Systemic and regional effects of experimental gradual splanchnic ischemia

Systemic and Regional Effects of Experimental Splanchnic Ischemia Antero

Heino,

Juha Hartikainen,

Minna

E. Merasto,

Erkki M.J. Koski, Esko Alhava,

Gradual and Jukka Takala

Purpose: We evaluated the effects of gradual intestinal isehemia on systemic and regional haemodynamics and oxygen transport. Materials and Methods: Superior mesenteric artery (SMA) blood flow was decreased by 40%, 70%. and 100% for IO-minute periods and thereafter released in 12 pigs. Hemodynamic changes were monitored continuously, and the intestinal perfusion was evaluated by changes in portal vein-arterial lactate gradient, intramucosal pH, tonometric Pcoz, tonometric-portal vein Pcoz gradient, and regional oxygen extraction. Results: Local signs of intestinal hypoperfusion developed during the SMA occlusion. lntramucosal pH and portal vein pH decreased from 7.18 f 0.04 to 6.81 + 0.04 (P < .Ol) and from 7.36 + 0.01 to 7.25 f 0.03 (P < .05), respectively. lntramucosal Pco2 and tonometric-portal vein Pcoz gradient increased from 12.4 2 1.3 to 21.2 + 1.8 kPa (P < .Ol) and from 6.0 f 1.3 to 14.0 + 1.9 kPa (P < .05), respectively. Portal vein-arterial lactate gradient and splanchnic oxygen extraction increased from 0.02 f 0.07 to 2.32 2 0.47 mmol/L

(P < .Ol) and from 0.44 + 0.03 to 0.60 ir 0.03 (P < .05), respectively. Systemic changes observed during the SMA occlusion were reduction of cardiac index (161 f 12 to 114 f 8 mL/min/kg, P < .Ol) and pulmonary capillary wedge pressure (4 + 1 to 3 ? 1 mm Hg) and increase in heart rate (124 f 5 to 173 + 11 beats/ min, PC .Ol) and mean arterial pressure (79 f 3 to 104 r 5 mm Hg, P < .Ol). Systemic oxygen extraction increased (P < .05), arterial pH increased (P < .05), and arterial lactate decreased (P < .Ol) during the SMA occlusion. Splanchnic ischemia defined as an increase in portal vein-arterial lactate gradient above mean +2 SD of the baseline occurred at 93 f 15 minutes corresponding 70% SMA occlusion. Conclusion: We conclude that signs of tissue hypoperfusion started to develop at 70% SMA occlusion and that regional tissue hypoperfusion in the splanchnic region may develop without any systemic signs of oxygen supply/demand mismatch. Copyright o 1997 by W.B. Saunders Company

T

This study evaluated the changes in systemic and regional haemodynamics and oxygen transport during progressive intestinal ischemia caused by graded occlusion of the superior mesenteric artery. Particularly, we assessed at what level of blood flow reduction regional tissue hypoxia develops and at what level of intestinal ischemia systemic signs of local hypoperfusion occur.

ISSUE HYPOXIA is an important cause of morbidity and mortality in critically ill patients. Impaired tissue oxygenation in the splanchnit region may contribute to the development of multiple organ failure. 7,8,13Detection of abnormalities in oxygen consumption, delivery, extraction, base excess, and blood lactate concentration have been postulated to be useful indicators of tissue hypoperfusion.4~9J0~22On the other hand, there is evidence that regional intestinal hypoperfusion may occur without systemic signs of inadequate regional hemodynamics. 22In previous studies, the hemodynamic responses of total and partial occlusion and reperfusion of the intestinal vasculature have been studied extensively.6J5,22,24However, the relationship between the severity and duration of gradually developing splanchnic &hernia to systemic hemodynamic and biochemical changes has not been well documented. From the Department of Surgery, Department of Medicine, Department of Anaesthesiology and Critical Care Research Program, and Department of Intensive Care, Kuopio University Hospital, Kuopio, Finland. Received August 5,1996; accepted January 3, 1997. Address reprint requests to Antero Heino, MD, Department of Surgery, Kuopio University Hospital, PL 1777, FIN-70211 Kuopio, Finland. Copyright 0 1997 by WB. Saunders Company 0883-9441/97/1202-0006$05.00/O 92

MATERIALS

AND

METHODS

The study protocol was approved by the Internal Review Board of Animal Experiments of the University of Kuopio.

Anesthesia Twelve female pigs, weighing 28 t 1 kg, were premeditated with intramuscular ketamine hydrochloride (30 mg/kg) and anaesthetized with intravenous pentobarbital sodium (15 mg/kg) followed by a continuous infusion of pentobarbital sodium (2 mg/min) and small boluses. Atracheostomy was performed, and the pigs were ventilated with 30% oxygen in room air to achieve normoventilation with an end tidal PCOZ of 40 ? 5 mm Hg at the end of the stabilization period with no changes in ventilator settings thereafter.

Surgical Procedures An arterial catheter was inserted into the left carotid artery for monitoring systemic arterial pressure, and a 7.5-Fr Swan-Ganz thermodilution catheter (Arrow, Arrow International Inc., PA) via the left jugular vein to the pulmonary artery for hemodynamic measurements. The intrathoracic location of the catheter was verified by pressure wave recordings. A midline laparotomy Journal

of Critical

Care, Vol 12, No 2 (June),

1997: pp 92-98

EFFECTS

OF EXPERIMENTAL

SPLANCHNIC

ISCHEMIA

was performed, and the root of the superior mesenteric artery (SMA) was exposed. A 4- or 6-mm electromagnetic flow probe (IVM, model FX-3; In Vivo Metric Systems, Anaheim, CA) and a snare occluder were placed around the artery. Splenectomy was performed, and a catheter was introduced via the splenic vein into the portal vein at the root of the superior mesenteric vein. A nasogastric 16.Fr tonometric catheter (Trip NGS catheter model 2002-48-16; Tonometrics Inc., Worcester, MA) was placed into the midileum through a small antimesenteric enterostomy, and a catheter was placed into the urinary bladder.

After a stabilization period of 60 minutes, the SMA occluder was adjusted to reduce the SMA blood flow stepwise by 40%, 70%, and 100% from the baseline. Each occlusion level was maintained for 60 minutes. Following the total occlusion of 60 minutes, the occluder was released and the measurements were continued for 60 minutes before the animal was killed. Systemic and pulmonary artery hemodynamics were recorded continuously during the study. Cardiac output and pulmonary capillaty wedge pressure (PCWP) were measured and blood samples were taken at 30 and 60 minutes after adjustments of the SMA blood flow, as well as at 5, 30, and 60 minutes after the reperfusion of the SMA.

Hemodynamic Measurements Systemic and pulmonary hemodynamics were recorded as l-minute median values of data collected at lo-second intervals. The mean value of the lo-minute periods preceding each cardiac output and PCWP measurements were used for analysis except for the first data point after reperfusion of the SMA, where a 3-minute mean value was used. Cardiac output was determined with the thermodilution method as the average of three repeated measurements using 1OmL bolus injections of 0.9% saline in room temperature. Cardiac index (CI) was calculated dividing the cardiac output by the weight of the animal and systemic vascular resistance index (SVRI) with the following equation: = (MAP

mark) were used to determine the blood gas values, hemoglobin concentration, and oxygen saturation values of the samples. Oxygen delivery (Doz) was measured as the product of cardiac output and arterial oxygen content (Caoz) and oxygen consumption (Voa) as the product of cardiac output and arterial-venous oxygen content gradient. Oxygen contents were calculated as 1.39 X hemoglobin concentration X oxygen saturation + dissolved oxygen. Oxygen extraction was derived from Voa and Doz.

Tonometric Measurements

Experimental Design

SVRI

93

- MCVP)/CI

where MAP is the mean arterial pressure and MCVP is the mean central venous pressure. The SMA blood flow was recorded through an amplifier (IVM, Model BA 201; In Vivo Metric Systems, Anaheim, CA) to an instrumentation tape recorder (Racal Store 7 DS; Racal Recorders Ltd, Southampton, England) and displayed on the screen of a cathode-ray oscillqscope. The SMA blood flow was estimated off-line using the recorded blood flow signal. This was performed by integrading the area under the blood flow signal over time. Because of the study set-up (gradual SMAocclusion), we were not able to occlude the SMA blood flow at regular intervals to assess zero flow calibration. Therefore, our SMA blood flow values during the study should not be considered as exact measurements, but as estimations of SMA blood flow between the baseline and total SMA occlusion.

Calculation of Oxygen Delivery and Consumption Blood samples were aspirated from the carotid artery, the pulmonary artery, and the portal vein. A blood gas analyzer and an oximeter (ABL 500, OS3; Radiometer, Copenhagen, Den-

The tonometer was filled with 0.9% saline. After 30 minutes of equilibration, the Pcoz of the sample and simultaneous arterial blood gas values were determined using a blood gas analyzer (ABL 500; Radiometer, Copenhagen, Denmark). Intramucosal pH value was calculated with the HendersonHasselbalch equation: pH = 6.1 + log ([HCOa-]/[Pcoz X 0.031) using the arterial bicarbonate concentration and the saline Pcoz, adjusted for the 30 minutes time of equilibrium.‘* Tonometricportal vein Pco2 gradient was calculated.

Lactate Blood lactate concentrations were measured from portal vein and arterial blood samples and determined by Boehringer Mannheim Total Entsymatic Test-Combination Cat. no 256 773 (EPOS analyzer 5060; Eppendorf Gerltebau, Hamburg, Germany). Portal vein-arterial lactate gradient was calculated, and an increase above mean + 2 SD of the baseline was considered as an indicator for the development of the splanchnic ischaemia. Intramucosal pH, Pco~, and tonometric-portal vein PCO~ gradient were assessed at the corresponding time point.

Statistical Methods The results were analyzed with Friedman ANOVA for repeated measurements. When a statistically significant change was observed, Wilcoxon matched-pairs Signed-ranks test was used to find the difference between the baseline values and the different time points. A P value c.05 was considered statistically significant. The results are expressed as mean ? SEM.

RESULTS

SMA blood flow (QsMA) at baseline, 40% occlusion, and 70% occlusion were 249 t 47 ml/mm, 1.54 ? 30 mL/min, and X2 t 15 mL/min, respectively. After the release of the occlusion, QsMA returned close to the baseline level (Table 1, Fig 1). Intramucosal pH decreased from 7.18 -C 0.04 to 6.81 2 0.04 (P < .Ol v baseline) at the end of the SMA occlusion and remained below the baseline value after the SMAreperfusion (Fig 1). Intramucosal Pco2 increased from 12.4 rt 1.3 kPa at baseline to 21.2 f 1.8 kPa at the end of SMA occlusion (P < .Ol v baseline) and decreased to 15.5 + 1.7 kPa at the end of the reperfusion (P = .0593 v baseline). Tonometric-portal vein Pcoz gradient

94

HEINO

Table

1. Superior

Mesenteric

Artery

Blood

Flow

Expressed

ETAL

increased from 6.0 t 1.3 kPa to 14.0 t 1.9 kPa at the end of the occlusion period (P < .05 v haseline). After the release of the SMA occlusion, tonometric-portal vein Pco;?decreased to 8.6 + 1.6 kPa at the end of the reperfusion. Portal vein lactate increased from 4.6 C 0.7 mmol/L to 6.4 k 0.5 mmolJL during the SMA occlusion, reached its peak value 5 minutes after the reperfusion (8.7 + 0.8

mmol/L, P < .05 v baseline), and decreased towards the end of the experiment. Portal veinarterial lactate gradient increased during the SMA flow reduction (P < .Ol at the end of the SMA occlusion v baseline) and reached the peak value 5 minutes after the release of the vascular occlusion (3.3 ‘I 0.5 mmol/L, P < .05 v baseline). Thereafter, it decreased during the reperfusion, but remained above the baseline value to the end of the experiment (Fig 1). Portal vein pH decreased during the SMA flow reduction (P -=c.05 at the end of ischemia v baseline) with a more pronounced drop at 5 minutes after the SMA reperfusion. Later during the reperfusion, portal vein pH started to increase, but remained below the baseline value. Splanchnic oxygen extraction increased from 0.44 + 0.03 to 0.60 + 0.03 (P < .05 v baseline) towards the end of the SMA occlusion. After reperfusion, there was a rapid drop in the splanchnit oxygen extraction (Fig 1). An increase in portal vein-arterial lactate gradient above mean +2SD of baseline was observed at 93 t 15 minutes corresponding 69 2 7% occlusion

A

B ‘?

as Absolute

Flow (C&u+& Percentage of Its Baseline fat 0 minutes) Q.un%l, and Percentage of Cardiac

Ttme (mid

QSMA (mUmin)

0

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Output

fQsu,&COl QSMAYJCO (%)

QSMA%

(%I 100.0 k 0.0

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160 t31* 154 i- 30*

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*I'<.01

Value

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vbaseline.

5oo

54

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1

T

-30

0

:l”‘;o

T

Time (min)

7.6

30

90 120 150 Time(min)

180

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270

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C

0.8:

7.5

6.9~, -30

60

0

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90 120 150 Time (min)

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270

0.23 -30

0

30

60

90 120 150 Time(min)

Fig 1. Effect of gradual occlusion and reperfusion of superior mesenteric artery on (A) superior portal vein-arterial lactate gradient (solid circle) and intramucosal pH (open circle), (Cl portal extraction. Mean 2 SEM. *P < .05; +,+P < .Ol vbaseline (0 min).

180

210

mesenteric artery blood pH, and fD) splanchnic

240

270

flow, (B) oxygen

EFFECTS

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95

level, intramucosal pH 6.93 +- 0.06 (P < .Ol v baseline), tonometric Pco2 16.6 +- 1.5 kPa (P < .05 v baseline), and tonometric-portal vein Pco2 gradient 8.9 t 1.5 kPa. Systemic Do2 and systemic VO, decreased early and progressively during the experiment (Fig 2). After the release of the SMA occlusion, a temporary increase in VoI! was observed, whereas at the end of the experiment systemic Vo2 declined almost back to the baseline value (Fig 2). During the ischemia, only minor changes were observed in the systemic oxygen extraction, whereas during the reperfusion it increased significantly (P < .05 v baseline) (Fig 2). Systemic arterial lactate level decreased during the partial ischemia, started to increase at 30 minutes after the total ischemia, and reached its peak value (5.3 + 0.6 mmol/L) 5 minutes after the release of the vascular occlusion (Fig 2). Arterial pH increased during the ischaemia (P < .05 v baseline), whereas 5 minutes after the reperfusion it decreased significantly below the

baseline value (P < .05) and increased thereafter. Arterial oxygen saturation remained unchanged during the SMA occlusion, but decreased from 97.6 t 1.3 at the end of ischaemia to 95.4 t 2.1 at 30 minutes after the reperfusion (P < .Ol). CI decreased gradually throughout the experiment (P < .Ol v baseline, Fig 3). After the reperfusion, a higher proportion of cardiac output was delivered to the SMA region compared with the baseline values (10.2 +- 1.4% v 5.5 t 0.7%, P < .Ol, Table 1). Heart rate increased significantly (P < .Ol) at 30 minutes after the total SMA occlusion and remained above baseline value during the whole reperfusion period (Fig 3). MAP and SVRI increased towards the end of SMA occlusion with the peak at 30 minutes after the total occlusion. After the release of the SMA occlusion, a rapid drop in MAP and SVRI were observed (Fig 3). Mean pulmonary artery pressure during the occlusion and reperfusion did not differ significantly from the baseline. PCWP decreased gradually from

A 35~

0.9-

B

0.X 0.7:

0.6: 0.5: 0.4

30

60

90 120 150 Time (min)

160

210

240

0.3

270

Ii

0.2: -30

1

0

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60

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2'0

Time (min) 7.55 7.5

F

D l2

* f *

1

8

1

0 7.251, -30

, 0

,

,

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, 60

,

,

,

,

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,

90 120 150 Time (min)

,

* T

10

I,,

,

180

210

,

,

240

7,

270

-30

,,,,,,,,,,,,,,,,,,,,,,,,,,,I,, 0 30 60

A

90 120 150 Time (min)

Fig 2. Effect of gradual occlusion and reperfusion of superior mesenteric artery on (A) systemic oxygen delivery consumption (solid circle), (B) systemic oxygen extraction, (C) arterial pH, and ID) arterial (solid circle) and portal lactate. Mean f SEM. For abbreviations see Fig 1.

180

210

240

270

(open circle) and [open circle) vein

HEINO

96

A

240 220

B

260

.E $ z g

1801

ET AL

240

200 180 1

$ w* E

120

160; 140: 120: 100:

60 40 2o,,,,,.,,.,,.,,,,..,.,,,.,.,,,., -30 0 30 60

C

90 120 150 Time (min)

180

210

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270

160

-30

0

30

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120 150 Time (min)

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rate,

(Cl mean

D ‘.’ 1.4Ii

140 **

400 -30

0

30

60

90

120

150

180

210

240

270

30

60

Time (min)

Fig 3. Effect arterial pressure,

of gradual occlusion and reperfusion and ID) systemic vascular resistance

of superior mesenteric artery on (A) cardiac index, index. Mean + SEM. For abbreviations see Fig 1.

4 t 1 mm Hg at baseline to 3 2 1 mm Hg at the end of SMA occlusion and to 2 t 1 mm Hg at the end of the reperfusion period (P < $05). DISCUSSION

Tissue hypoxia or oxygen supply/demand mismatch in the splanchnic region has been suggested to contribute to the development of multiple organ failure.7JJ3 Thus, detection of inadequate splanchnit perfusion early enough remains a challenge for clinicians treating critically ill patients. In clinical practice, monitoring tissue perfusion relies largely on systemic variables. Acid-base balance, oxygen delivery, consumption, extraction, and blood lactate concentration have been recommended to provide useful information about tissue perfusion.3,5,9,22In a recent study, Schlichting et aP* reported that information obtained from systemic and pulmonary artery catheters were not able to detect intestinal ischemia caused by a 5-hour total SMA occlusion. However, when the blood flow is reduced to zero, perfusion through the ischaemic

(61 heart

region ceases. As a result, there is no or only limited washout of ischemic metabolites and toxins, which may explain why no signs of ischemia develop. In our study, we speculated that during partial ischemia, ischemic toxins might pour into circulation and cause changes in systemic hemodynamics and oxygen transport parameters. However, opposite to our hypothesis, we were not able to demonstrate any specific systemic hemodynamic or biochemical signs of impaired tissue perfusion despite the development of progressive intestinal ischemia. In our study, systemic oxygen delivery and consumption decreased progressively and in parallel with the reduction of the SMA flow and cardiac output. Systemic oxygen extraction remained mainly unchanged, arterial pH increased, and arterial lactate level, if anything, decreased during the SMA occlusion. Under these conditions, the tonometer appeared to be the only feasible method for the early detection of intestinal hypoperfusion, which is in line with earlier studies.1,2J1,21,22

EFFECTS

OF EXPERIMENTAL

SPLANCHNIC

ISCHEMIA

97

We did observe changes in systemic hemodynamits during the splanchnic ischemia. However, these changes-reduction of cardiac output and pulmonary capillary wedge pressure, and tachycardiawere nonspecific and associated with gradually developing hypovolemia caused by the loss of intravascular fluid into the peritoneal cavity.14J6*23 Despite clear evidence of hypovolemia, we found an increase in mean arterial blood pressure, which is opposite to previous studies.15J8J9The reason for the mean blood pressure increase remains unclear and highly speculative. However, it confirms that normal blood pressure cannot be used to exclude significant hypovolemia. Systemic hemodynamics deteoriated following the reperfusion and washout of metabolites from the splanchnic region. The increased systemic oxygen consumption is likely to reflect the combined effects of recovery from the oxygen debt and the activation of inflammatory mediators. We speculate that the release of cardiotoxic and acidotic material from the ischemic intestine together with hypovolemia explain the further decrease in cardiac output during the reperfusion.i7 This together with worsening hypovolemia caused by redistribution of the reduced circulating blood volume into the intestinal vasculature and the uncoupling of the vasoregulative systems probably explain the reduced mean arterial blood pressure after the reperfusion. In our study, splanchnic ischemia was evaluated principally by increase in portal vein-arterial lactate gradient. Parallel with the increase in portal vein-arterial lactate gradient, intramucosal pH decreased and tonometric Pco~, tonometric-portal vein PCO* gradient, and splanchnic oxygen extraction increased. The critical time point for the

increase in the portal vein-arterial lactate above mean +2SD of baseline value occurred at 93 minutes from the start of the study corresponding to 70% SMA occlusion level. Also at this time, significant changes in intramucosal pH and tonometric Pcoz gradient were observed. This is in close agreement with Grum et a1,i2 who showed that tonometrically detected intramucosal pH decreased and was dependent on regional oxygen consumption, when oxygen delivery was decreased by 60% from the baseline. What could be the reason that splanchnic ischemia was not detected by systemic or pulmonary artery hemodynamics or blood samples? One possible explanation is that the increased lactate metabolism in the liver was able to handle the increased intestinal lactate production and prevented the development of systemic lactatemia and acidosis. Another possibility is that portal vein flow was reduced during the SMA occlusion. As a consequence, although portal vein lactate concentration increased, the cumulative amount of lactate entering systemic circulation was not changed.22 In our study, isolated SMA occlusion was used to produce splanchnic ischemia. An isolated SMA occlusion may occur in patients with large emboli or severe atherosclerotic disease, which is rather uncommon in clinical practice. Although our study shows that splanchnic ischemia may develop without systemic signs of tissue hypoperfusion, the clinical relevance of this finding should be interpreted with caution. We conclude that splanchnic hypoperfusion started to develop at 70% SMA occlusion, and that splanchnic ischemia may occur without specific systemic hemodynamic or biochemical changes suggesting oxygen supply/demand mismatch.

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15. Haglund U, Myrvold H, Lundgren 0: Cardiac and pulmonary function in regional intestinal shock. Arch Surg 113:963-969, 1978 16. Kangwalklai K, Saadat S, Bella E, et al: Space studies during occlusion of the superior mesenteric artery and upon its release. Surg Gynecol Obstet 137:263-266, 1973

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17. Lundgren 0, Haglund U: On the chemical nature of the blood borne cardiotoxic material released from the feline small bowel in regional shock. Acta Physiol Stand 103:59-70, 1978 18. NorlCn K, Rentzhog L, Wikstrijm S: Regional and central hemodynamics during segmental ischemia of the small intestine in the rat. Eur Surg Res 10:246-58, 1978 19. Redfors S, Hallblck DA, Haglund U, et al: Blood flow distribution, villous tissue osmolality and fluid and electrolyte transport in the cat small intestine during regional hypotension. Acta Physiol Stand 121:193-209, 1984 20. Ronco JJ, Fenwick JC, Tweeddale MG, et al: Identification of the critical oxygen delivery for anaerobic metabolism in critically ill septic and nonseptic humans. JAMA 270:17241730,1993 21. Schiedler MG, Cutler BS, Fiddian-Green RG: Sigmoid intramural pH for prediction of ischemic colitis during aortic surgery: A comparison with risk factors and inferior mesenteric artery stump pressures. Arch Surg 122:881-886, 1987 22. Schlichting E, Lyberg T: Monitoring of tissue oxygenation in shock: An experimental study in pigs. Crit Care Med 23:1703-1710,1995 23. Tjiong B, Bella E, Weiner M, et al: Fluid shifts and metabolic changes during and after occlusion of the superior mesenteric artery. Surg Gynecol Obstet 139:217-221, 1974 24. Vyden JK, Nagasawa K, Corday E: Hemodynamic consequences of acute occlusion of the superior mesenteric artery. Am J Cardiol34:687-690, 1974