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Is low-dose vasopressin the new reno-protective agent?
Acute kidney injury (AKI) remains a frequent and serious complication of surgical procedures and critical illness that is consistently associated with worse outcomes and increased long-term morbidity and mortality. Much work has gone into finding kidney protective measures with disappointingly few therapeutic options available to prevent or to treat AKI. Research has defined some effective kidney protective practices and the purpose of this chapter is to help the clinician to differentiate better clinical practices that are either ineffective, detrimental, or protective to the kidney. The chapter will first provide an introduction to kidney physiology with particular focus on areas that make it vulnerable to injury. The chapter will then shift focus to diagnosis of kidney injury including definitions and early biomarkers that can help risk stratify patients. Then, specific mechanisms of postoperative and critical illness-associated kidney injury will be outlined. The rest of the chapter will review evidence from renal-protective research studies pertinent to the preoperative, intraoperative, and postoperative periods. After reading this chapter, the clinician should have a more robust framework for adoption (mostly avoidance) of renal protective practices (stratified based on level of evidence available) to guide their clinical practice.
For much of the last four decades, low-dose dopamine has been considered the drug of choice to treat and prevent renal failure in the intensive care unit (ICU). The multifactorial etiology of renal failure in the ICU and the presence of coexisting multisystem organ dysfunction make the design and execution of clinical trials to study this problem difficult. However, in the last decade, several meta-analyses and one large randomized trial have all shown a lack of benefit of low-dose dopamine in improving renal function. There are multiple reasons for this lack of efficacy. While dopamine does cause a diuretic effect, it does very little to improve mortality, creatinine clearance, or the incidence of dialysis. Evidence is also growing of its adverse effects on the immune, endocrine, and respiratory systems. It may also potentially increase mortality in sepsis. It is the opinion of the authors that the practice of using low-dose dopamine should be abandoned. Other drugs and treatment modalities need to be explored to address the serious issue of renal failure in the ICU.
The vasoconstrictive and antidiuretic physiologic properties of vasopressin (antidiuretic hormone) have long been known. Until recently however, vasopressin was mostly used for diabetes insipidus and noctournal enuresis. This review summarizes the growing body of evidence regarding the perioperative use of vasopressin and its analogues in the management of certain forms of cardiovascular collapse. Physiologically, vasopressin is involved in regulating osmotic, volemic, and cardiovascular homeostasis. It acts via several specific vasopressin receptors that are variably distributed in the heart, kidneys and vasculature etc. Under normal conditions, its antidiuretic effect predominates and vasopressin only induces vasoconstriction at high concentrations. Regarding catecholamine-resistant vasodilatory shock, current evidence suggests that with adequate volume resuscitation, exogenous vasopressin in low "physiologic" doses (0.01-0.04 units/min) safely supports mean arterial pressure without adversely affecting myocardial function and splanchnic circulation. One possible explanation is that metabolic acidosis impairs the function of alpha-adrenergic (but not vasopressin) receptors, thus diminishing the response to catecholamines. Although there is yet no clear cut mortality benefit, vasopressin is now recommended as a second-line agent in septic shock for its catecholamine-sparing effect and as an alternative to epinephrine in cardiopulmonary resuscitation. It has also demonstrated efficacy in ameliorating vasoplegia after cardiopulmonary bypass as well as perioperative hypotension in patients on renin-angiotensin system antagionists preoperatively. In summary, accumulating clinical experience and formal studies indicate that vasopressin has a role in restoring vascular tone in refractory vasodilatory shock states with minimal adverse effects provided that euvolemia is assured.
Catecholamines remain fundamental in the treatment of circulatory failure; however, clinicians must focus their attention not only on the hemodynamic effects but also on using a more rationale approach considering the metabolic, endocrinologic, and immunologic consequences of catecholamine administration. Looking at alternative strategies to catecholamines in the treatment of shock, evidence of their beneficial effects on hemodynamic endpoints of vasopressin during septic shock is accumulating. Nevertheless, there are no data demonstrating the superiority of vasopressin to catecholamines in terms of mortality and morbidity, and no definitive conclusion can be drawn with respect to the potential detrimental effects of vasopressin on splanchnic circulation. Furthermore, the metabolic and immunologic consequences of vasopressin remain an open issue. Currently, the use of vasopressin is recommended only in clinical investigation protocols.
Pharmacological studies in humans and animals suggest the existence of vascular endothelial vasopressin (AVP)/oxytocin (OT) receptors that mediate a vasodilatory effect. However, the nature of the receptor subtype(s) involved in this vasodilatory response remains controversial, and its coupled intracellular pathways are unknown. Thus, we set out to determine the type and signaling pathways of the AVP/OT receptor(s) expressed in human vascular endothelial cells (ECs).
Saturation binding experiments with purified membranes of primary cultures of ECs from human umbilical vein (HUVEC), aorta (HAEC), and pulmonary artery (HPAEC) and [3H]AVP or[ 3H]OT revealed the existence of specific binding sites with a greater affinity for OT than AVP (Kd = 1.75 vs. 16.58 nm). Competition binding experiments in intact HUVECs (ECV304 cell line) with the AVP antagonist[ 125I]4-hydroxyphenacetyl-d-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-NH2 or the OT antagonist[ 125I]d(CH2)5[O-Me-Tyr-Thr-Orn-Tyr-NH2]vasotocin, and various AVP/OT analogs confirmed the existence of a single class of surface receptors of the classical OT subtype.
RT-PCR experiments with total RNA extracted from HUVEC, HAEC, and HPAEC and specific primers for the human V1 vascular, V2 renal, V3 pituitary, and OT receptors amplified the OT receptor sequence only. No new receptor subtype could be amplified when using degenerate primers. DNA sequencing of the coding region of the human EC OT receptor revealed a nucleotide sequence 100% homologous to that of the uterine OT receptor reported previously.
Stimulation of ECs by OT produced mobilization of intracellular calcium and the release of nitric oxide that was prevented by chelation of extra- and intracellular calcium. No stimulation of cAMP or PG production was noted. Finally, OT stimulation of ECs led to a calcium- and protein kinase C-dependent cellular proliferation response.
Thus, human vascular ECs express OT receptors that are structurally identical to the uterine and mammary OT receptors. These endothelial OT receptors produce a calcium-dependent vasodilatory response via stimulation of the nitric oxide pathway and have a trophic action.
Profound vasoconstriction in the peripheral circulation is the normal response to conditions in which the arterial pressure is too low for adequate tissue perfusion, such as acute hemorrhagic or cardiogenic shock. In other conditions, the most frequent of which is septic shock,1,2 hypotension occurs as a result of failure of the vascular smooth muscle to constrict. Such so-called vasodilatory shock is characterized not only by hypotension due to peripheral vasodilatation but also by a poor response to therapy with vasopressor drugs. This syndrome has long attracted interest and defied understanding, but recent work on the function of vascular smooth . . .
Low-dose dopamine administration (ie, doses < 5 microg/kg/min) has been advocated for 30 years as therapy in oliguric patients on the basis of its action on dopaminergic renal receptors. Recently, a large, multicenter, randomized, controlled trial has demonstrated that low-dose dopamine administered to critically ill patients who are at risk of renal failure does not confer clinically significant protection from renal dysfunction. In this review, we present the best evidence and summarize the effects of low-dose dopamine infusion in critically ill patients. We review the history and physiology of low-dose dopamine administration and discuss the reasons why dopamine is not clinically effective in the critically ill. In addition to the lack of renal efficacy, we present evidence that low-dose dopamine administration worsens splanchnic oxygenation, impairs GI function, impairs the endocrine and immunologic systems, and blunts ventilatory drive. We conclude that there is no justification for the use of low-dose dopamine administration in the critically ill.
Vasopressin is emerging as a rational therapy for vasodilatory shock states. Unlike other vasoconstrictor agents, vasopressin also has vasodilatory properties. The goal of the present review is to explore the vascular actions of vasopressin. In part 1 of the review we discuss structure, signaling pathways, and tissue distributions of the classic vasopressin receptors, namely V1 vascular, V2 renal, V3 pituitary and oxytocin receptors, and the P2 class of purinoreceptors. Knowledge of the function and distribution of vasopressin receptors is key to understanding the seemingly contradictory actions of vasopressin on the vascular system. In part 2 of the review we discuss the effects of vasopressin on vascular smooth muscle and the heart, and we summarize clinical studies of vasopressin in shock states.
Vasopressin is emerging as a rational therapy for vasodilatory shock states. In part 1 of the review we discussed the structure and function of the various vasopressin receptors. In part 2 we discuss vascular smooth muscle contraction pathways with an emphasis on the effects of vasopressin on ATP-sensitive K+ channels, nitric oxide pathways, and interaction with adrenergic agents. We explore the complex and contradictory studies of vasopressin on cardiac inotropy and coronary vascular tone. Finally, we summarize the clinical studies of vasopressin in shock states, which to date have been relatively small and have focused on physiologic outcomes. Because of potential adverse effects of vasopressin, clinical use of vasopressin in vasodilatory shock should await a randomized controlled trial of the effect of vasopressin's effect on outcomes such as organ failure and mortality.
Arginine vasopressin is being used increasingly to treat vasodilatory hypotension, although little is known of its effects on regional perfusion. Arginine vasopressin hemodynamic effects in physiology are mainly mediated through the V1a receptor on blood vessels. To investigate this further, we studied the effect of arginine vasopressin on systemic and renal blood flow in anesthetized, ventilated rabbits given either intravenous saline or endotoxin, and the impact of blocking V1a receptors.
Prospective, randomized, controlled study.
Animal research laboratory.
Male White New Zealand rabbits.
Measurement was made of mean arterial blood pressure, aortic and renal blood flow velocities (pulsed Doppler), and renal cortical and medullary flow (laser Doppler).
In a first series of animals, incremental intravenous boluses of arginine vasopressin ranging from 1 to 1000 ng were administered 90 mins postendotoxin or saline. In control rabbits (n = 9), increasing doses of arginine vasopressin elevated mean arterial blood pressure but reduced both aortic and renal blood flow velocity and renal cortical flow (p <.05). In endotoxic animals (n = 6), arginine vasopressin produced a similar increase in mean arterial blood pressure although aortic flow was maintained while renal blood flow velocity increased, mostly in its diastolic component (p <.05). Pretreatment with the V1a receptor antagonist in a second series of animals blunted all the effects observed in both control (n = 5) and endotoxic (n = 6) animals, suggesting that arginine vasopressin acted mainly through V1a subtype in this early phase of sepsis.
Preservation of renal blood flow with arginine vasopressin during endotoxemia, in particular to the cortex, suggests it could be a promising agent for hemodynamic support during septic shock.
Low-dose dopamine administration (ie, doses < 5 μg/kg/min) has been advocated for 30 years as therapy in oliguric patients on the basis of its action on dopaminergic renal receptors. Recently, a large, multicenter, randomized, controlled trial has demonstrated that low-dose dopamine administered to critically ill patients who are at risk of renal failure does not confer clinically significant protection from renal dysfunction. In this review, we present the best evidence and summarize the effects of low-dose dopamine infusion in critically ill patients. We review the history and physiology of low-dose dopamine administration and discuss the reasons why dopamine is not clinically effective in the critically ill. In addition to the lack of renal efficacy, we present evidence that low-dose dopamine administration worsens splanchnic oxygenation, impairs GI function, impairs the endocrine and immunologic systems, and blunts ventilatory drive. We conclude that there is no justification for the use of low-dose dopamine administration in the critically ill.
Objective:
To review all cases of septic shock treated with vasopressin to determine the effects on hemodynamic and renal function and to document any adverse effects.
Setting:
A 14-bed mixed medical-surgical ICU of St. Paul's Hospital, a 450-bed tertiary referral hospital affiliated with the University of British Columbia.
Patients:
All ICU patients who received vasopressin for treatment of severe septic shock between August 5, 1997, and March 21, 1999.
Results:
We identified 50 patients: age 60 (+/-14); APACHE II score 27 (+/-7). Baseline data (T0) was compared to data at T4, T24 and T48 (4, 24 and 48 h) on infusion. Mean arterial pressure (MAP) increased by 18% from T0 to T4 and remained stable at T24 (p=0.006) and T48 (p=0.008). Systolic pulmonary artery pressure (PAP) was unchanged at 45+/-13 mmHg. Mean cardiac index (CI) decreased by 11% at T4 (p=0.03). Urine output increased 79% at T4 (p=0.005) and further increases were not significant at T24 and T48. Mean pressor dosage decreased by 33% at T4 (p=0.001), by 53% at T24 (p=0.002) and by 48% at T48 (p=0.01). Hospital mortality was 85%. There were six cardiac arrests; all but one occurred at a vasopressin dose of 0.05 U/min or more.
Conclusions:
In this group of patients with severe septic shock, vasopressin infusion increased MAP and urine output and decreased catecholamine requirements. Doses higher than 0.04 U/min were not associated with increased effectiveness and may have been associated with higher adverse effects.
The hypotension of septic shock is due to systemic vasodilation. On the basis of a clinical observation, we investigated the possibility that a deficiency in vasopressin contributes to the vasodilation of septic shock.
In 19 patients with vasodilatory septic shock (systolic arterial pressure [SAP] of 92 +/- 2 mm Hg [mean +/- SE], cardiac output [CO] of 6.8 +/- 0.7 L/min) who were receiving catecholamines, plasma vasopressin averaged 3.1 +/- 1.0 pg/mL. In 12 patients with cardiogenic shock (SAP, 99 +/- 7 mm Hg; CO, 3.5 +/- 0.9 L/min) who were also receiving catecholamines, it averaged 22.7 +/- 2.2 pg/mL (P < .001). A constant infusion of exogenous vasopressin to 2 patients with septic shock resulted in the expected plasma concentration, indicating that catabolism of vasopressin is not increased in this condition. Although vasopressin is a weak pressor in normal subjects, its administration at 0.04 U/min to 10 patients with septic shock who were receiving catecholamines increased arterial pressure (systolic/diastolic) from 92/52 to 146/66 mm Hg (P < .001/P < .05) due to peripheral vasoconstriction (systemic vascular resistance increased from 644 to 1187 dyne.s/cm5; P < .001). Furthermore, in 6 patients with septic shock who were receiving vasopressin as the sole pressor, vasopressin withdrawal resulted in hypotension (SAP, 83 +/- 3 mm Hg), and vasopressin administration at 0.01 U/min, which resulted in a plasma concentration (approximately 30 pg/mL) expected for the level of hypotension, increased SAP from 83 to 115 mm Hg (P < .01).
Vasopressin plasma levels are inappropriately low in vasodilatory shock, most likely because of impaired baroreflex-mediated secretion. The deficiency in vasopressin contributes to the hypotension of vasodilatory septic shock.
Low-dose dopamine is commonly administered to critically ill patients in the belief that it reduces the risk of renal failure by increasing renal blood flow. However, these effects have not been established in a large randomised controlled trial, and use of dopamine remains controversial. We have done a multicentre, randomised, double-blind, placebo-controlled study of low-dose dopamine in patients with at least two criteria for the systemic inflammatory response syndrome and clinical evidence of early renal dysfunction (oliguria or increase in serum creatinine concentration).
328 patients admitted to 23 participating intensive-care units (ICUs) were randomly assigned a continuous intravenous infusion of low-dose dopamine (2 microg kg(-1) min(-1)) or placebo administered through a central venous catheter while in the ICU. The primary endpoint was the peak serum creatinine concentration during the infusion. Analyses excluded four patients with major protocol violations.
The groups assigned dopamine (n=161) and placebo (n=163) were similar in terms of baseline characteristics, renal function, and duration of trial infusion. There was no difference between the dopamine and placebo groups in peak serum creatinine concentration during treatment (245 [SD 144] vs 249 [147] micromol/L; p=0.93), in the increase from baseline to highest value during treatment (62 [107] vs 66 [108] micromol/L; p=0.82), or in the numbers of patients whose serum creatinine concentration exceeded 300 micromol/L (56 vs 56; p=0.92) or who required renal replacement therapy (35 vs 40; p=0.55). Durations of ICU stay (13 [14] vs 14 [15] days; p=0.67) and of hospital stay (29 [27] vs 33 [39] days; p=0.29) were also similar. There were 69 deaths in the dopamine group and 66 in the placebo group.
Administration of low-dose dopamine by continuous intravenous infusion to critically ill patients at risk of renal failure does not confer clinically significant protection from renal dysfunction.
Septic shock is associated with vasopressin deficiency and a hypersensitivity to its exogenous administration. The goal of the current study was to determine whether short-term vasopressin infusion in patients experiencing severe septic shock has a vasopressor sparing effect while maintaining hemodynamic stability and adequate end-organ perfusion.
Patients experiencing septic shock that required high-dose vasopressor support were randomized to a double-blinded 4-h infusion of either norepinephrine (n = 11) or vasopressin (n = 13), and open-label vasopressors were titrated to maintain blood pressure. To assess end-organ perfusion, urine output and creatinine clearance, gastric mucosal carbon dioxide tension, and electrocardiogram ST segment position were measured.
Patients randomized to norepinephrine went from a median prestudy norepinephrine infusion of 20.0 microg/min to a blinded infusion of 17.0 mug/min at 4 h, whereas those randomized to vasopressin went from a median prestudy norepinephrine infusion of 25.0 microg/min to 5.3 microg/min at 4 h (P < 0.001). Mean arterial pressure and cardiac index were maintained in both groups. Urine output did not change in the norepinephrine group (median, 25 to 15 ml/h) but increased substantially in the vasopressin group (median, 32.5 to 65 ml/h; P < 0.05). Similarly, creatinine clearance did not change in the norepinephrine group but increased by 75% in the vasopressin group (P < 0.05). Gastric mucosal carbon dioxide tension and electrocardiogram ST segments did not change significantly in either group.
The authors conclude that short-term vasopressin infusion spared conventional vasopressor use and improved some measures of renal function in patients with severe septic shock.
To assess the frequency of vasopressin deficiency in septic shock.
Prospective cohort study.
Intensive care unit at Raymond Poincaré University Hospital.
A cohort of 44 patients who met the usual criteria for septic shock for < 7 days. A second cohort of 18 septic shock patients were enrolled within the first 8 hrs of disease onset.
None.
General demographics, severity scores, vital signs, standard biochemical data, and circulating vasopressin levels were systematically obtained at baseline in the two cohorts. Vasopressin deficiency was defined by a normal plasma vasopressin level in the presence of a systolic blood pressure of <100 mm Hg or in the presence of hypernatremia. Baroreflex sensitivity was systematically evaluated in patients of the first cohort when vasopressin deficiency was noted. In the second cohort of patients, plasma levels of vasopressin were obtained at baseline, 6, 24, 48, and 96 hrs after shock onset. In the first population, plasma vasopressin levels were inversely correlated to the delay from shock onset. Fourteen patients had relative vasopressin deficiency: 12 patients had systolic blood pressure <100 mm Hg, with impaired baroreflex sensitivity in four, and three patients had hypernatremia. In the second population, only two patients had relative vasopressin deficiency. The plasma levels of vasopressin significantly decreased over time (p < 10-3).
Plasma vasopressin levels are almost always increased at the initial phase of septic shock and decrease afterward. Relative vasopressin deficiency is seen in approximately one-third of late septic shock patients.
To measure changes in medullary and cortical renal blood flow during experimental hyperdynamic sepsis and the effect of subsequent norepinephrine infusion on such flows. DESIGN Experimental animal study.
Animal laboratory of university-affiliated physiology institute. SUBJECTS Eighteen anesthetized merino sheep.
A transit-time flow probe was placed around the left renal artery. Laser Doppler flow probes were inserted in the left renal medulla and cortex by micromanipulation to measure changes in regional intrarenal blood flow.
Systemic pressures, cardiac output, renal, and intrarenal blood flows were measured continuously. A bolus of Escherichia coli (7.5 x 10(9) colony forming units) was given intravenously to induce hyperdynamic sepsis. After the onset of hyperdynamic sepsis, all animals were randomly allocated to either norepinephrine (0.4 microg.kg-1.min-1 for 30 mins) or observation for 30 mins in random order. E. coli injection induced a significant decrease in mean arterial pressure (102.2 +/- 15.2 mm Hg to 74.3 +/- 16.1 mm Hg, p <.05) and an increase in mean cardiac output (4.60 +/- 1.62 L/min to 5.93 +/- 1.18 L/min, p <.05). However, renal blood flow did not change significantly (326.4 +/- 139.4 mL/min to 293.1 +/- 117.5 mL/min, not significant) despite a 30% increase in renal conductance (3.27 +/- 1.52 to 4.13 +/- 2.01 mL.min-1.mm Hg-1, p <.05). Cortical blood flow decreased by 15% (not significant) and medullary flow by 5% (not significant) during sepsis, but individual changes were unpredictable. On the other hand, norepinephrine infusion caused a significant improvement in mean arterial pressure (74.3 +/- 16.1 to 105.7 +/- 17.7 mm Hg, p <.05) and a further increase in cardiac output (5.93 +/- 1.18 to 7.13 +/- 1.52 L/min, p <.05). Mean renal blood flow also increased (293.1 +/- 117.5 to 384.5 +/- 168.1 mL/min, p <.05) despite decreased renal conductance (4.13 +/- 2.01 to 3.73 +/- 1.91 mL.min-1.mm Hg-1, p <.05). Infusion of norepinephrine significantly increased medullary blood flow by 35% compared with baseline (p <.05) and by 54% compared with untreated sepsis (p <.05), whereas the increases in cortical blood flow (16 and 53%, respectively) were not significant.
Hyperdynamic sepsis caused renal vasodilation but had limited effects on regional intrarenal blood flow. Norepinephrine infusion (0.4 microg.kg-1.min-1) during sepsis significantly increased global and medullary renal blood flow and restored renal vascular tone toward but not above normal.
Acute renal failure is a serious condition that affects as many as 20% of ICU patients. The most common causes of acute renal failure in the ICU patient are severe sepsis and septic shock. The mortality of acute renal failure in septic critically ill patients remains high despite our increasing ability to support vital organs. This is partly the result of our poor understanding of the pathogenesis of sepsis-induced renal dysfunction. Accordingly, a review of our current understanding of the pathogenesis of septic acute renal failure is timely and relevant.
Throughout the past half century, acute renal failure of acute illness has essentially been considered a hemodynamic disease caused by kidney ischemia, a view derived by findings in animal models. Unfortunately most such models are greatly deficient in that they do not reproduce the high cardiac output, low systemic vascular resistance state typically seen during human sepsis. Furthermore, most models inducing so-called acute tubular necrosis are based on ischemia-reperfusion (renal artery clamping), an event with little relevance to human sepsis. Recent research highlights a new possible and emerging concept for the pathogenesis of septic acute renal failure: acute apoptosis. This concepts fits well with the typical paucity of histologic changes seen in so-called acute tubular necrosis and with growing evidence of a role for apoptosis in organ injury during sepsis and inflammation in general. Furthermore, the authors present evidence that some potential treatments recently shown to affect the mortality of critically ill patients, (activated protein C, intensive insulin treatment, and low-volume mechanical ventilation) might have antiapoptotic activity.
This review suggests that, on the evidence available, septic acute renal failure is more likely to be an immune or toxic state rather than simply a hemodynamic condition. The authors speculate that future insights into its pathogenesis might lead to a paradigm shift away from the concept of acute tubular necrosis, which has never been convincingly shown in sepsis, to that of acute tubular apoptosis.
Protection of renal function and prevention of acute renal failure (ARF) are important goals of resuscitation in critically ill patients. Beyond fluid resuscitation and avoidance of nephrotoxins, little is known about how such prevention can be achieved. Vasoactive drugs are often administered to improve either cardiac output or mean arterial pressure in the hope that renal blood flow will also be improved and, thereby, renal protection achieved. Some of these drugs (especially low-dose dopamine) have even been proposed to have a specific beneficial effect on renal blood flow. However, when all studies dealing with vasoactive drugs and their effects on the kidney are reviewed, it is clear that none have been demonstrated to achieve clinically important benefits in terms of renal protection. It is also clear that, with the exception of low-dose dopamine, there have been no randomized controlled trials of sufficient statistical power to detect differences in clinically meaningful outcomes. In the absence of such data, all that is available is based on limited physiological gains (changes in renal blood flow or urine output) with one or another drug in one or another subpopulation of patients. Furthermore, given our lack of understanding of the pathogenesis of ARF, it is unclear whether haemodynamic manipulation is an appropriate avenue to achieve renal protection. There is a great need for large randomized controlled trials to test the clinical, instead of physiological, effects of vasoactive drugs in critical illness.
To develop a nonlethal model of hyperdynamic sepsis, and to measure vital organ blood flows in this setting.
Randomized crossover animal study.
Animal laboratory of university-affiliated physiology institute.
Seven Merino cross sheep.
Surgical implantation of transit-time flow probes around sagittal sinus and circumflex coronary, superior mesenteric, and left renal arteries, and of an electromagnetic flow probe around the ascending aorta. After recovery, randomization to either 6 h of observation under normal conditions (control) or 6 h of observation after the induction of hyperdynamic nonlethal sepsis (sepsis), with each animal crossing over to the other treatment after a 2-week interval. Measurements and main results: Injection of Escherichia coli induced nonlethal hyperdynamic sepsis within 5 to 6 h with hypotension (mean arterial pressure [+/- SD], 85 +/- 7 mm Hg vs 69 +/- 8 mm Hg), increased cardiac output (4.0 +/- 0.9 L/min vs 7.2 +/- 1.2 L/min), tachycardia (60 +/- 10 beats/min vs 160 +/- 15 beats/min), fever, oliguria, and tachypnea. Compared to control animals, hyperdynamic sepsis increased renal (330 +/- 101 mL/min vs 214 +/- 75 mL/min), mesenteric (773 +/- 370 mL/min vs 516 +/- 221 mL/min), and coronary (54 +/- 24 mL/min vs 23 +/- 10 mL/min) blood flow (p < 0.05). There was no significant change in sagittal sinus flow. Despite increased coronary flow, myocardial contractility decreased (800 +/- 150 L/min/s vs 990 +/- 150 L/min/s). Despite increased mesenteric and renal blood flow, there was hyperlactatemia (0.5 +/- 0.1 mmol/L vs 1.9 +/- 0.3 mmol/L); despite increased renal blood flow, all experimental animals acquired oliguria (160 +/- 75.3 mL/2 h vs 50.2 +/- 13.1 mL/2 h) and increased serum creatinine levels (0.07 +/- 0.02 mmol/L vs 0.11 +/- 0.02 mmol/L).
Injection of E coli induced hyperdynamic nonlethal sepsis. During such hyperdynamic sepsis, blood flow to heart, gut, and kidney was markedly increased; however, organ dysfunction developed. We speculate that global ischemia may not be the principal mechanism of vital organ dysfunction in hyperdynamic sepsis.