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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 4  |  Page : 1177-1184

Assessment of the central venous-to-arterial carbon dioxide tension difference (pCO2 delta) in adult patients with sepsis: a systematic review


1 Department of Anaesthesia and Intensive Care, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Anaesthesia and Intensive Care, Mehalla General Hospital, Al Gharbia, Egypt

Date of Submission15-Dec-2018
Date of Decision05-Jan-2019
Date of Acceptance08-Jan-2019
Date of Web Publication31-Dec-2019

Correspondence Address:
Ahmed A. M Abd El Aziz
Mehalla City, Al Gharbia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_406_18

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  Abstract 


Objective
The aim was to review studies that assessed the central venous-to-arterial carbon dioxide tension difference (pCO2 delta) in septic adult patients, published between 1990 and 2016 in the MEDLINE (PubMed, Medscape, and Science Direct) and EMF-Portal, and methodological quality was evaluated.
Materials and methods
A systematic search of MEDLINE (PubMed, Medscape, and Science Direct), EMF-portal, and Internet was conducted on all articles published from 1990 to 2016. English-language reports of pCO2 delta in patients with sepsis were reviewed. The initial search presented 135 articles, where 30 fulfilled the inclusion criteria. Articles not reporting on pCO2 in patients with sepsis in the title or abstract were not included. A total of 11 independent investigators extracted data on methods. Comparisons were made by structured review, with the results tabulated. Ten studies emphasized old and new definitions of sepsis, pCO2 delta, and mortality; seven about pCO2 delta and tissue perfusion variables; seven about pCO2 delta and cardiac output; and nine about pCO2 delta and therapeutic interventions.
Findings
High pCO2 delta values were seen to be associated with poorer clinical outcomes, including worsened hemodynamic parameters, poorer tissue perfusion, and greater in-hospital mortality and mortality after 28 days. Higher serum lactate levels and lower SvcO2 values were seen when the patients presented with pCO2 delta greater than 6 mmHg, compared with those showing pCO2 delta less than 6 mmHg. The usefulness of pCO2 delta alone or other tissue perfusion variables for assessing tissue perfusion in sepsis and septic shock is limited.
Conclusion
Delta pCO2 is a valuable complementary tool to guide tissue perfusion in sepsis and septic shock with previous tissue perfusion variables, but this pCO2 delta parameter is not enough alone to detect tissue perfusion and or to be used alone as a marker of prognosis in severe sepsis and septic shock.

Keywords: arterial carbon dioxide, central venous, management, mortality, sepsis


How to cite this article:
Ahmed AE, Mohamed YI, Gaballah KM, Abd El Aziz AA. Assessment of the central venous-to-arterial carbon dioxide tension difference (pCO2 delta) in adult patients with sepsis: a systematic review. Menoufia Med J 2019;32:1177-84

How to cite this URL:
Ahmed AE, Mohamed YI, Gaballah KM, Abd El Aziz AA. Assessment of the central venous-to-arterial carbon dioxide tension difference (pCO2 delta) in adult patients with sepsis: a systematic review. Menoufia Med J [serial online] 2019 [cited 2020 Feb 16];32:1177-84. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1177/274272




  Introduction Top


Sepsis is a clinical syndrome that arises when a patient reacts adversely to an infection and develops organ dysfunction as a consequence. Sepsis is recently defined as a dysregulated host response to an infection, causing life-threatening organ dysfunction [1]. Sepsis is one of the main causes of admission to ICUs. This heterogeneous and complex syndrome can result in a 20–50% mortality rate, depending on the severity of the clinical condition, which in turn is conditioned to the presence of organ dysfunction mediated by different mechanisms of cell damage [2]. The way in which the different individual mechanisms interact is not fully understood, though sepsis is known to involve microvascular anomalies and a decrease in oxygen supply and/or deficient utilization of the available oxygen, which constitutes a central element of such organ dysfunction. The early identification of tissue damage is therefore crucial in the management of these patients [3]. The measurement of certain physiological variables for assessing tissue perfusion status has been proposed in the initial care of such patients. Surviving Sepsis Campaign recommended the measurement of venous oxygen saturation (SvO2), evaluated as mixed venous saturation or central venous oxygen saturation (SvcO2), and lactate concentration in this respect, with the definition of a series of target values intended to secure adequate patient resuscitation [4]. This proposal was essentially based on the early intervention protocol published by Rivers and colleagues, advocating the 'normalization' of SvcO2, central venous pressure, and mean arterial pressure, with the purpose of improving tissue perfusion. Other investigators, fundamentally Jones et al. [5], reinforced the idea that lactate can also be used in protocols of this kind [5]. In recent years, some studies have reported the inverse correlation between central venous-to-arterial carbon dioxide differenceP(cv-a) CO2 and cardiac index (CI) in patients with sepsis [6]. Carbon dioxide produced by peripheral tissues is removed by venous blood; therefore, reduced blood flow develops anaerobic metabolism causing elevation ofP(v-a) CO2. Experimental studies have suggestedP(cv-a) CO2 could be used as a marker of tissue hypoxia [7]. Unfortunately, the measurement ofP(cv-a) CO2 requires pulmonary artery catheter insertion, which is seldom utilized now [8]. Central venous-to-arterial carbon dioxide difference [P(cv-a) CO2] as an estimate ofP(v-a) CO2, is derived from the insertion of central venous catheter that has been applied to most patients with septic shock [8]. AsP(cv-a) CO2 potentially represents a more accessible parameter thanP(v-a) CO2, P(v-a) CO2 has also been investigated regarding its possibility to assess tissue hypoperfusion. Cuschieri et al. [9] showed a strong agreement betweenP(v-a) CO2 and [P(cv-a) CO2], and found [P(cv-a) CO2] and CI also present inverse correlation [9]. Therefore, the aim of this work was to review studies that assessed the central venous-to-arterial carbon dioxide tension difference (pCO2 delta) in adult patients with sepsis.


  Materials and Methods Top


Data sources

A systematic search was carried out on the central venous-to-arterial carbon dioxide tension difference [P(cv-a) CO2] as a marker of tissue perfusion and prognosis in sepsis and septic shock. A search using MEDLINE (PubMed, Medscape, Science Direct), EMF-portal, and internet was conducted on all articles published from 1990 to 2016. The research focused on old and new definitions of sepsis/pCO2 delta, mortality/pCO2 delta, tissue perfusion variables/pCO2 delta, and cardiac output or CI/pCO2 delta and therapeutic interventions. Additional records were identified by reference lists in retrieved articles. The search was established in the electronic databases from 1990 to 2016.

Study selection

Eligible articles were published in peer-reviewed journals and written in English. Articles not reporting on the central venous-to-arterial carbon dioxide tension difference [P(cv-a) CO2] in patients with sepsis in the title or abstract were not included. Full-text articles were screened, and the final inclusion decisions were made according to the following criteria: original studies; systematic reviews or meta-analyses; primary or first-line treatment and, if necessary, secondary treatment described; and treatment success, complications, and adverse effects described.

Data extraction

Articles not reporting on the central venous-to-arterial carbon dioxide tension difference in patients with sepsis in the title or abstract were excluded. A total of 11 independent investigators extracted data on methods, health outcomes, and traditional protocol. Surveys about symptoms and health without exposure assessment, report without peer-review, not within national research program, letters/comments/editorials/news, and studies not focused on exposure from the prevalence of nocturnal enuresis were excluded.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid [10].

US Preventive Services Task Force classification is as follows [10]:

  1. Level I: evidence obtained from at least one properly designed randomized controlled trial
  2. Level II-1: evidence obtained from well-designed controlled trials without randomization
  3. Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
  4. Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
  5. Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.


Study quality assessment

Quality of all the studies was assessed. Important factors included study design, ethical approval, calculation of evidence power, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured systematic review was done with the results tabulated. Ten studies emphasized the old and new definitions of sepsis, pCO2 delta, and mortality; seven about pCO2 delta and tissue perfusion variables; seven about pCO2 delta and cardiac output or CI; and nine about pCO2 delta and therapeutic interventions.


  Results Top


Study selection and characteristics

A systematic search was carried on on the central venous-to-arterial carbon dioxide tension difference (pCO2 delta) in patients with sepsis. The search using MEDLINE (PubMed, Medscape, and Science Direct), EMF-Portal and internet was conducted on all articles published from 1990 to 2016. Articles not reporting on venous-to-arterial difference of carbon dioxide with mortality, tissue perfusion variables, cardiac output or CI as well as therapeutic interventions in the title or abstract were not included. A total of 11 independent investigators extracted data on methods, health outcomes, and traditional protocol. Potentially relevant publications were identified; 135 articles were excluded as they are away from our inclusion criteria. A total of 33 studies were reviewed, as they met the inclusion criteria. Ten studies reported about the old and new definitions of sepsis, pCO2 delta, and mortality; seven about pCO2 delta and tissue perfusion variables; seven about pCO2 delta and cardiac output or CI; and nine about pCO2 delta and therapeutic interventions.

Regarding these studies, five cases analysis studies [11],[12],[13],[14],[15],[16] were in the second level regarding the pyramid of EBM and revealed that definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology, management, and epidemiology of sepsis, suggesting the need for reexamination. Moreover, the importance of percentage lactate clearance, even as a resuscitation goal, has been documented in both sepsis and general critical patient population. A prospective study [2] was in level II-2 or level B; we found that high pCO2 delta values were seen to be associated with poorer clinical outcomes, including worsened hemodynamic parameters, poorer tissue perfusion, and greater in-hospital mortality and mortality after 28 days. Moreover, four randomized control studies [5],[8],[10],[14] were in level I or level A and reported that regarding mortality, the importance of the serial determination of pCO2 delta in terms of its prognostic usefulness must be underscored. The studies offering data referred to serial measurements found the second measurement of pCO2 delta to be more closely correlated with mortality than the first measurement [Table 1]. Additionally, two randomized control studies [17],[18] were in level I or level A and reported higher serum lactate levels and lower SvcO2 values when the patients presented with pCO2 delta greater than 6 mmHg, compared with those showing pCO2 delta less than 6 mmHg. Moreover, two case analyses [15] were in the second level regarding the pyramid of EBM and found no statistically significant differences for lactate, though mixed venous oxygen saturation was found to be lower in the high pCO2 delta group. Moreover, three prospective studies [8],[19],[20],[21]. were in level II-2 or level B and showed a decrease in lactate between 0 and 12 h of −38 ± 39 versus −17 ± 33%, respectively, and the decrease in lactate between 0 and 6 h to be 33.3 ± 28.9 versus 7.8 ± 41.2, respectively [Table 2]. Moreover, there were two cases analysis studies [15],[22] in the second level regarding the pyramid of EBM, and they showed that an expected inverse relationship between the two variables, though some recorded low (but still statistically significant) correlation or determination coefficients between them, with additional important dispersion of the analyzed points. Four prospective studies [8],[19],[20],[23] were in level II-2 or level B, and these reported that patients whoseP(cv-a) CO2 was greater than 6 mmHg always presented greater lactate level than whoseP(cv-a) CO2 was less than 6 mmHg, and CI and ScvO2 were lower in patients whoseP(cv-a) CO2 was greater than 6 mmHg than patients withP(cv-a) CO2 less than 6 mmHg. Insufficient CI would lead to hypoxia because of low flow state, and the shortage of blood flow cannot take CO2 away from tissue, which would elevateP(cv-a) CO2. Also, one randomized case–control study [24] comes to level I or (level A) and reported that patients whoseP(cv-a) CO2 greater than 6 mmHg always present greater lactate level than whoseP(cv-a) CO2 less than 6 mmHg, and CI, ScvO2 lower than patients thatP(cv-a) CO2 less than 6 mmHg. Insufficient CI would lead to hypoxia because of low flow state [Table 3] and [Table 4]. Moreover, two randomized case–control study [18] were in level I or level A and reported fluid or inotropic drug administration to exert a positive effect upon the variable. This is important, as prior knowledge of how pCO2 delta can be modified is relevant when constructing a management algorithm for these patients in the context of clinical studies evaluating pCO2 delta as a resuscitation goal in patients with septic shock. However, four prospective studies [8],[19],[25] were in level II-2 or level B, and these reported that the Cv-aCO2/Da-vO2 ratio is a variable that can identify patients with anaerobic metabolism under different critical conditions, including septic shock. This variable therefore might also be of clinical relevance in the management of patients with sepsis. Beside, two cohort studies [15] were in the second level regarding the pyramid of EBM and reported that one such method involves sidestream dark-field sublingual video microscopy, which affords different parameters for assessing the microcirculation. This system has been used to document different microcirculatory alterations in patients with septic shock, and the improvements obtained as a result of certain interventions.
Table 1: Old and new definitions of sepsis as well as the venous-to-arteria difference of carbon dioxide and mortality

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Table 2: The venous-to-arterial difference of carbon dioxide and tissue perfusion variables

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Table 3: The venous-to-arterial difference of carbon dioxide and cardiac output or cardiac index

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Table 4: The venous-to-arterial difference of carbon dioxide and therapeutic interventions

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  Discussion Top


Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. Singer et al. [11] and Vincent et al. [12] reported that old definition of sepsis is SIRS + suspected infection. The 2012 definition required suspected infection and presence of some of the following: general variables, inflammatory variables, hemodynamic variables, organ dysfunction variables, and tissue perfusion variables. However, the new definition involves suspected or documented infection and increase in SOFA score by greater than 2 or for out-of-ICU patients, two of three criteria for quick SOFA score [11],[12]. Moreover, Shankar-Hari et al. [13] reported old definition of severe sepsis is a complex of the following: sepsis-induced tissue hypoperfusion or organ dysfunction, sepsis-induced hypotension, lactate above upper limits of laboratory normal, urine output less than 0.5 ml/kg/h for greater than 2 h despite adequate fluid resuscitation, acute lung injury with PaO2/FiO2 less than 250 in the absence of pneumonia as infection source, creatinine greater than 2.0 mg/dl, bilirubin greater than 2 mg/dl, platelet count less than 100.000 μl, and coagulopathy with INR greater than 1.5. However, in the new definition, the term severe sepsis has been discarded [12],[13]. Old definition of septic shock involves sepsis + hypotension despite adequate fluid resuscitation. However, the new definition of septic shock involves sepsis + vasopressor requirement to maintain mean arterial pressure greater than 65 and lactate greater than 2 mmol/dl despite adequate fluid resuscitation. The studies generally showed high pCO2 delta values to be associated to poorer clinical outcomes, including worsened hemodynamic parameters, poorer tissue perfusion, and greater in-hospital mortality and mortality after 28 days in sepsis and septic shock [2]. Regarding mortality, the importance of the serial determination of pCO2 delta in terms of its prognostic usefulness must be underscored. The studies offering data referred to serial measurements found the second measurement of pCO2 delta to be more closely correlated to mortality than the first measurement [10]. Although different studies have shown both SvO2 and lactate, considered individually, to be of prognostic value in terms of mortality [5],[10],[11], the recording of pCO2 delta appears to offer additional information. This was seen in three studies that analyzed patients who were able to reach adequate SvO2 goals after 6 h of resuscitation, in which the presence of a normal pCO2 delta was seen to imply a better prognosis. This may indicate the usefulness of serial measurements during the initial resuscitation of patients with septic shock, where first the SvO2 goal is reached, followed by the achievement an additional target based on pCO2 delta. The cutoff point of 6 mmHg for stratifying the two groups (normal and high pCO2 delta) was quite consistent in all the studies – the publication of Bakker and colleagues Vincent JL [12] generally being taken as the reference in recording this parameter. However, it must be noted that the importance of serial measurements has been best established in the case of lactate concentration. In this regard, the importance of percentage lactate clearance, even as a resuscitation goal, has been documented in both sepsis and the general critical patient population [13]. Moreover, several studies evaluated pCO2 delta in relation to other tissue perfusion variables. Arnold R et al. [14] and Bakker et al. [15] recorded higher serum lactate levels and lower SvcO2 values when the patients presented pCO2 delta greater than 6 mmHg, compared with those showing pCO2 delta lesss than 6 mmHg, whereas Bakker et al. [12] reported no statistically significant differences for lactate, though mixed venous oxygen saturation was found to be lower in the high pCO2 delta group. Jansen TC et al. [16] classified their patients according to the pCO2 delta value upon admission and after 6 h. The group with persistently elevated pCO2 delta (high after 0 and 6 h) showed greater lactate values compared with the patients who normalized their pCO2 delta value (high at 0 h and normal after 6 h). Three studies [8],[17],[18] found the percentage decrease in lactate concentration to be greater in the presence of pCO2 delta less than 6 mmHg. Beest PA et al. [17] recorded a decrease in lactate between 0 and 12 h of −38 ± 39 versus −17 ± 33% (P = 0.04), respectively, whereas Mallat et al. [8] found the decrease in lactate between 0 and 6 h to be 33.3 ± 28.9 versus 7.8 ± 41.2. In turn, Zhao HJ et al. [18] classified their patients according to the SvcO2 target value and pCO2 delta after 6 h. In the patients who reached the SvcO2 target, lactate clearance was greater in the subgroup with normal pCO2 delta versus the patients with high pCO2 delta, whereas no such differences were noted in the group that failed to reach the SvcO2 targets [18]. Taking into account that the increase in pCO2 delta is related to low flow states and the consequent accumulation of CO2, a series of studies evaluated the association of this parameter to CI. These publications generally recorded an expected inverse relationship between the two variables, though some recorded low correlation or determination coefficients between them with additional important dispersion of the analyzed points [12],[13],[14],[15],[16],[17],[18],[19]. On the contrary, two studies reported no such relationship [16],[17],[18],[19],[20]. The aforemention finding may reflect the physic pathological complexity in interpreting pCO2 delta elevation in the context of these patients, as well as the evident individual variability found. As a result, the usefulness of pCO2 delta in indirectly assessing CO may prove inconsistent. The normal range ofP(cv-a) CO2 is 2–5 mmHg, and over 6 mmHg would indicated inadequate cardiac output and tissue hypoperfusion [8]. Although ScvO2 values were higher than 70% in all 30 cases of ScvO2 group, 12 (40%) patients hadP(cv-a) CO2 greater than 6 mmHg, which indicated tissue hypoperfusion of those patients. This is consistent with the reports of Du W et al. [21] and in agreement with reports which found thatP(cv-a) CO2 has a negative relationship with CI [12],[21]. Moreover, this may have contributed to the higher CI of ScvO2+P(cv-a) CO2 group. In other research, patients whoseP(cv-a) CO2 was over 6 mmHg always present greater lactate level than whoseP(cv-a) CO2 was less than 6 mm Hg, and CI and ScvO2 were lower than patients havingP(cv-a) CO2 less than 6 mmHg [17]. Insufficient CI would lead to hypoxia because of low flow state, and the shortage of blood flow cannot take CO2 away from tissue, which would elevateP(cv-a) CO2 [17]. In addition to its prognostic implications, Zhao et al. [15] evaluated the effect of therapeutic interventions upon pCO2 delta, showing fluid or inotropic drug administration to exert a positive effect upon the variable. This is important, as prior knowledge of how pCO2 delta can be modified is relevant when constructing a management algorithm for these patients in the context of clinical studies evaluating pCO2 delta as a resuscitation goal in patients with septic shock [15]. Despite the evidence found, different authors have addressed the limitations of this variable in evaluation of tissue hypoperfusion. In effect, pCO2 delta may be normal in cases of evident hypoperfusion and high CO, and may also be elevated in the absence of hypoperfusion, taking into account the Haldane effect [16]. The Cv-aCO2/Da-vO2 ratio is a variable that can identify patients with anaerobic metabolism under different critical conditions, including septic shock [22],[23],[24]. This variable therefore might also be of clinical relevance in the management of patients with sepsis. New methods for more directly evaluating tissue perfusion have been developed in recent years [26]. One such method involves sidestream dark-field sublingual video microscopy, which affords different parameters for assessing the microcirculation. This system has been used to document different microcirculatory alterations in patients with septic shock, and the improvements obtained as a result of certain interventions [12],[25]. However, the use of this technology at the patient bedside faces many challenges, and its relevance in the management of patients of this kind remains to be established. This explains why the aforementioned easily measurable parameters are still considered to be valid.


  Conclusion Top


This review concluded that higher delta pCO2 values have been correlated to poorer clinical outcomes including lower CI, lower ScvO2, higher lactate levels, lower lactate clearance rates, and higher mortality rates in patients with severe sepsis and septic shock. Moreover, P(cv-a) CO2 is a valuable complementary tool to guide tissue perfusion in sepsis and septic shock with previous tissue perfusion variables, but this delta pCO2 parameter is not enough alone to detect tissue perfusion and/or to be used alone as a marker of prognosis in severe sepsis and septic shock.

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Conflicts of interest

There are no conflicts of interest.



 
  References Top

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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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