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. Author manuscript; available in PMC: 2020 May 1.
Published in final edited form as: Shock. 2019 May;51(5):580–584. doi: 10.1097/SHK.0000000000001208

Alterations in mitochondrial function in blood cells obtained from patients with sepsis presenting to an emergency department

David H Jang 1, Clinton J Orloski 1, Shawn Owiredu 1, Frances S Shofer 1, John C Greenwood 1,2, David M Eckmann 2,3
PMCID: PMC6292743  NIHMSID: NIHMS974293  PMID: 29905672

Abstract

Objective

Mitochondrial dysfunction has been implicated as a key cellular event leading to organ dysfunction in sepsis. Our objective is to measure changes in mitochondrial bioenergetics in subjects with early presentation of sepsis to provide insight into the incompletely understood pathophysiology of the dysregulated host response in sepsis.

Design

Prospective observational study

Setting

Single site tertiary academic emergency department

Subjects

We enrolled a total of 48 subjects were enrolled in the study, 10 with sepsis or septic shock, 10 with infection without sepsis, 14 older and 14 younger healthy controls.

Interventions

Peripheral blood mononuclear cells (PBMCs) were measured with high-resolution respirometry (OROBOROS O2K).

Measurements and Main Results

The median age in patients with sepsis, infection only, older control and younger controls were 63, 34, 61, and 39 years old, respectively. In the Sepsis group, the median 1st 24-hour SOFA score was 8, and the initial median lactate was 4.2 mmol/dL, compared to 1.1 in the Infection Group. The 30-day mortality of the sepsis/septic shock group was 50%, with a median length of stay of 7-days. The Sepsis Group had significantly lower routine and Max respiration when compared to the other groups as well as uncoupled Complex I respiration. There was also a significant decrease in ATP-linked respiration along with the Spare Reserve Capacity in the Sepsis Group when compared to the other group. There were no age-related differences in respiration between the Older and Younger control group.

Conclusions

Bedside measurement of mitochondrial respiration can be minimally invasive and performed in a timely manner. Mitochondrial dysfunction, detected by decreased oxygen consumption utilized for energy production and depleted cellular bioenergetics reserve.

Keywords: mitochondria, sepsis, respiration

Introduction

Sepsis is a leading cause of mortality in the United States (1). Over half of all cases of sepsis initially present to the emergency department (ED) with the majority requiring admission to an intensive care unit (ICU) (1, 2). In 2016, the Society for Critical Care Medicine (SCCM) and the European Society for Intensive Care Medicine defined sepsis as life-threatening organ dysfunction secondary to a dysregulated host response to infection, which can be quantified by a 2-point increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score (3, 4).

The sepsis syndrome is incompletely understood, whose pathophysiologic mechanisms consists of a wide array of derangements that include exaggerated systemic inflammation, impaired microcirculation, and tissue hypoperfusion leading to the development of multi-organ dysfunction and death. Another mechanism of organ dysfunction in sepsis includes cellular bioenergetic dysfunction. The role of the mitochondria, as a source of ATP production and reactive oxygen species, is being increasingly recognized as playing a critical role in sepsis (5, 6).

Mitochondrial dysfunction may be a key cellular event leading to multi-organ failure (MOF) in sepsis (7–9). Mitochondrial dysfunction has been shown to correlate with disease severity in both animal models and humans (10, 11). Current diagnostic strategies in identifying patients with sepsis rely on clinical presentation and markers of end-organ dysfunction, including lactate and global measurements of tissue oxygen supply and demand, such as ScvO2 and SvO2 (6). The measurement of mitochondrial function in sepsis represents an attractive avenue of research to assess prognosis, disease severity, and a potential opportunity for mitochondrial-directed therapy.

There are relevant instruments that allow sensitive measurement of cellular respiration using patient’s peripheral blood mononuclear cells (PBMCs, a mixed population of lymphocytes and monocytes) or platelets, with results available within one to two hours which could be used to monitor response to therapy and to help develop treatment (12, 13). Mitochondrial studies performed using human PBMCs offer a practical alternative to invasive tissue biopsies, and previous data demonstrate that a strong correlation exists between mitochondrial dysfunction in blood cells and in heart, liver, and kidney in humans and animal shock models (14, 15). There are a number of studies performed on patients with sepsis admitted to the ICU well after the acute resuscitation phase (11, 16, 17). It is established that immune cells undergo activation in response to infection but are often down-regulated soon afterward in the prolonged phase where multi-organ dysfunction occurs. It is not clear the changes in mitochondrial respiration that may occur in early presentation of sepsis.

The application of measuring cellular bioenergetic function in patients with early presentation of sepsis from the ED is limited (18, 19). The purpose of this study is to evaluate cellular respiration in early presentation of sepsis through the ED prior to initial resuscitation.

Materials and Methods

The University of Pennsylvania’s Institutional Review Board approved this study and informed consent was obtained from all patients or appropriate surrogates. This was a four-group, controlled study performed from January 2016 to April 2018 at a single academic, tertiary care center. All patients 18 years and older who presented to the ED with suspected sepsis were screened for enrollment. Patients were screened for eligibility within the first hour of arrival to the ED. Screening criteria for inclusion were: (1) had 2 of 4 of the systemic inflammatory response syndrome (SIRS) criteria, (2) a suspected or known source of infection, (3) lactate greater than 2.0 mg/dL, (4) had not yet received intravenous fluids or antibiotics. Patients were excluded if they (1) had a white blood cell count <0.5 × 103/μL, (2) cyanotic heart disease, (3) pregnant or lactating. The four study arms include: (1) Sepsis group: Includes sepsis or septic shock, defined using Sepsis-3 definitions; (2) Infection group: Subjects with infection but without organ dysfunction; (3) Older control group: Healthy older subjects; (4) Younger control group: Healthy younger subjects.

All enrolled patients underwent phlebotomy with volumes of 15 ml drawn in K2EDTA tubes, as this has resulted in the best yield and prohibits platelet activation. Blood samples were freshly prepared and analyzed within 1 hour of blood draw. We obtained a population of PBMCs from the plasma buffy coat using a combination of Ficoll-PaqueTM PLUS (GE) and Leucosep tubes (Greiner Bio-one) and centrifugation at room temperature. A cell count and viability with trypan blue exclusion was performed with the Cell Countess II (Invitrogen). Unless otherwise specified, all reagents were obtained from Sigma-Aldrich and Invitrogen.

The measurement of respiration in PBMCs was evaluated with a series of chemical injections known as a substrate-uncoupler-inhibitor titration (SUIT) protocol performed in MiR05 buffer. Initially, PBMCs were left to stabilize at a routine respiration state, revealing resting cellular energy demands on oxidative phosphorylation. To evaluate the contribution of respiration independent of ADP phosphorylation, oligomycin (2.5 μM) was added inducing LEAK respiration state that represents the dissipative component of respiration not available for performing biochemical work. Maximal capacity of the mitochondrial electron transport system, also known as maximal respiration or Max, was measured after careful titration of the protonophore, carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (CCCP (0.5 μM steps)) until no further increase in respiration was detected. Rotenone (2 μM) and antimycin-A (2.5 μM), which are Complex I (CI) and Complex III (CIII) inhibitors, respectively, were then sequentially added to completely inhibit respiration providing the residual oxygen consumption (ROX) or non-mitochondrial respiration. ROX then was subtracted from the different respiratory parameters for further analyses. Finally, we calculated the difference of Max and routine respiration to obtain the Spare Respiratory Capacity (SRC), which is considered a reflection of a cell’s reserve capacity to deal with increased cellular demand or stress. We also calculated respiration linked to ATP synthesis as the difference between routine and LEAK following injection of oligomycin. We then performed a specialized protocol in PBMCs to evaluate specific complex-linked activity for each group using digitonin based on our previous work (20, 21).

Study data were collected and managed using REDCap electronic data capture tools hosted at the University of Pennsylvania. Variables collected include patient demographics, laboratory and radiographic data, respiratory support, medications administered, ED length of stay (LOS), hospital LOS, and survival at 30 days. Severity of illness was estimated using the Sequential Organ Function Assessment (SOFA) score. Given this was an ED study, the quick SOFA (qSOFA) score was also assessed and recorded.

Statistics for mitochondrial bioenergetics were calculated by using GraphPad Prism v.7 (GraphPad Software Inc.). Data were tested for normal distribution with the D’Agostino and Pearson omnibus normality test. Data are presented as mean ± SD if not indicated otherwise. Differences between all groups were assessed using ANOVA in repeated measures. Post-hoc pairwise comparisons using Tukey Kramer t-tests to adjust for multiple comparisons were used to assess differences between groups and respiratory states. A P value of <0.05 was considered statistically significant.

Results

A total of 48 subjects were enrolled in the study, 10 with sepsis or septic shock, 10 with infection without sepsis, 14 healthy older controls and 14 healthy younger controls. Patient demographics and clinical characteristics of the entire cohort are described in Table 1. The median age in the Sepsis, Infection, Older control, and Younger control groups were 63, 34, 61 and 29 years old, respectively. In the Sepsis group, the median 1st 24-hour SOFA score was 8, and the initial median lactate was 4.2 mmol/dL, compared to 1.1 in the Infection Group. The 30-day mortality of the Sepsis group was 50%, with a median hospital length of stay of 7 days.

Table 1.

Characteristics of subjects

Characteristics Sepsis group
(n=10)		 Infection group
(n=10)		 Older/Younger control group
(n=28)
Age (IQR) 63
(54, 77)		 34
(28, 64)		 61/29
(56/25, 72/38)
Sex (male/female) 4/6 6/4 7/7 and 7/7
Source of Infection
 Pneumonia 3 4 -
 Urinary 1 2 -
 Skin 3 - -
 Abdominal 3 1 -
 Viral - 3 -
MAP 62
(56, 69)		 79.2
(71.3, 103.6)		 -
WBC 13
(6, 15)		 11.7
(9.4, 14.9)		 -
Platelet 164
(70, 180)		 208
(177, 276)		 -
Creatinine 1.34
(0.91, 1.75)		 0.97
(0.84, 1.02)		 -
1st 24-hour SOFA score 8
(7, 11)		 0
(0, 1)		 0
(0, 0)
qSOFA score 3
(2, 3)		 0.5
(0.0, 1.0)		 0.0
(0.0, 0.0)
SIRS 3
(3, 4)		 2
(2, 3)		 0.0
(0.0, 0.0)
Lactate 4.2
(3, 12)		 1.1
(0.7–2.3)		 0.0
(0.0–0.0)
In-hospital length of stay (days) 7
(3, 12)		 2
(0, 5)		 0
30 day mortality 50% 0% 0%
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*

Data are number of patients or median (interquartile range).

MAP, mean arterial pressure; WBC, white blood cell; SOFA, sequential [sepsis-related] organ failure assessment; qSOFA, quick SOFA; SIRS, systemic inflammatory response syndrome.

We compared mitochondrial respiration in PBMCs obtained from subjects in all four groups. All the units of respiration were measured in pmol O2·s−1·10−6 cells. All values reported as the mean ± SD. All respiration measurements can be seen in Table 2. The Sepsis group had significantly lower routine and Max respiration when compared to the other groups as seen in Figure 1.

Table 2.

Mitochondrial Respiration (pmol O2 · s−1 · 10−6 PBMCs)

Mitochondrial Respiration (pmol O2 • s−1 • 10−6 PBMCs)
Sepsis group Infection group Older control group Younger control group
Respiratory State Mean SD Mean SD Mean SD Mean SD
Routine 8.20 3.56 20.79 5.07 20.81 2.53 19.76 2.11
LEAK 1.90 0.94 5.05 3.64 2.20 0.88 1.90 0.72
Max 10.67 2.76 33.48 11.09 41.87 6.91 34.33 10.32
ROX 1.54 0.91 2.42 1.26 1.16 0.54 1.19 0.83
Uncoupled Complex I 18.54 5.62 34.00 10.17 43.38 11.52 43.14 12.62
Complex IV 58.20 24.41 66.92 30.65 68.50 11.79 67.47 13.39
ATP-Linked 6.29 3.38 15.75 6.25 18.61 2.47 17.86 1.96
Spare Respiratory Capacity 4.19 2.44 12.70 8.03 21.06 5.76 19.14 4.32
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Figure 1. Mitochondrial respiration in intact PBMCs.

Figure 1

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Mitochondrial respiration obtained in intact PBMCs. Values presented as mean ± SD.

*P < 0.0001 compared to both other groups.

Both ATP-linked respiration and SRC were calculated for all groups. Figure 2 demonstrates that there was a significant decrease in ATP-linked respiration in the Sepsis group when compared to the other groups. There was also a significant decrease in SRC in the Sepsis group when compared to the other groups.

Figure 2. ATP-linked respiration and Spare Respiratory Capacity.

Figure 2

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Results are shown in box-and-whisker plots showing median (horizontal line), interquartile range (box) and range (whiskers) for each condition.

*P < 0.05 Sepsis group compared to all other groups.

The additional measures of respiration in permeabilized PBMCs provide more detailed respiratory states as seen in Figure 3. There was a significant decrease in uncoupled CI respiration in the Sepsis group when compared to the other groups. There were no significant differences in the other respiratory states measured, including Complex II (CII), Complex IV (CIV) and LEAK.

Figure 3. Mitochondrial respiration in permeabilized PBMCs.

Figure 3

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Complex-linked activity was obtained in permeabilized PBMCs. There were no statistically difference in uncoupled CII, LEAK, and ROX (not pictured). Values presented as mean ± SD.

*P < 0.05 Sepsis group compared to all other groups.

Discussion

In a cohort of 48 ED patients, we compared mitochondrial respiration in PBMCs between those with sepsis (including septic shock), infection without sepsis, and healthy older and younger controls. This study examines cellular respiration in early presentation of sepsis as samples were obtained prior to resuscitative efforts such as fluid challenges or antibiotic administration. The key findings of this study are that PBMCs obtained from subjects in the Sepsis group when compared to the other three groups exhibited an overall decrease in mitochondrial respiration. In addition, the overall decrease in respiration may be related to a decrease in uncoupled CI respiration in the Sepsis group.

Alterations in oxygen consumption are reported in both clinical and experimental models of sepsis. These alterations in oxygen utilization indicate the importance of the mitochondria in the pathophysiology of sepsis (11). The majority of studies report derangements in energy production in samples obtained from patients in the ICU, well after the initial resuscitation of these patients from the emergency department. Important alterations include an increase in cytokine and nitric oxide levels in sepsis along with increased respiration which may be a reflection of mitophagy that occurs in the later phase of sepsis (22, 23). One study explored the role serum obtained from patients with sepsis may have on mitochondrial function in fibroblast cells. There was a significant decrease in cellular respiration along with increased hydrogen peroxide production and elevated serum cytokine levels such as IL-6. Another study incubated HK-2 cells (derived from adult human kidneys) in fresh medium containing LPS from Escherichia coli 055:B5 and found an increase in nitric oxide and superoxide anion with a decrease in mitochondrial function (24).

PBMCs obtained from the Sepsis group demonstrated a significant decrease in routine respiration. Routine respiration represents the combination of ATP generation with ATP synthase and LEAK which represents the dissipative component of respiration. The difference between the routine respiration and LEAK provides insight into the ATP producing capacity of the cell and how it may be affected in acute illnesses such as sepsis. Our data illustrate that PBMCs in the Sepsis group have lower ATP-linked respiration, which is likely the result of multiple causes including mitochondrial damage, excessive ROS/RNS production, and mitochondrial inhibition (25). A reduction in ATP-linked production in sepsis may be related to problems with oxygen utilization. It has been demonstrated that there is impaired oxygen delivery due to microcirculation dysregulation (26,27).

There was a significant reduction in SRC in the Sepsis group when compared to the other groups. Under normal conditions, cells with a low SRC may function well until faced with a stress response such as an infection. During these periods of stress, the combination of increased metabolic demand and decreased reserve can result in cellular dysfunction (28). Medical resuscitation in patients with sepsis involves augmenting hemodynamics to increase oxygen delivery to help meet metabolic demands. PBMCs that fail to meet the metabolic demands during sepsis may exhibit immune dysregulation that contributes to a failure of the host response to sepsis (9). While this is a small study sample, further work in this area needs to explore the utility of using a cell’s SRC to monitor illness severity and response to treatment. Ultimately, measuring mitochondrial function may serve as a better marker of sepsis identification and disease severity compared to other biomarkers such as lactate and oxygen balance.

We also performed a comprehensive analysis of various respiratory states in permeabilized PBMCs. In addition to an overall decrease in respiration found in the Sepsis group, we found specifically that there was a significant decrease in uncoupled CI-linked respiration. The finding of decreased CI respiration is consistent with other studies that found down regulation of CI activity in critically ill patients (29). An increase in nitric oxide (NO), mediated by inducible nitric oxide synthase causing the formation of peroxynitrate appears to play a key role in CI inhibition (25, 30). Others have postulated that a decrease in ADP and antioxidants may impair CI activity, which was found using muscle biopsies from septic patients (31). We believe the use of PMBCs is preferable to direct tissue biopsy, as it allows for repeated measures and is also minimally invasive. In our study we found no difference in CIV or CII respiration, which is in contrast to other’s who have found a down regulation of both CIV and CI in patients with sepsis but may be due to tissue type (26).

One of the strengths of our study is the enrollment of subjects with early presentation of sepsis. Samples were obtained prior to any clinical interventions such as administration fluids, antibiotics, and pressor support that may confound the interpretation of baseline respiration prior to the initiation of care. Our results support the concept that mitochondrial dysfunction occurs early in sepsis, which may persist many days after initial resuscitation (31). Another strength in our study was the inclusion of a healthy older control and younger control group as our Sepsis group was older than the Infection group. One of the potential causes of the differences in key respiratory state seen between the Sepsis and Infection group may be due to age-related changes in the mitochondria. With advanced age there are multiple changes that occur in the mitochondria that include loss of mitochondrial DNA volume, increased mutations, and oxidative stress (32). We compared respiration between the Older and Younger control group and found no difference (P = 0.99). This eliminates that the differences in respiration seen in the Sepsis and Infection group when compared to both Control groups is likely an effect of age. A final strength of our work is the rapid turnaround of mitochondrial results which has strong clinical applicability in terms of being able to obtain potential clinical data to gauge severity of disease, response to treatment as well as the development of potential mitochondrial-directed therapy based on mechanism (33).

Limitations

There are important limitations to consider when interpreting the results of this study. One of limitation of this study was that we did not explore the effect of mitogenesis on respiration. Serial measurements would help better classify changes in mitochondrial respiration and behavior with treatment. Another limitation of this study is the connection between the use of human blood cells as a marker of mitochondrial function in vital organs such as the brain and kidney. Different organs have varying metabolic requirements may respond differently to a varied inflammatory host response. Limited study comparing blood mitochondrial function between shock states has been performed to date.(14, 15) The advantage of using blood cells as a measure of organ mitochondrial function is very attractive from both a clinical and research perspective as PBMCs are easily accessible and are obtained with minimal invasiveness. Moreover, repeat measures can be obtained to follow mitochondrial function over time and in response to treatment.

Conclusions

We used PBMCs to demonstrate that subjects with early presentation of sepsis have an overall decrease in the key parameters of respiration such as routine, Max and uncoupled CI respiration when compared to our other groups.

Acknowledgments

This work was funded:

  • NIH grant K08HL136858 (DHJ)

  • Office of Naval Research grant N000141612100 (DME)

  • Penn Acute Research Collaboration (DHJ and JCG)

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