Randomised, double-blind, parallel group, placebo-controlled study to evaluate the analgesic efficacy and safety of VVZ-149 injections for postoperative pain following laparoscopic colorectal surgery.

INTRODUCTION: In spite of advances in understanding and technology, postoperative pain remains poorly treated for a significant number of patients. In colorectal surgery, the need for developing novel analgesics is especially important. Patients after bowel surgery are assessed for rapid return of bowel function and opioids worsen ileus, nausea and constipation. We describe a prospective, double-blind, parallel group, placebo-controlled randomised controlled trial testing the hypothesis that a novel analgesic drug, VVZ -149, is safe and effective in improving pain compared with providing opioid analgesia alone among adults undergoing laparoscopic colorectal surgery. METHODS AND ANALYSIS: Based on sample size calculations for primary outcome, we plan to enrol 120 participants. Adult patients without significant medical comorbidities or ongoing opioid use and who are undergoing laparoscopic colorectal surgery will be enrolled. Participants are randomly assigned to receive either VVZ-149 with intravenous (IV) hydromorphone patient-controlled analgesia (PCA) or the control intervention (IV PCA alone) in the postoperative period. The primary outcome is the Sum of Pain Intensity Difference over 8 hours (SPID-8 postdose). Participants receive VVZ-149 for 8 hours postoperatively to the primary study end point, after which they continue to be assessed for up to 24 hours. We measure opioid consumption, record pain intensity and pain relief, and evaluate the number of rescue doses and requests for opioid. To assess safety, we record sedation, nausea and vomiting, respiratory depression, laboratory tests and ECG readings after study drug administration. We evaluate for possible confounders of analgesic response, such as anxiety, depression and catastrophising behaviours. The study will also collect blood sample data and evaluate for pharmacokinetic and pharmacodynamic relationships. ETHICS AND DISSEMINATION: Ethical approval of the study protocol has been obtained from Institutional Review Boards at the participating institutions. Trial results will be disseminated through scientific conference presentations and by publication in scientific journals. TRIAL REGISTRATION NUMBER: NCT02489526; pre-results.

Angiotensin-converting enzyme inhibition and beta-adrenoceptor blockade regress established ventricular remodeling in a canine model of discrete myocardial damage.

OBJECTIVES: This study was designed to assess the effect of angiotensin-converting enzyme inhibition and beta-adrenoreceptor blockade on established ventricular remodeling. BACKGROUND: Angiotensin-converting enzyme inhibitor therapy attenuates the development of ventricular remodeling when given shortly after myocardial infarction. However, regression of established ventricular remodeling after infarction has received little attention. METHODS: The relative effects of angiotensin-converting enzyme inhibitor therapy and beta-adrenoceptor blockade on established ventricular remodeling were assessed in a canine model characterized by increased left ventricular mass and chamber dilation as a result of localized myocardial necrosis produced by transmyocardial direct current shock. Dogs were randomly assigned to 3 months of therapy with captopril (25 mg twice daily, n = 7) or metoprolol (100 mg twice daily, n = 7) or to a control group with no intervention (n = 6), 11 +/- 4 (mean +/- SD) months after acute myocardial damage. RESULTS: Compared with the control group, dogs in both the captopril and metoprolol groups had reduced left ventricular mass as measured by magnetic resonance imaging (-8.1 +/- 3.8 vs. 1.7 +/- 2.8 g, p = 0.003 and -9.6 +/- 5.6 vs. 1.7 +/- 2.8 g, p = 0.001), respectively. Captopril and metoprolol also produced a reduction in left ventricular end-diastolic volume (-7.6 +/- 6.0 and -6.0 +/- 5.8 ml, respectively) compared with the control value (-1.6 +/- 3.8 ml) (p = 0.14 [NS]). Both agents reduced mean arterial pressure but had disparate effects on pulmonary wedge pressure and right atrial pressure. There was no significant correlation between change in ventricular mass or volume and change in any measured hemodynamic or neurohormonal variable. CONCLUSIONS: These data suggest that pharmacologic intervention with angiotensin-converting enzyme inhibition or beta-adrenoceptor blockade can result in regression of established ventricular remodeling. The mechanism of this response will require further study, but these data did not support a close association between regression of remodeling and hemodynamic unloading of the ventricle or systemic neuroendocrine factors.

Relative effects of alpha 1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog.

BACKGROUND: Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock. METHODS AND RESULTS: The study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8 +/- 3.4 to 65.4 +/- 2.6 g, P = NS; LVV, 45.4 +/- 2.7 to 51.6 +/- 2.7 mL, P = NS; C: LVM, 68.4 +/- 3.2 to 91.4 +/- 2.9 g, P = .0001; LVV, 56.6 +/- 3.0 to 71.9 +/- 2.4 mL, P = .0003). Terazosin, an alpha 1-adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7 +/- 4.6 to 105.7 +/- 3.4 g, P = .01; LVV, 61.8 +/- 3.8 to 76.8 +/- 3.3 mL, P = .002). An angiotensin II subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0 +/- 4.6 to 109.7 +/- 5.3 g, P = .0001; LVV, 66.0 +/- 1.9 to 78.4 +/- 3.6 mL, P = .007). CONCLUSIONS: High-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. the failure of alpha 1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through alpha 1-receptors or angiotensin II acting through the type 1 receptor in the remodeling process in this model.

Hemodynamic, left ventricular structural and hormonal changes after discrete myocardial damage in the dog.

Transmyocardial direct-current (DC) shock produces localized left ventricular myocardial necrosis without obstruction to coronary blood flow. In 43 dogs sequential measurements of hemodynamic, neuroendocrine and myocardial structural changes were made at baseline and for 16 weeks after DC shock. Six dogs (14%) died in the peri-shock period. By 1 week after shock, left ventricular mass, as measured by nuclear magnetic resonance imaging, had increased from a mean value +/- SD of 67.9 +/- 10.1 to 82.5 +/- 12.9 g (p = 0.0001). Left ventricular end-diastolic volume was unchanged at 1 week but increased at 16 weeks from 56.1 +/- 10.3 to 70.3 +/- 10.7 ml (p = 0.0003). Left ventricular mass demonstrated a further increase at 12 months (107.8 +/- 14.8 g). Rest cardiac output was significantly decreased at 4 months (3.67 +/- 1.23 to 3.18 +/- 0.81 liters/min, p less than 0.01) as was stroke volume (43 +/- 9 to 37 +/- 7 ml, p less than or equal to 0.01). Left ventricular ejection fraction decreased progressively from 73% to 38% at 1 year. At 4 months there were increases in mean pulmonary artery pressure (18 +/- 4 to 23 +/- 4 mm Hg, p less than 0.01), pulmonary capillary wedge pressure (9 +/- 3 to 15 +/- 3 mm Hg, p less than 0.01) and right atrial pressure (5 +/- 4 to 9 +/- 3 mm Hg, p less than 0.01). Plasma norepinephrine was increased at 4 months (318 +/- 190 to 523 +/- 221 pg/ml, p = 0.0003), whereas plasma renin activity was not significantly changed (4.3 +/- 2.6 vs. 5.2 +/- 3.4 ng/ml per h). Microsphere regional blood flow studies demonstrated a 50% reduction in skeletal muscle blood flow at 4 months (0.06 +/- 0.06 ml/min per g compared with 0.12 +/- 0.09 in normal dogs, p = 0.05), and a reduction in the endocardial/epicardial blood flow ratio (1.11 +/- 0.13 compared with 1.24 +/- 0.13 in normal dogs, p = 0.02). Therefore, in this model of acute left ventricular damage, left ventricular hypertrophy precedes progressive left ventricular dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced vascular compliance as a marker for essential hypertension.

In 38 patients with established essential hypertension and 32 age-matched normotensive control subjects proximal and distal arterial compliance were determined by computer-based assessment of the diastolic decay of a brachial arterial tracing and a modified Windkessel model of the circulation. In the hypertensive subjects compared to the normotensive subjects mean arterial pressure was 25% higher (P less than .001), systemic vascular resistance 23% higher (P less than .01), proximal compliance 19% lower (P less than .01), and distal compliance 72% lower (P less than .001). The reduction in distal compliance was highly age-dependent. In the youngest age range (45 to 54 years) little overlap appeared between hypertensive and normotensive groups, whereas in the oldest subjects studied (65 to 75 years) distal compliance was comparably low in the two groups. Thus, distal vascular compliance provides a sensitive and specific marker for the abnormal vasculature associated with hypertension and may be particularly useful in identifying the disease in young individuals with borderline blood pressure.

Systemic and regional hemodynamic effects of alpha-adrenoceptor blockade in chronic left ventricular dysfunction in the conscious dog.

In seven dogs with long-standing left ventricular dysfunction induced 16 weeks earlier by repetitive transmyocardial direct current (DC) shock, the acute hemodynamic effect of the alpha 1-adrenoceptor antagonist urapidil was studied. Left ventricular end-diastolic pressure (LVEDP) was significantly increased from preshock levels at the time of study and cardiac output was reduced. Plasma norepinephrine was significantly increased from control levels and was not altered by urapidil infusion. The mean arterial pressure fell in response to alpha 1-blockade from 111 to 85 mm Hg, the LVEDP fell from 16 to 9 mm Hg, and cardiac output increased from 2.90 to 3.70 L/min (all p less than 0.01). Regional blood flows measured by microsphere injection revealed an increase in blood flow to skeletal muscle, which had not been significantly decreased by the left ventricular dysfunction in this model, and further decreases in splanchnic flow, which was already depressed compared with that in normal dogs. Therefore acute alpha-adrenoceptor blockade improves central hemodynamics in experimental heart failure but does not normalize the resting blood flow maldistribution in this model.

Cardiovascular and neurohormonal effects of atrial natriuretic peptide in conscious dogs with and without chronic left ventricular dysfunction.

Atrial natriuretic peptide (hANP 4-28) was infused for 1 h (0.3 microgram/kg/min) in 11 normal awake dogs and seven awake dogs with chronic left ventricular dysfunction, induced 16 weeks earlier by repetitive DC shock. The responses were similar in the two groups and included decreases in arterial pressure (107-99 mm Hg), heart rate (83-72 beats/min), and cardiac output (3.6-2.8 L/min), without changes in right or left ventricular filling pressures. Systemic vascular resistance (SVR) tended to rise during the infusion and was significantly increased (2,847-3,442 dyn s cm-5, p less than .05) during the postinfusion recovery period. Regional blood flows (microspheres) during infusion revealed a decrease in skin and splanchnic flow. Despite the apparent vasoconstrictor effect, plasma norepinephrine (PNE), renin activity (PRA), and arginine vasopressin (AVP) levels all fell during ANP infusion. These data suggest that ANP exerts a cardioinhibitory effect, possibly similar to that of arginine vasopressin (AVP), and that the net systemic vasoconstrictor effect of ANP in these dogs is mediated by a complex interrelationship between direct vascular effects, neurohormonal inhibition, and central reflex activation.

Reduced atrial natriuretic factor after ligation of the left coronary artery in rats.

The diuretic-natriuretic responses of eight assay rats to extracts of atrial tissue obtained 3 months after left coronary ligation were less than the responses to extracts of tissue from sham-operated controls. The mean difference in diuresis (sham-operated response minus ligated response) was 370 (range 22 to 656) microliter/20 minutes (p less than 0.01) and in natriuresis 56 (range -92 to 222) microEq/20 minutes (p = 0.19). The differences in diuretic responses to these extracts was directly related to the severity of elevation of left ventricular end-diastolic pressure in these rats (r = -0.82, p = 0.01). These results in a model with varying degrees of left ventricular dysfunction suggest that myocardial damage is associated with a chronic decrease in atrial natriuretic factor. Reduced circulating atrial natriuretic factor therefore could contribute to the previously observed impaired ability of coronary ligated rats to excrete a saline load and to the sodium retention observed in clinical heart failure. Conclusive evidence will depend on the development of techniques to measure plasma levels of this hormone.

M-mode and two-dimensional echocardiographic analysis of the septum in experimental right ventricular infarction: correlation with hemodynamic alterations.

We investigated the changes that occur in the shape and the motion of the ventricular septum in experimental right ventricular (RV) infarction with M-mode and two-dimensional echocardiography. The echocardiographic findings were correlated with the hemodynamic alterations. Right ventricular infarction was produced by mercury embolization of the right coronary artery in five anesthetized closed-chest dogs. After embolization, the transseptal end-diastolic left-right ventricular pressure gradient reversed (3 +/- 1) to -1 +/- 1 mm Hg, p less than 0.001). The septal shape was altered by the flattening of the septum at end-diastole and a return to the normal septal shape during systole. Systolic septal motion was reversed after embolization (1 mm toward the left ventricle before embolization to 3 mm toward the RV after embolization, p less than 0.01). Septal thickening was not altered. We concluded that isolated RV free wall infarction results in the reversal of the transseptal end-diastolic pressure gradient and is associated with the flattening of the septum at end-diastole. During systole, the septum returns to its normal shape and moves toward the RV. In addition, systolic septal thickening is preserved. The motion of the septum toward the RV, together with normal septal thickening, may provide mechanical assistance to RV ejection with RV free wall infarction.

Vascular hemodynamic impedance in congestive heart failure.

The objective of this study was to determine whether pulse-contour analysis could provide a measure of the differences in peripheral vascular state between patients with congestive heart failure (CHF) and healthy persons. Vascular hemodynamic impedance parameters were determined from brachial artery pressure waveforms recorded in 14 patients with CHF, aged 20 to 55 years (mean 36 +/- 12) and in 7 healthy control subjects, aged 22 to 55 years (mean 33 +/- 12). Cardiac output, heart sounds and electrocardiogram were also monitored. Cardiac output was 32% lower (p less than 0.01) and heart rate was 43% higher (p less than 0.001) in the CHF group than in the control group. The mean arterial pressure did not differ between groups. Systemic vascular resistance was 47% higher (p less than 0.05) and distal vascular compliance 73% lower (p less than 0.001) in the CHF group than in control group. Proximal vascular compliance was unchanged. These studies suggest that distal compliance assessed from pulse-contour analysis is a more sensitive and specific index than systemic vascular resistance to the vascular changes in CHF.

Hemodynamic and hormonal response to transdermal nitroglycerin in normal subjects and in patients with congestive heart failure.

The hemodynamic and hormonal responses to nitroglycerin administered transdermally in a gel-like matrix were evaluated in nine patients with severe congestive heart failure and in nine normal subjects. In normal subjects, peripheral vasodilation was accompanied by reflex sympathetic stimulation as reflected by an increase in heart rate and plasma norepinephrine. In patients with heart failure, nitroglycerin produced sustained hemodynamic effects that began 30 minutes after the application and fully persisted for at least 6 hours. A significant decrease in right and left ventricular filling pressures was associated with an increase in stroke index and a significant decrease in forearm and pulmonary vascular resistances. There was no change in heart rate and systemic arterial pressure or in plasma norepinephrine or plasma renin activity. After 24 hours, pressures had partially returned to control levels, but mean pulmonary artery pressure was still significantly lower than in the control period. After removal of the nitroglycerin, each patient exhibited a decrease in cardiac index and an increase, above the control values, in pulmonary and systemic arterial pressures and pulmonary, systemic and forearm vascular resistances. This transient rebound appeared to be unrelated to stimulation of the sympathetic or renin-angiotensin systems. Thus, transdermal absorption of this new form of nitroglycerin appears to provide a nitrate vascular effect that is sustained for 24 hours, but an endogenous vasoconstrictor effect may influence the hemodynamic response over the first 24 hours.

A nonsurgical canine model of chronic left ventricular myocardial dysfunction.

A simple technique of producing left ventricular myocardial damage accompanied by chronic complete heart block in dogs is described. The method is accomplished by repetitive transmyocardial DC shock with a guide wire introduced percutaneously and positioned in the left ventricle along the intraventricular septum and an external paddle at the left ventricular apex. Twelve weeks after the procedure significant hemodynamic changes included a fall in heart rate from a control of 76 +/- 19 (SD) to 43 +/- 9 beats/min (P less than 0.001), a rise in left ventricular filling pressure from 9 +/- 4 to 28 +/- 10 mmHg (P less than 0.001), and a fall in cardiac output from 3.1 +/- 1 to 2.3 +/- 0.6 l/min (P less than 0.05). Weekly echocardiography revealed a progressive increase in left ventricular end-diastolic diameter from 3.56 +/- 0.72 to 4.84 +/- 0.47 cm (P less than 0.01). Survival rate was 70%. Therefore, this relatively noninvasive technique is an effective means of producing chronic left ventricular myocardial dysfunction in the dog.

Effect of dilation of the distal coronary bed on flow and resistance in severely stenotic coronary arteries in the dog.

Studies were performed to evaluate the hemodynamic response of severely stenotic coronary arteries to dilation of the distal coronary bed. A critical stenosis was produced with an adjustable wire snare on the left anterior descending or circumflex arteries of open chest dogs. Coronary flow, distal coronary pressure and aortic pressure were measured. In one group of experiments, coronary arteriolar dilatation was induced by transient occlusion of the artery distal to the stenosis. After the release of a transient occlusion in vessels without a critical stenosis, flow increased (from 33 +/- 4 to 85 +/- 8 ml/min, P less than 0.01), distal pressure decreased slightly (from 86 +/- 4 to 80 +/- 4 mm Hg, P less than 0.01), and large vessel resistance did not change significantly (from 0.06 +/- 0.02 to 0.08 +/- 0.03 units). After the release of a transient occlusion in vessels with a critical stenosis, flow decreased (from 23 +/- 3 to 12 +/- 2 ml/min, P less than 0.01), distal pressure decreased to persistently low levels (from 63 +/- 2 to 29 +/- 2 mm Hg, P less than 0.01), and large vessel resistance increased (from 1.4 +/- 0.3 to 6.7 +/- 1.8 units, P less than 0.01). In a separate group of experiments, radio-opaque contrast medium was used to dilate the distal coronary bed. In these studies dilation of the distal coronary of arteries with a critical stenosis again resulted in a decrease in coronary blood flow (from 35 +/- 4 to 19 +/- 3 ml/min, P less than 0.01), a decrease in distal coronary pressure (from 84 +/- 6 to 35 +/- 6 mm Hg, P less than 0.01) and an increase in large arterial resistance (from 1.0 +/- 0.2 to 5.5 +/- 1.2 units, P less than 0.02). Therefore, in coronary vessels with severe stenosis, dilation of the distal coronary bed may result in a paradoxical decrease in coronary blood flow.

Myocardial damage after repetitive direct current shock in the dog: correlation between left ventricular end-diastolic pressure and extent of myocardial necrosis.

Acute myocardial necrosis was produced in 27 anesthetized dogs by repetitive DC 75 joule shock delivered with one electrode in the left ventricular cavity and the other on the left chest wall. A total of 1 shock/kg body weight delivered at 10 sec intervals resulted in discrete anterior wall necrosis of 7% to 31% (mean, 17.6%) of the mass of left ventricular myocardium. After some transient bradycardia, normal sinus rhythm was restored. Depression of left ventricular function 15 min after shock (rise in LVEDP from 4.0 +/- 1.5 to 17 +/- 2 mm Hg and fall in cardiac output from 2.29 +/- 0.24 to 1.82 +/- 0.12 L/min) recovered only slightly during the ensuing 2 hr. A significant correlation (r=0.85) was observed between the LVEDP at 2 hr after shock and the extent of necrosis determined histochemically and histologically at the time of sacrifice 3 hr after shock. Thus, in this form of acute myocardial damage, pump dysfunction is closely related to the area of necrosis.