutions. This study included 200 patients, a sample size which may not seem as robust as earlier studies. The index study included only patients admitted to emergency medical services, and hence the results may not be extrapolated to surgical patients with severe sepsis/septic shock. As patient recruitment was not consecutive, the possibility of selection bias might have been introduced. ScvO2was not measured continuously, which might have led to ascertainment bias as we might have missed abnormal ScvO2values.

CONCLUSION

The mean baseline ScvO2was lower in our study cohort. In the hypoxic group, patients with hospital mortality had persistently lower ScvO2level during the first 6 h of resuscitation. Importantly, higher mortality in the hyperoxic group with higher serum lactate emphasizes the point that ScvO2value should be analyzed along with serum lactate levels as complimentary resuscitation endpoints.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Ethical conduct of research

This study was approved by the Institutional Review Board / Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines during the conduct of this research project.