Monitoring Microcirculatory Blood Flow during Cardiopulmonary Bypass in Paediatric Cardiac Surgery Patients as a Predictor for Anaerobic Metabolism

Tissue hypoxia due to low cardiac output or CPB induced inflammatory response is an important predictor of multiorgan failure [1]. Systemic blood pressure and ratio of oxygen demand versus supply are commonly used techniques for monitoring tissue oxygenation [2]. Early Goal Directed Therapy (GDT) that includes targeted haemodynamic parameters, mix venous oxygen saturation and lactate level improves patient outcome in septic shock as well as in severe sepsis [3]. Multiorgan dysfunction resulting in death, has been reported in a number of patients inspite of maintaining systemic haemodynamic parameters and mixed venous saturation [4,5].

Shock such as cardiogenic, septic, hypovolemic or obstructive aetiology leads to decrease in tissue perfusion, which reflects as increase in P(v-a)CO₂ on blood gas analysis [5-7].

An inverse relationship between P(v-a)CO₂ and cardiac output has been described. Even after achieving haemodynamic and mix venous oxygen saturation targets, a persistently high P(v-a)CO₂ indicates inadequate resuscitation in septic patients [8]. Thus, P(v-a)CO₂ is an important marker to track global tissue perfusion and early detection of rise in CO₂ due to anaerobic metabolism [9].

Recent studies have tried to demonstrate the reliability of P(v-a)CO₂ as a tool in resuscitation of septic patients [10]. The haemodynamic management of patients in shock aims at improving tissue oxygenation. ScvO₂ is a useful tool reflecting the global transport and metabolism of oxygen. Persistently low ScvO₂ indicates inadequate tissue perfusion leading to tissue hypoxia and is associated with increase in postoperative morbidity [11-13].

Low ScvO₂ along with increase in postoperative complications has been observed in a recent study on individualized goal directed therapy [14]. A high ScvO₂ value may not reflect adequacy of microcirculation, limiting its use in routine clinical practice [15,16].

Interestingly, central venous-to-arterial PCO₂, differences P(v-a)CO₂, with central venous PCO₂ as a surrogate for mixed venous PCO₂ has recently been proposed as a useful tool for GDT in ICU-septic patients to identify persistent hypoperfusion when a ScvO₂> 70% has been reached [17]. Decreased tissue blood flow (ischemic hypoxia) represents the major determinant of increased P(v-a)CO₂[18], and P(v-a)CO₂ could therefore be considered as an indicator of adequate venous blood flow to remove CO₂ produced by peripheral tissues [19,20]. Lactate clearance, measured at a particular time interval, also assesses tissue oxygen delivery [21].

Materials and Methods

This prospective observational study was carried out after approval by Institutional Ethics Committee and written and informed consents were obtained for all patients/parents who participated in the study. The time period was 1^st August 2015 to 30^th April 2016, and conducted at UN Mehta Institute of Cardiology and Research Centre, Ahmedabad, Gujarat, India. A total of 110 children, who underwent CPB during cardiac surgery, were included. Exclusion criteria were age more than 18 years, emergency surgery and refusal to participate in study.

Preoperative variables including demographics, diagnosis and previous medical history were collected. Intraoperative variables like CPB time, MAP, flow rate, cross clamp time, were recorded for all the patients. ABG and VBG were checked at four points: 1) Before CPB; 2) 10 minutes; 3) 30 minutes after initiation of CPB; and 4) off CPB.

Postoperative vitals, urine output, ABG, VBG, CBC, serum lactate, Chest X-ray (CXR) and Renal Function Test (RFT) were collected for 72 hours.

We measured oxygen tension, saturation, carbon dioxide tension, haemoglobin and lactate from both ABG and VBG analysis. By using following formula, we calculated arterial oxygen content (CaO₂), venous oxygen content (CvO₂), difference between venous and arterial oxygen content (C(a-v)O₂), oxygen extraction ratio (O₂ER), difference between arterial and venous carbon dioxide content P(v-a)CO₂, and P(v-a)CO₂/C(a-v)O₂ ratio [22].

CaO₂ = (1.34 x SaO₂x Hb)+(0.003 x PaO₂)

CvO₂=(1.34 x SvO₂x Hb)+(0.003 x PcvO₂)

C(a−v)O₂= CaO₂−CcvO₂

P(v-a)CO₂ gap = PvCO₂−PaCO₂

P(v-a)CO₂/C(a-v)O₂ratio = P(v-a)CO₂gap/C(a−v)O₂

O₂ER = C(a-v)O₂/CaO₂

Patients were followed during 72 hours of ICU stay, the ICU length of stay and ICU mortality were computed.

Statistical Analysis

Statistical analysis was carried out using SPSS version 20.0 software (SPSS Inc, USA). One-way ANOVA test and independent sample t-test were used to compare categorical and continuous variables respectively. Data were presented as mean±SD or proportion as appropriate. The p-value less than 0.05 was considered to be significant.

Results

The demographic and the preoperative CPB data have been presented in [Table/Fig-1,2 and 3]. Age ranged between the one month to 84 months.

[Table/Fig-1]:

Demographic profile of the study population.

Variables	Height (cm)	Weight (kg)	Body surface area (kg/m2)	CPB time (min)	Cross clamp time (min)
Mean	71.3303	6.7418	0.3837	95.3545	63.3107
Median	69.0000	6.2000	0.3531	87.0000	57.0000
Standard deviation	16.11076	3.05324	0.14125	43.17037	34.01961
Range	43-120	2.3-14	0.17-0.74	95.3-43.1	63.3-34.0

[Table/Fig-2]:

Describes data of pre CPB arterial and venous ph, PCO₂, PO₂, Hb, SpO₂ and temperature.

Preoperative CPB	Artery(Mean±SD)	Vein(Mean±SD)	p-value
pH	7.343±0.09	7.336±0.09	0.5647
PCO2 (mm Hg)	43.65±10.30	45.11±9.90	0.2850
SpO2 (%)	89.58±15.56	70.82±16.51	<0.001
Hb (gm/dl)	12.59±9.47	11.32±5.67	0.2288
PO2 (mm Hg)	180.65±160.9	45.86±17.01	<0.001

* CPB: Cardiopulmonary bypass, PCO₂:Partial pressure of carbon dioxide, SpO₂: Saturation of oxygen, Hb: Haemoglobin, PO₂: Partial pressure of oxygen.

[Table/Fig-3]:

Shows data and calculation after 10, 30 minutes after CPB and off CPB initiation.

Variables	10 minute after CPB(Mean±SD)	30 minute after CPB(Mean±SD)	Off CPB(Mean±SD)	p-value
pH Artery	7.38±0.07	7.43±0.07	7.35±0.09	<0.001
pH Vein	7.33±0.07	7.39±0.07	7.31±0.08	<0.001
PCO2Artery (mmHg)	42.87±8.61	37.01±6.42	40.59±9.05	<0.001
PCO2 Vein (mmHg)	50.08±9.08	44.65±7.68	47.41±10.52	<0.001
P(v-a)CO2 (mmHg)	7.20±3.48	7.36±3.92	6.68±5.55	0.490
CaO2(ml O2/dl)	12.77±1.54	13.16±3.37	15.44±2.86	<0.001
CvO2 (ml O2/dl)	9.63±2.16	10.21±3.41	12±2.80	<0.001
C(a-v)O2 (ml O2/dl)	3.14 ± 1.36	3.08±1.40	4.54±4.20	<0.001
P(v-a)CO2/C(a-v)CO2	2.73±1.55	2.90±1.68	2.00±3.23	0.009
SpO2 Artery (%)	107.31±85.72	99.10±3.87	94.29±9.93	0.149
SpO2 Vein (%)	78.29±12.74	79.55±15.05	74.19±12.58	0.009
Lactate Artery (mg/dl)	4.24±2.14	3.95±2.51	4.31±3.48	0.593
Lactate Vein (mg/dl)	4.12±1.86	3.76±2.27	4.28±3.03	0.270
Sugar artery (gm %)	195.98±85.10	234.06±79.06	249.46±88.58	<0.001
Sugar vein (gm %)	191.5±83.22	224.06±81.04	238.40±81.92	<0.001
Hb Artery (gm %)	9.02±1.08	9.80±1.20	12.67±9.74	<0.001
Hb Vein (gm %)	9.00±1.06	10.30±3.59	11.84±1.98	<0.001
PO2 Artery (mmHg)	270.42±109.6	261.64±70.7	176.49±132.17	<0.001
PO2 Vein (mmHg)	50.33±27.43	48.05±16.33	52.96±58.76	0.641
Do2 (ml O2/ min)	290.90±35.02	301.62±76.19	----------------	0.181

* PCO₂: Pressure of carbon dioxide, SpO₂: Saturation of oxygen, PO₂: Partial pressure of oxygen, DO₂: Oxygen delivery, Hb: Haemoglobin, CaO₂: Arterial oxygen concentration, CvO₂: Ventricle oxygen concentration (a-v) O₂: Difference of Arterial and venous oxygen content.

White Blood Cell (WBC) and Haemoglobin (Hb), creatinine and platelet count till third postoperative day are described in [Table/Fig-4]. There was significant fall in platelet count on second postoperative day, however, the count started recovering from day three.

[Table/Fig-4]:

Postoperative laboratory data.

	Preoperative(Mean±SD)	Postoperative Day 1(Mean±SD)	Postoperative Day 2(Mean±SD)	Postoperative Day 3(Mean±SD)	p-value
Total count (/Cumm)	10802±3726.8	16240.4±6660.4	13386.3±5043.1	11968.4±5945.4	<0.001
Hb (gm %)	13.07±2.78	14.29±9.02	11.98±1.87	13.23±13.75	0.326
Creatinine (mg/dl)	0.452±0.09	0.505±0.15	0.570±0.32	0.527±0.26	0.001
Platelet (/Cumm)	3409.6±1288.8	1818.4±839.08	1336.9±758.6	1468.8±1044.3	<0.001

Discussion

Difference between mixed venous and arterial CO₂content reflect the cardiac output, as per Fick equation. A linear relationship between venous to arterial CO₂ content difference and cardiac output has been described [22].

According to the modified Fick equation applied to CO₂, PCO₂ gap is linearly related to CO₂ production (VCO₂) and inversely related to cardiac index. Considering the respiratory quotient (VCO₂/VO₂ ratio), VCO₂ is directly related to O₂ consumption (VO₂) [20,23]. Under conditions of adapted cardiac output to VO₂, even if the CO₂ produced is higher than normal because of an additional anaerobic CO₂ production, in the presence of sufficient flow to wash out the CO₂ produced by the tissues, the P(v-a)CO₂ should not be increased. Conversely, low blood flow can result in a widening of the P(v-a)CO₂ even if no additional CO₂ production occurs because of a CO₂ stagnation phenomenon [19,24]. Venous hypercarbia is a marker of limited blood flow during cardiac arrest and shock states [5,9,25].

Mekontso-Dessap A et al., suggested that the P(v-a)CO₂/(Ca-v)CO₂ ratio might be a reflection of anaerobic metabolism, demonstrating a positive correlation between this parameter and lactate [9]. A study by Neviere R et al., thus demonstrated the key role of microvascular blood flow on gastric CO₂ accumulation [23].

Meanwhile, Creteur J et al., found a significant correlation among sublingual CO₂, gastric mucosal CO₂ and microcirculatory heterogeneity in human septic shock during dobutamine infusion and suggested that the primary determinant of tissue CO₂ accumulation was the microcirculatory blood flow [26]. Hence, there is an evident link between blood flow and tissue or local CO₂ accumulation conducting to increase tissue or venous-to-arterial CO₂ differences, but sometimes normal macro haemodynamics does not prevent elevation of P(v-a)CO₂.

In a study by Mekontso-Dessap A et al., global anaerobic metab-olism reflected as increase in P(v-a)CO₂ to oxygen consumption ratio [9].

During conditions of tissue hypoxia but with preserved blood flow (even though during anaerobic metabolism carbon dioxide production (VCO₂) decreases less than oxygen consumption (VO₂)), venous blood flow might be high enough to ensure adequate washout of the CO₂ produced by hypoxic cells, thereby preventing a P(v-a)CO₂ increase.

The increase in venous PCO₂ would reflect a state of insufficient flow relative to CO₂ production [26]. This condition has been demonstrated previously. Indeed, Vallet B et al., showed that the venous-to-arterial CO₂ gap (PCO₂ gap) increased during low blood flow-induced tissue hypoxia (ischemic hypoxia) while it remained unchanged during hypoxemia-induced hypoxia (hypoxic hypoxia) [18].

Our study, unlike others, was performed in paediatric cardiac surgical patients, who underwent CPB during cardiac surgery.

We hypothesize that P(v-a)CO₂/C(a-v)O₂, could be a better marker of anaerobic metabolism and low flow during CPB. Most of the studies performed, were in adult group of patients having sepsis. Our study has proved that P(v-a)CO₂/C(a-v)O₂ can detect anaerobic metabolism earlier than lactate.

ROC curve at 30 minute of cardiopulmonary bypass time shows that P(v-a)CO₂/C(a-v)O₂ was more specific and sensitive than lactate to detect anaerobic metabolism. We suggest to use P(v-a)CO₂/C(a-v)O₂ as a marker to detect low flow on CPB [Table/Fig-5]. In our study, we found that platelet count decrease was significant on second postoperative day. However, recovery started from third postoperative day.

[Table/Fig-5]:

ROC curve of patients whose lactate level were high, compared with P(v-a)CO₂/C(a-v)O₂ ratio.

Limitation

Studies involving large population and multiple centers are required to support the study, as our present study is single centric and with a small size.

Conclusion

We suggest to use P(v-a)CO₂/C(a-v)O₂ ratio as a marker to detect anaerobic metabolism on CPB. Unfortunately, the calculation of CO₂ content is very complex and subject to errors due to the number of variables included in the formula.

* CPB: Cardiopulmonary bypass, PCO₂:Partial pressure of carbon dioxide, SpO₂: Saturation of oxygen, Hb: Haemoglobin, PO₂: Partial pressure of oxygen.* PCO₂: Pressure of carbon dioxide, SpO₂: Saturation of oxygen, PO₂: Partial pressure of oxygen, DO₂: Oxygen delivery, Hb: Haemoglobin, CaO₂: Arterial oxygen concentration, CvO₂: Ventricle oxygen concentration (a-v) O₂: Difference of Arterial and venous oxygen content.

[1]. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008 Intensive Care Medicine 2008 34(1):17-60.  [Google Scholar]

[2]. Shoemaker WC, Appel PL, Kram HB, Tissue oxygen debt as a determinant of lethal and nonlethal postoperative organ failure Crit Care Med 1988 16:1117-20.  [Google Scholar]

[3]. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Early goal-directed therapy in the treatment of severe sepsis and septic shock N Eng J Med 2001 345:1368-77.  [Google Scholar]

[4]. Russell JA, Phang PT, The oxygen delivery/consumption controversy. Approaches to management of the critically ill Am J RespirCrit Care Med 1994 149:533-37.  [Google Scholar]

[5]. Mecher CE, Rackow EC, Astiz ME, Weil MH, Venous hypercarbia associated with severe sepsis and systemic hypoperfusion Crit Care Med 1990 18:585-89.  [Google Scholar]

[6]. Adrogue HJ, Rashad MN, Gorin AB, Yacoub J, Madias NE, Assessing acid–base status in circulatory failure. Differences between arterial and central venous blood N Engl J Med 1989 320:1312-16.  [Google Scholar]

[7]. Ospina-Tascón GA, Umaña M, Bermúdez WF, Bautista-Rincón DF, Valencia JD, Madriñán HJ, Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? Intensive Care Medicine 2016 42(2):211-21.  [Google Scholar]

[8]. Vallee F, Vallet B, Mathe O, Parraguette J, Mari A, Silva S, Central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock? Intensive Care Med 2008 34:2218-25.  [Google Scholar]

[9]. Mekontso-Dessap A, Castelain V, Anguel N, Bahloul M, Schauvliege F, Richard C, Combination of venoarterial PCO₂ difference with arteriovenous O₂ content difference to detect anaerobic metabolism in patients Intensive Care Med 2002 28:272-77.  [Google Scholar]

[10]. Van Beest PA, Lont MC, Holman ND, Loef B, Kuiper MA, Boerma EC, Central venous–arterial pCO₂ difference as a tool in resuscitation of septic patients Intensive Care Med 2013 39:1034-39.  [Google Scholar]

[11]. Reinhart K, Rudolph T, Bredle DL, Hannemann L, Cain SM, Comparison of central-venous to mixed-venous oxygen saturation during changes in oxygen supply/demand Chest 1989 95:1216-21.  [Google Scholar]

[12]. Donati A, Loggi S, Preiser JC, Orsetti G, Munch C, Gabbanelli V, Goal-directed intraoperative therapy reduces morbidity and length of hospital stay in high-risk surgical patients Chest 2007 132:1817-24.  [Google Scholar]

[13]. Pearse R, Dawson D, Fawcett J, Rhodes A, Grounds RM, Bennett ED, Changes in central venous saturation after major surgery, and association with outcome Crit Care 2005 9:R694-99.  [Google Scholar]

[14]. Futier E, Constantin JM, Petit A, Chanques G, Kwiatkowski F, Flamein R, Conservative versus restrictive individualized goal-directed fluid administration in major abdominal surgery: a prospective randomized trial Arch Surg 2010 145(12):1193-200.  [Google Scholar]

[15]. Pearse RM, Hinds CJ, Should we use central venous saturation to guide management in high-risk surgical patients? Crit Care 2006 10:181  [Google Scholar]

[16]. Pope JV, Jones AE, Gaieski DF, Arnold RC, Trzeciak S, Shapiro NI, Multicenter study of central venous oxygen saturation (ScvO₂) as a predictor of mortality in patients with sepsis Ann Emerg Med 2010 55:40.e1-46.e1.  [Google Scholar]

[17]. Cuschieri J, Rivers EP, Donnino MW, Katilius M, Jacobsen G, Nguyen HB, Central venous-arterial carbon dioxide difference as an indicator of cardiac index Intensive Care Med 2005 31:818-22.  [Google Scholar]

[18]. Vallet B, Teboul JL, Cain S, Curtis S, Venoarterial CO₂ difference during regional ischemic or hypoxic hypoxia J Appl Physiol 2000 89:1317-21.  [Google Scholar]

[19]. Lamia B, Monnet X, Teboul JL, Meaning of arterio-venous PCO₂ difference in circulatory shock Minerva Anestesiol 2006 72:597-604.  [Google Scholar]

[20]. Bakker J, Vincent JL, Gris P, Leon M, Coffernils M, Kahn RJ, Veno-arterial carbon dioxide gradient in human septic shock Chest 1992 101:509-15.  [Google Scholar]

[21]. Arnold RC, Shapiro NI, Jones AE, Schorr C, Pope J, Casner E, Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis Shock 2009 32(1):35-39.  [Google Scholar]

[22]. Mesquida J, Saludes P, Gruartmoner G, Espinal C, Torrents E, Baigorri F, Central venous-to-arterial carbon dioxide difference combined with arterial-to-venous oxygen content difference is associated with lactate evolution in the haemodynamic resuscitation process in early septic shock Critical Care 2015 19:126  [Google Scholar]

[23]. Neviere R, Chagnon JL, Teboul JL, Vallet B, Wattel F, Small intestine intramucosal pCO₂ and microvascular blood flow during hypoxic and ischemic hypoxia Crit Care Med 2002 30:379-84.  [Google Scholar]

[24]. Neviere R, Mathieu D, Chagnon JL, Lebleu N, Wattel F, The contrasting effects of dobutamine and dopamine on gastric mucosal perfusion in septic patients Am J Respir Crit Care Med 1996 154:1684-88.  [Google Scholar]

[25]. Weil MH, Rackow EC, Trevino R, Grundler W, Falk JL, Griffel MI, Difference in acid–base state between venous and arterial blood during cardiopulmonary resuscitation N Engl J Med 1986 315:153-56.  [Google Scholar]

[26]. Creteur J, De Backer D, Sakr Y, Koch M, Vincent JL, Sublingual capnometry tracks microcirculatory changes in septic patients Intensive Care Med 2006 32:516-23.  [Google Scholar]