Levophed

After induction of cecal perforation, 20 anesthetized sheep were randomized to be treated, when arterial blood pressure fell below 75 mm Hg, with vasopressin (fixed dose of 0.02 U/minute), norepinephrine (0.5-5 [mu] g/kg/minute titrated to maintain mean arterial pressure between 75 and 85 mm Hg), vasopressin + norepinephrine (vasopressin at fixed dose 0.01 U/minute plus norepinephrine titrated as for norepinephrine only group), or no vasopressor (Ringer's lactate [control]). Mean arterial pressure was well maintained in all treatment groups. Superior mesenteric arterial blood flow was significantly lower in the vasopressin + norepinephrine group than in the vasopressin group. Vasopressin alone or combined with norepinephrine limited the increase in blood lactate concentration and ileal PCO^sub 2^-gap compared with control and norepinephrine groups. Urine output was higher in the vasopressin group than in control and norepinephrine groups. Survival time was longer in the vasopressin (30 + or - 6 hours) and vasopressin + norepinephrine (30 + or - 3 hours) groups than in the norepinephrine group (20 + or - 1 hours, p

Keywords: norepinephrine; peritonitis; sheep; survival time; histologic abnormality

Septic shock is the circulatory insufficiency that develops in response to overwhelming systemic infection. The central characteristics of septic shock are systemic vasodilation and myocardial depression resulting in hypotension requiring vasopressor agents such as norepinephrine to maintain mean arterial blood pressure (MAP) (1, 2).

Arginine vasopressin is a vasomodulatory hormone with unique properties including pulmonary vasodilation and systemic and renal efferent arteriolar vasoconstriction (3). It is also an intriguing vasopressor because it has little presser effect in normal subjects (4-6) but markedly increases blood pressure when sympathetic nerve function is impaired (7-9). Endogenous vasopressin concentrations may be directly related to the perfusion of vital organs and consequently survival. Indeed, Landry and coworkers (10) found that plasma concentrations of vasopressin were inappropriately low in patients with septic shock, and suggested the usefulness of exogenous replacement therapy. Other studies have shown significant increases in MAP and in urine output during the administration of low doses of vasopressin in patients with septic shock (11-15).

The present study was thus designed to study the effects of low-dose vasopressin alone, or in combination with norepinephrine, on hemodynamics, histologic changes, and survival time in a sheep model of septic shock due to peritonitis.

METHODS

Experimental Preparation

This study was approved by our Institutional Review Board for animal care. Care and handling of the animals was in accord with National Institutes of Health guidelines. Twenty-four mature female sheep (weight 29.2 + or - 3.0 kg) were included in the study. After endotracheal intubation under intramuscular injection of 40 mg xylazine (Bayer, Lcverkuscn, Germany) and 150 mg ketamine (Ketalar; Warner-Lambert Manufacturing Ltd, Dublin, Ireland), the sheep were anesthetized with infusion of the mixture of midazolam (Dormicum; Hoffmann-La Roche, Basel, Switzerland) and fentanyl (Janssen Pharmaceutica, Beerse, Belgium), using an infusion pump (Perfusor secura; Braun, Melsungen AG, Germany), and mechanically ventilated with a mixture of air and oxygen (Servo ventilator 900B; Siemens-Elema, Solna, Sweden). Muscle paralysis was obtained by administration of pancuronium bromide, administered at an initial dose of 0.15 mg/kg and subsequent infusion of 0.075 mg/kg/hour. Respiratory rate was 14 breaths/minute, and tidal volume was adapted to keep end-tidal PCO^sub 2^ (47210A Capnometer; Hewlett-Packard, Waltham, MA) between 28 and 38 mm Hg. The left lower forelimb vein was cannulated for intravenous administration of anesthesia and pancuronium bromide. The right lower forelimb vein was catheterized for intravenous infusion of Ringer's lactate. The right femoral artery was catheterized for monitoring of arterial blood pressure and withdrawal of arterial blood samples. Through the right jugular vein, a balloon-tip pulmonary artery catheter (93A-439H-7.5F; Baxter Edwards Critical-Care, Irvine, CA) was placed under guidance of pressure waves (Sirecust monitor 404; Siemens, Davis, CA). Through a midline laparotomy, the cecal and ileocecal junction was identified. After a 1-cm perforation in the cecal tip, spillage of fecal material (~30 ml) into the peritoneal cavity was directed to the right lower quadrant. Ultrasonic flow probes were placed around the left femoral artery and the superior mesenteric artery for simultaneous determination of regional blood flow. Before closure of the abdomen, a tonometric catheter (TRIP, NGS catheter; Tonometrics, Helsinki, Finland) was inserted into the ileum to measure ileal intramucosal CO2 tension (PiCO^sub 2^). The abdomen was then closed with a running suture of 0 Dexon. A Foley catheter was introduced via the urethra to collect urine. In all sheep, fluid maintenance was approximately 1,000 ml of Ringer's lactate during the course of surgery, titrated to keep pulmonary arterial occlusion pressure (PAOP) constant thereafter. Potassium chloride (7.45% Kalii Chloridum; Braun) was added to the Ringer's lactate solution as needed to keep plasma potassium concentrations between 3.5 to 5.0 mmol/L throughout the experiment.

Experimental Protocol

Four sheep were studied without peritonitis, the only difference in the procedure being that there was no cecal perforation or spillage of fecal material into the peritoneal cavity. The experiments were slopped by potassium chloride injection after 46 hours.

The other 20 sheep were randomized to one of four experimental groups of five sheep each. The original solution of norepinephrine (Levophed, 2 mg/ml; Sanofi-Pharma, Brussels, Belgium) was diluted in saline to obtain a 0.8-mg/mL solution. The original solution of vasopressin (POR 8, 5 U/ml; Ferring, Vienna, Austria) was diluted to obtain a 1-U/mL solution.

Group 1. Control group. No vasopressor was administered.

Group 2. Vasopressin group. When MAP fell to less than 75 mm Hg, vasopressin solution was infused at a fixed dose of 0.02 U/minute.

Group 3. Norepinephrine group. When MAP fell to less than 75 mm Hg, a norepinephrine infusion was started at 0.5 [mu]g/kg/minute and increased by 0.5 [mu]g/kg/minute increments every 5 minutes as necessary to maintain MAP between 75 and 85 mm Hg, up to a maximum dose of 5 [mu]g/kg/minute.

Group 4. Vasopressin + norepinephrine group. When MAP fell to less than 75 mm Hg, a vasopressin infusion was administered at a fixed dose of 0.01 U/minute, together with a norepinephrine infusion titrated as for group 3.

Measurements were repeated each hour throughout the experiment, including MAP, pulmonary artery pressure, pulmonary arterial occlusion pressure, cardiac output, femoral and superior mesenteric arterial blood flows, end-tidal PCO^sub 2^, minute volume, blood gases, arterial hemoglobin concentration, arterial blood lactate and electrolyte (potassium, sodium, calcium, chloride) concentrations, PiCO^sub 2^, and urinary output.

Pressures were monitored continuously using a pressure-monitoring kit (Baxter, Uden, Holland) with amplifiers (Servomed; Hellige, Freiburg, Germany) and a pen recorder (2600S; Gould (Instruments Division), Cleveland, OH). All pressures were determined at end-expiration. Cardiac output was measured in triplicate by the thermodilution technique (Swan-Ganz catheter; Baxter, Irvine, CA), using 10 ml of iced saline solution (0[degrees]C) at end-expiration. Systemic vascular resistance (SVR) and pulmonary vascular resistance were calculated using standard formulae. Blood flows of the superior mesenteric and femoral arteries were simultaneously measured using an ultrasound volume flowmeter (T208, Transonic Systems, Ithaca, NY, calibrated by the manufacturer).

Exhaled gases were directed through a mixing chamber for sampling of expired oxygen fractions (P.K. Morgan Ltd, Chatham, UK). Expired minute volume was measured with a spiromctcr (Haloscale Respirometer; Wright, Edmonton, London, UK) over a 2-minute period. Arterial and mixed venous blood samples were simultaneously withdrawn for immediate determination of blood gas (ABL500; Radiometer, Copenhagen, Denmark), arterial and mixed venous oxygen saturations, and total hemoglobin (OSM 3 Hemoximeter; Radiometer). Blood lactate and electrolyte (K+, Na+, Ca^sup 2+^, Cl-) concentrations were determined by an analyzer (ABL625; Radiometer). PiCO^sub 2^ was measured by saline tonometry using the standard technique. The tonometer balloon was filled with 2.5 ml of saline and allowed to equilibrate for approximately 60 minutes. Saline was anaerobically aspirated, the first milliliter was discarded, and the remaining 1.5 ml was analyzed immediately using the blood gas analyzer. The PCO^sub 2^-gap was calculated as the difference between PiCO^sub 2^ and arterial PCO^sub 2^. The fluid balance was calculated as the difference between infusion volume and urine output.

Postmortem Examination

When the sheep died, tissue samples were surgically excised from the lung, the liver, and the gut, and immediately immersed in 4% formalin (pH 7). The samples were sectioned and stained with hematoxylin and eosin for light microscopy. All biopsies were coded to enable processing and evaluation. A pathologist unfamiliar with the conditions of the study examined all fields of the slides in a blinded fashion, and 10 micrographs from each specimen were taken from consecutive squares to define the degree of the anatomic abnormality in a semiquantitative way. The degree of each abnormality was graded numerically from 0 to 3 in the intestine specimens and from 0 to 2 in the other tissue samples (16).

Statistics

Data were analyzed by a two-way (time and treatment) analysis of variance for repeated measurements. When the F value was statistically significant, a Dunnett's test was used. Missing values were estimated using the method proposed by Yates that minimizes the error sum of squares (17). The error degree of freedom is reduced by the number of missing data. By doing this, (1) the estimates of group and time effects are exactly the same as those obtained by the correct least square procedure and (2) the error sum of squares is exactly the same as given by the correct procedure. The correct least square approach uses the Type III or Type IV sum of squares, in which the characteristics equations are solved by the general inverse technique. A Kruskal-Wallis test was used to evaluate the differences in the degrees of anatomic abnormalities. Kaplan-Meier survival curves were constructed and analyzed by the Mantel-Cox log-rank test. A p value less than 0.05 was considered statistically significant. All values are expressed as mean + or - SD.

RESULTS

In the initial animals studied without peritonitis, the model proved stable: animals developed no hyperthermia or leukocytosis; heart rate, cardiac output and arterial pressure remained stable; and there were no biochemical abnormalities such as hyperlactatemia or increased PCO^sub 2^-gap. The four animals survived 46 hours after closure of the abdomen. No significant anatomic changes were noted at the end of the experiment.

In the remaining 20 sheep, no significant differences were observed among the four groups in hemodynamic or metabolic parameters at baseline (Figures 1-4). Vasoactive interventions were started approximately 11 hours after the surgical procedure in all animals (11 + or - 2 hours in the vasopressin group, 11 + or - 1 hours in the norepinephrine group, and 11 + or - 1 hours in the vasopressin + norepinephrine group), when MAP dropped below 75 mm Hg. Sheep in the norepinephrine group received 1.4 + or - 0.5 [mu]g/kg/minute of norepinephrine, and sheep in the vasopressin + norepinephrine group received 1.1 + or - 0.3 [mu]g/kg/minute of norepinephrine. MAP was well maintained in all treatment groups (p

Cardiac output increased in all groups after the induction of peritonitis (Figure 2). Cardiac output was significantly lower in the vasopressin group than in the vasopressin + norepinephrine group. Superior mesenteric arterial blood flow was significantly lower in the vasopressin + norepinephrine group than in the vasopressin group. Systemic vascular resistance was significantly higher in the vasopressin + norepinephrine and vasopressin groups than in the control group. There were no significant differences between groups in stroke volume, left ventricular stroke work, oxygen delivery and consumption, oxygen extraction, and femoral arterial blood flow.

Vasopressin alone or combined with norepinephrine, but not norepinephrine alone, significantly limited the increase in blood lactate concentration seen in the control animals (Figure 3). There were no significant differences in blood lactate levels between the vasopressin and vasopressin + norepinephrine groups, or the control and norepinephrine groups. Pco^sub 2^-gap increased significantly in the control and norepinephrine groups. The Pco^sub 2^-gap was lowest in the vasopressin + norepinephrine group (Figure 3).

Figure 4 shows cumulative infusion volume, cumulative urine output, and the fluid balance. Less intravenous fluids were needed in all treatment groups than in the control group. Fluid requirements were also lower in the vasopressin + norepinephrine group than in the vasopressin or norepinephrine group. Conversely, the urine output was higher in the vasopressin group than in the control and norepinephrine groups. Fluid balance was more positive in the control group than in the treatment groups, and of the four groups it was lowest in the vasopressin + norepinephrine group (p

There were no significant differences between the groups in sodium or other electrolyte concentrations (Table E1, online supplement), or in the dose of potassium chloride administered (5.4 + or - 0.5 mmol/hour in the control group, 4.8 + or - 0.6 mmol/hour in the norepinephrine group, 4.8 + or - 0.6 mmol/hour in the vasopressin group, and 5.0 + or - 0.7 mmol/hour in the vasopressin + norepinephrine group).

The survival time was significantly longer in all treatment groups than in the control group (p

DISCUSSION

This septic shock model produced by the spillage of feces into the peritoneum, followed by general fluid administration, reproduces many of the clinical features of human septic shock, including hyperthermia, leukocytosis, tachycardia, increased cardiac output, arterial hypotension, low systemic vascular resistance, altered coagulation, and hyperlactatemia. Without antibiotic administration, and with no other support than Ringer's lactate fluid loading, death occurred approximately 17 hours after the induction of peritonitis.

Vasopressin is an endogenous peptide hormone secreted by the neurohypophysis in response to an increase in serum osmolality or a decrease in plasma volume (18). There are several mechanisms involved in regulating the secretion of vasopressin, including hypothalamic osmoreceptors, left atrial stretch receptors, and arterial baroreceptors (19). The normal plasma vasopressin concentration in a hemodynamically stable subject is 2.2-4.0 pg/ml for a serum osmolality of

Vasopressin has little vasopressor activity in normal subjects, in whom continuous infusions up to 0.26 U/minute failed to show vasopressor effects (20, 25, 26). Yet in patients with septic shock, vasopressin has strong vasoconstrictive effects, demonstrated in several studies by an increased MAP and systemic vascular resistance (10-15). These human studies of vasopressin administration in septic shock have generally used doses of 0.01-0.04 U/minute (10-13), so we selected a dose of 0.01-0.02 U/minute for our 29-kg sheep.

The vasoconstrictor effect of vasopressin is more potent than that of angiotensin II or norepinephrine (27). In addition, vasopressin can potentiate the vasoconstrictor action of conventional catecholamine vasopressors (28) and interact with the elevated endogenous levels of circulating catecholamines that are known to occur during septic shock (29). Indeed, in the present study, MAP was better maintained in the vasopressin group than in the norepinephrine group, even though the dose of vasopressin was very low. Several clinical studies have reported that catecholamine requirements are reduced during vasopressin administration (11, 12, 14, 15, 30). In hypotensive septic shock, the catecholamine [alpha]-1 adrenergic receptors may be desensitized or down-regulated to standard catecholamine vasopressors. Although the phosphatidylinositol second-messenger system is involved in vasopressin and catecholamine action (31), the vascular vasoconstriction is mediated by different receptors. Because vasopressin binds to its own V^sub 1^ vascular receptor, it may still assist in restoring peripheral vascular tone if the catecholamine [alpha]-1 adrenergic receptors are down-regulated.

In the present study, vasopressin + norepinephrine limited the increase in superior mesenteric blood flow that was seen in the vasopressin alone group. Vasopressin is known to be a potent constrictor of vascular and intestinal smooth muscle (32-34). Vasopressin can decrease mesenteric artery blood flow (33, 34), and this property has been used clinically in the control of gastro-intestinal hemorrhage (35, 36). This reduction in splanchnic blood flow is potentially deleterious in septic shock. We did not see such a decrease in superior mesenteric blood flow perhaps because the dose of vasopressin was very low. In addition, in the present study, vasopressin alone or vasopressin + norepinephrine limited the increase in blood lactate concentration and Pco^sub 2^-gap more than norepinephrine alone.

Elevated plasma vasopressin concentrations have been implicated in depression of myocardial function (19, 37). In the present study, cardiac output increased less with vasopressin alone than with vasopressin + norepinephrine; this may have been due to the lower dose of vasopressin in the vasopressin + norepinephrine group. However, the positive inotropic effect of norepinephrine was likely contributory (19, 37). To illustrate this possibility, Wilson and coworkers (37) studied the pumping ability of the canine isolated working heart, and found that high vasopressin concentrations could elevate left ventricular end diastolic pressure and reduce coronary blood flow. However, when the vasopressin-treated heart was challenged with epinephrine, myocardial function returned to control values except for an even lower coronary blood flow. The authors concluded that the adverse effects of vasopressin on the heart are masked during the early phase of shock when catecholamine concentrations are high, and only revealed when catecholamine supplies are exhausted but elevated vasopressin plasma levels remain.

As an antidiuretic hormone, vasopressin acts on the renal tubule at low plasma concentrations (19). In our study, urine output was significantly higher in the vasopressin and vasopressin + norepinephrine groups. Although urine output was also higher in the norepinephrine group compared with the control group, it was not as high as in the vasopressin and vasopressin + norepinephrine groups. In a recent, randomized clinical study, Patel and coworkers (30) showed that patients treated with vasopressin (0.01-0.08 U/minute) had greater urine output and increased creatinine clearance compared with patients treated with norepinephrine. The difference in urine output between norepinephrine and vasopressin may be due to their different effects on the glomerular arteriole. Indeed, the glomerular afferent arteriole is constricted by norepinephrine (38), whereas, in contrast, vasopressin appears to constrict only the glomerular efferent arteriole (39), thus maintaining the glomerular filtration rate. It is known that vasopressin acts on the renal collecting duct to promote water and sodium reabsorption (40, 41). It has also been shown that addition of vasopressin results in net chloride reabsorption (42-44). In the present study, plasma sodium concentrations did not decrease, and normal plasma sodium concentrations (mean 140 mmol/L) were also confirmed in patients with septic shock treated with 0.04 U/minute of vasopressin (10).

Norepinephrine prolonged survival by 3 hours compared with the control group, but vasopressin, or vasopressin + norepinephrine, prolonged survival by as much as 13 hours. In a study of patients with septic shock, Malay and coworkers (12) found that all patients with septic shock receiving 0.04 U/minute vasopressin survived a 24-hour study period compared with three of live patients in a placebo group. The possible reasons for the prolongation of survival in the vasopressin or vasopressin + norepinephrine group are multiple. First, better maintained arterial blood pressure may have simply improved organ perfusion. Also, the lower blood lactate concentrations and Pco^sub 2^-gap suggest less ischemia in the gut. Less fluid infusion and more urine output will have prevented tissue edema and therefore improved oxygenation. Indeed, the histologic findings revealed less damage, suggesting better functional organ capacity in these animals.

We acknowledge the limitations of this study. First, although the model shows many of the features of human septic shock, it may not replicate the human situation exactly, as the sheep is a ruminant. Second, peritonitis induced by fecal spillage is only one of many possible causes of human septic shock. Third, for experimental reasons, fecal spillage was allowed during the experiment, whereas eradication of the infectious focus is an important part of the management of the patient with septic shock. In addition, no antibiotic therapy was administered, as this was a lethal model. Fourth, anesthesia and ventilation were maintained in all animals throughout the study to minimize suffering and experimental bias, which may not reflect the clinical situation in all patients. Finally, for technical reasons it was not possible to measure plasma vasopressin concentrations in the animals.

Despite these limitations, we conclude that low dose vasopressin, alone or in combination with norepinephrine, maintains arterial blood pressure, mesenteric blood flow, and cardiac output, limits the increase in blood lactate concentrations and Pco^sub 2^-gap, and prolongs survival time in this clinically relevant model of sepsis. Prospective, randomized clinical studies are needed to test whether vasopressin administration can alter the outcome of septic shock.

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Qinghua Sun, George Dimopoulos, Duc Nam Nguyen, Zizhi Tu, Nathalie Nagy; Anh Dung Hoang, Peter Rogiers, Daniel De Backer, and Jean-Louis Vincent

Department of Intensive Care, Erasme Hospital, Free University of Brussels, Brussels, Belgium

(Received in original form May 21, 2002; accepted in final form May 22, 2003)

Correspondence and requests for reprints should be addressed to Jean-Louis Vincent, M.D., Ph.D. Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium. E-mail: jlvincen@ulb.ac.be

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