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Effect of low-dose vasopressin infusion on vital organ blood flow in the conscious normal and septic sheep.

SUMMARY

The effect of low-dose vasopressin (AVP) on vital regional circulations may be clinically relevant but has not been fully described. We sought to determine the effect of low-dose AVP on systemic haemodynamics, coronary, mesenteric and renal circulations in the conscious normal and septic mammal.

We studied seven Merino sheep using a prospective randomized cross-over double-blind placebo-controlled animal design. We inserted flow probes around aorta, coronary, mesenteric and renal arteries and, three weeks later, we infused low-dose A VP (0.02 IU/min) or placebo in the normal and septic state induced by intravenous E.coli. In normal sheep, A VP (0.02 IU/min) induced a 17% decrease in mesenteric blood flow (393.0[+ or -]134.9 vs 472.1 [+ or -] 163.8 ml/min, P<0.05) and a 14% decrease in mesenteric conductance (P<0.05). In septic sheep, AVP decreased heart rate and cardiac output by 28% and 22%, respectively (P<0.05). It also decreased mesenteric blood flow and mesenteric conductance by 23% (flow: 468.5[+ or -]159.7 vs 611.3[+ or -]136.3 ml/min, P<0.05; conductance: 6.3[+ or -]2.7 vs 8.2[+ or -]27 ml/min/mmHg; P<0.05). Renal blood flow was unchanged but urine output and creatinine clearance increased (P<0.05). We conclude that low-dose A VP infusion has similar effects in the normal and septic mammalian circulation: bradycardia, decreased cardiac output, decreased mesenteric blood flow and conductance and increased urine output and creatinine clearance. This information is important to clinicians considering its administration in humans.

Key Words: vasopressin, sepsis, septic shock, renal blood flow, mesenteric blood flow, coronary blood flow, creatinine clearance

Vasopressin (AVP) is an antidiuretic and vasopressor hormone, which, at high doses, induces marked mesenteric vasoconstriction (1-3). Because of these properties, AVP has been used for the treatment of patients with diabetes insipidus and variceal haemorrhage due to hepatic failure (1).

More recently, some studies have shown that a relative AVP deficiency may exist in patients with septic shock (4) and that such deficiency may contribute to the diminished vessel tone seen in this setting (4-5). These observations have established a biological rationale for AVP as a possible effective vasopressor in septic shock patients (4-9) when administered at low dose (0.02-0.04 IU/min). Its ability to improve blood pressure at such low doses has been demonstrated in several small clinical studies (7-9). It has been assumed that, at such low doses, AVP should have limited adverse effects on regional blood flows. In spite of the increasing reports of its use in human sepsis, little is known about the effects of low-dose AVP infusion on vital organ flows in the normal and septic mammalian circulation in the conscious animal.

Accordingly, we conducted a prospective randomized cross-over double-blind, placebo-controlled animal experiment to study the effect of AVP infusion at low dose on vital organ flows in the conscious normal and septic sheep.

MATERIALS AND METHODS

Animal preparation

The local institutional Animal Ethics Committee approved this study. Seven Merino sheep weighing between 35 and 45 kg were procured for chronic instrumentation. The animals underwent three separate operative procedures for the placement of flow probes. Anaesthesia for all of these procedures was induced with sodium thiopentone (15 mg/kg) for endotracheal tube placement (cuffed size 10). Maintenance anaesthesia was by means of oxygen/ air/isoflurane (1-2%). Fractional inspired oxygen was altered to maintain [P.sub.a][O.sub.2]~100 mmHg and ventilation controlled to maintain [P.sub.a][O.sub.2]~40 mmHg. Anaesthesia was the same for each operative procedure.

The first procedure was oophorectomy and carotid loop creation. After two weeks' recovery, a left-sided thoracotomy was performed. The pericardium was opened to expose the heart and great vessels. Transit time flow probes (Transonics Systems, Ithaca, N.Y.) were placed on the circumflex artery (3 mm) and on the ascending aorta (20 mm). Two weeks later, a left-sided flank incision was made and retroperitoneal dissection performed to expose the superior mesenteric and left renal arteries. Transit time flow probes (6 and 4 mm, respectively) were placed on these arteries. The animals were allowed to recover for three weeks. The use of chronically implanted transit time flow probes has been previously validated (10).

The day before experimentation, a carotid loop arterial tygon catheter (ID 1.0 mm, ED 1.7 mm) and two jugular venous polythene catheters (ID 1.2 mm, ED 1.7 mm) were placed for the measurement of arterial and central venous pressures. The arterial and one venous cannula were connected to pressure transducers (TDXIII, Cobe, Lakewood, Colorado, U.S.A.) tied to the wool on the sheep's back. Correction factors were included in the data collection program to compensate for the height of the transducers above the heart. The second venous catheter was used as an infusion line. A urinary catheter was inserted for urine flow measurements and sample collection.

The transit time flow probes were connected to a flowmeter (T201, Transonics Systems, Ithaca, N.Y.) via a four channel sequential scanner (TM04, Transonics Systems), except the 20 mm flow probes that were connected directly to a flowmeter (T206, Transonics Systems). Analogue signals of arterial pressure, central venous pressure (CVP), cardiac output (CO) and regional blood flows were collected on computer using custom software written at the Howard Florey Institute. Cardiac output was measured by the transit flow probe placed around the ascending aorta as previously described (11). Heart rate (HR) was measured from the CO signal. Following analogue to digital conversion, data were collected at 100 Hz for ten seconds at ten-minute intervals throughout the experimental protocol.

Protocol and measurements

All animals were studied in the normal and septic state. First they were studied in the normal state.

Normal sheep

On the day of the experiment, animals underwent a two-hour pre-infusion baseline observation period.

Sheep were then randomized to infusion of either AVP (0.02 IU/min) or placebo (saline 12 ml/h) for six hours.

Intravenous normal saline was administered to maintain CVP constant (2-4 mmHg). Mean arterial pressure (MAP), CO, HR, coronary flow (CF), mesenteric flow (MF) and renal flow (RF) were recorded at ten-minute intervals. Urinary flow was measured and urine sampled two-hourly. Creatinine clearances were calculated at two hours, four hours and six hours. At the end of six hours, the infusion was stopped. The catheters were removed and the animals were allowed to recover.

After one week, the animals were crossed over to the alternative treatment. Thus, if the first week, they had been randomized to placebo, the second week they would receive AVP or, if the first week they had been randomized to AVP, the second week they would receive placebo.

After these experiments were completed, the animals were given a period of two weeks without any intervention.

After this period they moved to the septic phase.

Septic sheep

These experiments started with vascular catheter insertion first. The day after catheter insertion, following a two-hour observation period, the animals were rendered septic by an intravenous bolus injection of 3 x [10.sup.9] colony forming units of E. coli, as previously described (11).

The onset of hyperdynamic sepsis was prospectively defined by the simultaneous presence of the following criteria: i) greater than 50% increase in heart rate (HR), ii) greater than 50% increase in CO and iii) greater than 10% decrease in MAP. All animals received intravenous 0.9% saline at a rate of 2-3 ml/ kg/h to keep CVP constant.

Following the development of hyperdynamic sepsis, which typically occurred within six hours of E.coli injection, the sheep were randomized to one of two treatments: either AVP (0.021U/min) or vehicle (saline at 12 ml/h) for six hours.

Throughout the infusion period, MAP, CO, HR, CF, MF and RF were measured at ten-minute intervals and urine volume was measured and a sample collected two-hourly. Creatinine clearances were calculated at two, four and six hours during the septic state. No fluid boluses, mechanical ventilation or antibiotics were given.

After approximately a period of two weeks of rest, the sheep were crossed over to the other arm of the study, such that if the septic sheep had received AVP they would now receive placebo or viceversa.

Biochemical analysis

Plasma creatinine was measured with a Synchron CX-5 Clinical System (Beckman, Brea, CA, U.S.A.).

Statistical analysis

Comparisons of haemodynamics and regional blood flows between these two groups were performed according to the methodology described by Matthews and Altman (12) using the mean value for each variable during the time of observation.

Non-parametric paired statistics were used to compare the means for each variable over the 180 minutes of observation. Thus, comparison of placebo with AVP in the normal state and then, separately, in the septic state was performed using Wilcoxon's signed rank test.

A P<0.05 was considered statistically significant.

RESULTS

Normal sheep

Infusion of AVP (0.021U/min) did not significantly change MAP (84.3[+ or -]8.1 mmHg vs. 85.3[+ or -]5.9 mmHg; NS). Compared with infusion of vehicle, there was a tendency for AVP infusion to decrease HR (from 57.1[+ or -]10.0 to 50.3[+ or -]4.4 beats/min; NS), CO (from 3.52[+ or -]0.85 to 3.05[+ or -]0.68 1/min; NS) and total peripheral conductance (from 41.4[+ or -]0.5 to 37.0[+ or -] 9.7 ml/min/mmHg; NS), but these changes did not reach significance.

Infusion of AVP had differential actions on the regional circulation. Compared to the control group, AVP infusion induced a 14% decrease in mesenteric conductance (from 5.6[+ or -]1.7 to 4.8[+ or -]2.0 vs ml/min/ mmHg, P<0.05), which resulted in a 17% decrease in mesenteric blood flow (from 472.1[+ or -]163.8 to 393.0[+ or -] 134.9 ml/min, P<0.05) (Figures 1a and 1b). However, compared with vehicle, low dose AVP infusion had no effect on renal blood flow (227.0[+ or -]55.6 vs 212.7[+ or -] 61.7 ml/min; NS), renal conductance (2.7[+ or -]0.6 vs 2.5[+ or -]0.7 ml/min/mmHg; NS), coronary blood flow (24.0[+ or -]8.3 vs 25.4[+ or -]7.3 ml/min; NS) and coronary conductance (0.28[+ or -]0.09 vs 0.30[+ or -]0.08 ml/min/ mmHg; NS).There were no significant changes in urine output or creatinine clearance from baseline when comparing AVP to control animals.

[FIGURE 1a OMITTED]

[FIGURE 1b OMITTED]

Septic sheep

The induction of sepsis by administration of IV E.coli resulted in the development of the systemic inflammatory response syndrome: tachycardia (HR>140/min), fever (temperature >41[degrees]C) and tachypnoea (respiratory rate >30 breaths/min). The animals looked unwell for several hours, lay quietly in the cage and did not drink. Their mean arterial pressure fell and their cardiac output increased (hyperdynamic sepsis).

During low-dose AVP infusion there was no significant change in MAP (78.3[+ or -]6.7 mmHg) compared with the vehicle (77.5[+ or -]12.5 mmHg). However, AVP significantly reduced heart rate from 126.8[+ or -] 16.0 to 91.4[+ or -]15.1 beats/min (P<0.05) and CO from 5.82[+ or -]0.61 to 4.56[+ or -]1.37 1/min (P<0.05) (Figures 2a and 2b). AVP also reduced total peripheral conductance (78.0[+ or -]19.7 vs 61.9[+ or -]25.9 ml/min/mmHg; P<0.05).

[FIGURE 2a OMITTED]

[FIGURE 2b OMITTED]

Compared with infusion of vehicle, AVP significantly reduced mesenteric blood flow by 23% (from 611.3[+ or -]136.3 to 468.5[+ or -]159.7 ml/min, P<0.05) and mesenteric conductance by 23% (from 8.2[+ or -]2.7 to 6.3[+ or -]2.7 ml/min/mmHg; P<0.05) (Figure 3a and 3b). However, it did not alter renal blood flow (285.8[+ or -] 38.8 vs 316.4[+ or -]102.0 ml/min; NS) or renal conductance (3.8[+ or -]0.9 vs 4.2[+ or -]1.6 ml/min/mmHg; NS). Coronary flow (from 50.3[+ or -]16.3 to 34.7[+ or -]14.2 ml/min; P<0.05) was significantly decreased and coronary conductance also fell but not significantly (from 0.7[+ or -]0.2 to 0.5[+ or -] 0.2 ml/min/mmHg; NS).

The administration of AVP was associated with a significant increase in urine output and creatinine clearance compared to the control animals (P<0.05) (Figure 4a and 4b).

[FIGURE 3a OMITTED]

[FIGURE 3b OMITTED]

[FIGURE 4a OMITTED]

DISCUSSION

Our study demonstrated that infusion of a low dose of AVP infusion (0.02 IU/min in sheep of approximately 40 kg) had no significant effect on systemic haemodynamics but induced significant mesenteric vasoconstriction (decreased conductance) with decreased mesenteric blood flow in normal sheep. The same AVP infusion, when given to septic sheep, decreased cardiac output (CO) as well as mesenteric blood flow through significant mesenteric vasoconstriction. Furthermore, in normal sheep, AVP infusion was associated with a nonsignificant increase in urine output. This increase was more marked during sepsis and became statistically significant, in combination with a significant increase in creatinine clearance. These findings in a conscious large mammal have potential clinical relevance and require further discussion.

[FIGURE 4b OMITTED]

Central haemodynamic effects

In terms of central haemodynamic variables, we found no significant changes in MAP with AVP infusion at a rate of 0.02 IU/min in either normal or septic sheep. In normal human subjects, AVP has little effect on MAP (14), whereas more recent studies showed that AVP could increase MAP in clinical septic shock (4-9). It has been suggested that these different responses of MAP to AVP infusion are secondary to the low concentrations of AVP in septic shock (2,14). However, many of the studies showing an effect of AVP in MAP have combined AVP with another vasopressor agent. These observations suggest that AVP may potentiate the effect of other vasopressors but that, when used alone, it may have only a limited pressor effect. To our knowledge, there has not been any controlled trial comparing isolated low-dose AVP infusion to placebo in human septic shock. In a recent study in humans, Minzing et al needed to infuse an average of 0.47 IU/min of AVP to maintain blood pressure in septic shock (15). This is more than 20 times the dose we administered to our sheep. In animals, fixed low-dose AVP infusion at a dose equal to ours has been studied recently in a lethal model of sepsis in anaesthetized sheep". AVP was found to extend survival time and delay the onset of progressive hypotension. In this study, low-dose AVP could clearly be shown to induce vasoconstriction.

Low-dose AVP infusion significantly decreased cardiac output (CO) in septic animals and showed a trend towards decreasing CO in normal sheep. In both normal and septic sheep, these decreases in CO were associated with bradycardia and a reduction in total peripheral conductance (increase in systemic vascular resistance). These observations are not physiologically surprising. AVP is known to act on the area postrema to enhance baroreflex activity and, compared with other vasopressor agents, causes a greater fall in CO and HR for a given rise in pressure. In a clinical study, AVP infusion decreased CO by 14% (7). Our findings are also consistent with previous studies using higher doses of AVP (7,16-19). Although we cannot speculate whether this decreased CO would be clinically detrimental or not, our results strongly suggest that low-dose AVP infusion can decrease CO through decreased HR and peripheral vasoconstriction. These observations suggest that it might be undesirable to administer low-dose AVP in hypodynamic septic shock without the addition of a chronotropic agent (20).

Mesenteric circulation

Low-dose AVP infusion significantly decreased mesenteric blood flow in both normal and septic sheep. These findings are indirectly supported by studies in other clinical situations such as cardiopulmonary resuscitation and portal hypertension (21,22) where AVP has been used at higher doses. They demonstrate that, even at low dose, AVP reduces global mesenteric blood flow. The observation that, even at low doses, AVP remains a powerful mesenteric vasoconstrictor is supported by several recent studies in humans and animals (18,19,23-25). The clinical implications of such global mesenteric vasoconstriction and decreased gut blood flow are unknown. In our model, furthermore, aggressive fluid resuscitation was not performed. Such fluid resuscitation may attenuate AVP-induced decreases in mesenteric blood flow. This possible effect warrants further investigation. Nonetheless, our findings raise concerns about the physiological safety of low-dose AVP infusion. Given the lack of major mesenteric vasoconstriction with other vasopressor agents (26,27) they invite caution with its prescription.

Coronary circulation

Low-dose AVP was associated with a consistent trend towards coronary vasoconstriction and a decrease in coronary flow in septic sheep, which failed to achieve statistical significance. It is probable that the tendency of AVP to decrease coronary blood flow reflects changes in myocardial oxygen demand induced by decreased heart and rate and cardiac output.

Renal circulation

Low-dose AVP did not significantly affect renal blood flow but showed a slight trend toward an increased flow in septic animals. AVP however, increased urine output and creatinine clearance in the septic sheep and was associated with similar trends in normal animals. Previous studies have demonstrated that AVP infusion increased urine output (7,13,28,29) and creatinine clearance' but, to our knowledge, this is the first study to measure directly the effect of low dose AVP infusion on renal blood flow in conscious animals. Our findings suggest that, at a low dose, AVP might slightly increase renal blood flow and may have only a limited effect on the [V.sub.2] receptors responsible for anti-diuresis such that other effects on intra-renal haemodynamics (30) may overcome its normal antidiuretic effect. Our observations also confirm that, during the infusion of vasoactive drugs, urine output and creatinine clearance do not reliably reflect changes in renal blood flow. The mechanism by which AVP increases urine output and creatinine clearance remain speculative but, given AVP's vascular effects, might involve changes in glomerular vessel tone and consequent increases in glomerular filtration pressure.

Weaknesses and strengths of this study

Our study has several weaknesses and strengths. Our assessment of organ function was confined to urine output and creatinine clearance. In the clinical context, however, assessment of renal function beyond the indirect measurement of glomerular filtration rate by means of creatinine clearance is very difficult and of uncertain clinical significance. The assessment of gut function is also very difficult. Finally, we cannot draw any conclusions about the clinical consequences of our experimental observations. Physiological changes do not equate to differences in clinical outcomes. Only human randomized controlled trials of sufficient statistical power can address such issues.

We did not measure regional organ oxygen consumption because we have found that it is difficult to maintain the patency of chronically implanted venous cannulae in sheep. The liver is also a vital organ but hepatic blood flow was not measured. Given the decrease in mesenteric blood flow, hepatic blood flow might have also been adversely affected.

Our model of sepsis does not completely reproduce severe human sepsis. Severe human sepsis is associated with a mortality approaching 30%, while none of our experimental animals died. However, in this model, SIRS developed and three major criteria for a hyperdynamic circulation were present from the start and shown to be continuously present throughout the study period. There was also no confounding effect of immediately preceding surgical intervention 13. Nonetheless, the septic state was not sustained beyond 8-12 hours and our observations may not apply to lethal (13), prolonged or recurrent sepsis. Importantly, however, our animals were conscious and free of the confounding effects of anaesthesia or sedation on organ blood flow, which have affected previous animal studies (13).

No blood cultures were taken to test whether the animals were still bacteraemic at the time of organ flow assessment and no antibiotics were given to more closely simulate the human situation. In our model, there was a delay of several hours between the administration of the bacterial inoculum and the development of the hyperdynamic state. Others have observed this delay while studying sheep. On the other hand, in human beings, clinical observations suggest a shorter period between an event likely to cause bacteraemia and the onset of a septic circulation. Our model did not involve fluid resuscitation. Such resuscitation may attenuate the decrease in cardiac output or mesenteric flow we observed and requires investigation. All of these differences between our model and human sepsis must be taken into account in the interpretation of our findings. Finally, we used a fixed dose of AVP and did not adjust the infusion rate to achieve pre-set haemodynamic values. We chose the dose as the infusion rate reported in clinical series and other experiments (1,4,7,13) in order to maximize reproducibility and simplify the treatment protocol.

In conclusion, we have conducted the first study of prolonged low-dose AVP infusion in conscious large mammals under normal and septic conditions, while continuously measuring systemic haemodynamics and coronary, mesenteric and renal blood flow, as well as urine output and creatinine clearance. We found that low-dose AVP infusion induces a significant increase in mesenteric vascular resistance (decreased conductance) with an associated decrease in mesenteric blood flow. We also found that it decreases heart rate and cardiac output, while it significantly increases urine output and creatinine clearance in septic animals. These observations provide useful information and physiological insights for clinicians faced with the selection of vasoactive drugs in critically ill patients.

Accepted for publication on May 9, 2006.

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(30.) Levy B, Vallee C, Lauzier F et al. Comparative effects of vasopressin, norepinephrine, and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock. Am J Physiol Heart Cite Physiol 2004; 287:H209-H215.

D. DI GIANTOMASSO *, H. MORIMATSU ([dagger]), R. BELLOMO ([double dagger]), C. N. MAY ([section])

Howard Florey Institute, University of Melbourne, and Departments of Intensive Care and Surgery, Austin Health, Heidelberg and University of Melbourne, Melbourne, Victoria, Australia

(*) M.B., B.S., Departments of Intensive Care and Surgery, Austin Health, Heidelberg and University of Melbourne.

([dagger]) M.D., Departments of Intensive Care and Surgery, Austin Health, Heidelberg and University of Melbourne.

([double dagger]) Ph.D., Howard Florey Institute, University of Melbourne.

([section]) Ph.D., Howard Florey Institute, University of Melbourne.

Address for reprints: Professor Rinaldo Bellomo, Department of Intensive Care, Austin Hospital, Heidelberg, Vic 3084.

This study was supported by an institute grant (no. 983001) from the National Health and Medical Research Council of Australia and by grants from the Austin Hospital Anaesthesia and Intensive Care Trust Fund, the Australian and New Zealand Intensive Care Society Foundation and the Laerdal Foundation.
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Title Annotation:Original Papers
Author:Di Giantomasso, D.; Morimatsu, H.; Bellomo, R.; May, C.N.
Publication:Anaesthesia and Intensive Care
Date:Aug 1, 2006
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