Drop In Systemic Blood Pressure Research Articles

Complement-mediated dialysis reaction during regular hemodialysis treatment: a case report

BackgroundHemodialysis reactions (HDRs) are similar to complement activation-related pseudo allergy (CARPA), a hypersensitivity reaction that occurs when administering certain (nano)drugs intravenously. The pathomechanism of CARPA was described based on animal experiments. Typical CARPA-like dialysis reactions, which occur at the start of hemodialysis, have been reported using polysulfone dialyzers. However, to our knowledge, this is the first dialysis reaction that occurred towards the end of hemodialysis treatment.Case presentationThis report describes a 52-year-old Caucasian male patient who had been receiving chronic hemodialysis for 3 years and exhibited a CARPA reaction during his third hour of treatment. Upon activation of the microbubble alarm, the extracorporeal system recirculated for five minutes. Following reconnection, the patient exhibited a drop in systemic blood pressure, chest pain, and dyspnea after five minutes. Symptoms disappeared spontaneously after reducing the speed of the blood pump, placing the patient in a Trendelenburg position, and administering a bolus infusion from the dialysis machine. The remaining dialysis treatment was uneventful.ConclusionNumerous case reports about reactions occurring with modern high-efficiency polysulfone dialyzers have been published. However, due to changes in the material structure by the manufacturers, we have not encountered such cases lately. The recently reported increase in thromboxane-B2 and pulmonary arterial pressure and complement activation upon re-infusion of extracorporeal blood following dialysis may explain the reaction observed here.

Design, synthesis and biological evaluations of a long-acting, hypoxia-activated prodrug of fasudil, a ROCK inhibitor, to reduce its systemic side-effects

ROCK, one of the downstream regulators of Rho, controls actomyosin cytoskeleton organization, stress fiber formation, smooth muscle contraction, and cell migration. ROCK plays an important role in the pathologies of cerebral and coronary vasospasm, hypertension, cancer, and arteriosclerosis. Pharmacological-induced systemic inhibition of ROCK affects both the pathological and physiological functions of Rho-kinase, resulting in hypotension, increased heart rate, decreased lymphocyte count, and eventually cardiovascular collapse. To overcome the adverse effects of systemic ROCK inhibition, we developed a bioreductive prodrug of a ROCK inhibitor, fasudil, that functions selectively under hypoxic conditions. By masking fasudil's active site with a bioreductive 4-nitrobenzyl group, we synthesized a prodrug of fasudil that is inactive in normoxia. Reduction of the protecting group initiated by hypoxia reveals an electron-donating substituent that leads to fragmentation of the parent molecule. Under normoxia the fasudil prodrug displayed significantly reduced activity against ROCK compared to its parent compound, but under severe hypoxia the prodrug was highly effective in suppressing ROCK activity. Under hypoxia the prodrug elicited an antiproliferative effect on disease-afflicted pulmonary arterial smooth muscle cells and pulmonary arterial endothelial cells. The prodrug displayed a long plasma half-life, remained inactive in the blood, and produced no drop in systemic blood pressure when compared with fasudil-treated controls. Due to its selective nature, our hypoxia-activated fasudil prodrug could be used to treat diseases where tissue-hypoxia or hypoxic cells are the pathological basis of the disease.

57-01: Electrical remodeling of repolarization abnormality after surgical treatment in pheochromocytoma: a retrospective analysis

Background: Pheochromocytoma, a rare neuroendocrine tumor, clinically characterized by high blood pressure, palpitations and headache, is often associated with abnormalities of the ventricular repolarization phase(1), in particular with the presence of U wave(2). This dispersion of ventricular repolarization is the basis of ventricular arrhythmias. Method: We analyzed a series of ECG of 10 patients (9M/1F, 43 ± 18 years aged) affected by pheochromocytoma, collected before and after surgical treatment. We evaluated hear rate (HR), P wave, PR, QRS, QTc, number of U wave present in each twelve lead ECG, electrolytes values, systemic blood pressure and 24-hour urinary excretion of 3-methoxytyramine, normetanephrine and metanephrine. Results: All patients were in sinus rhythm, without any brunch block. There was no difference in term of electrolytes, duration of P wave, PR, QRS, QTc, HR. We found clear presence of U wave in all patients before surgery, while there was a significative reduction/suppression in number of U wave counted in 12 lead ECG after surgery. After surgery, as expected, we observed a clear drop in systemic blood pressure and 3-methoxytyramine, normetanephrine and metanephrine urinary level. We observed a linear correlation between number of U wave in 12 lead ECG and 3-methoxytyramine levels (r= 0.615, p =0.015). Conclusion: A careful analysis of the electrocardiogram is mandatory in patients with hypertensive crisis, particularly the phase of ventricular repolarization characterized by U wave; this finding should lead the clinician to suspect the diagnosis of pheochromocytoma.

Retrobulbar blood flow and visual field alterations after acute ethanol ingestion

BackgroundThe purpose of this study was to test the effect of ethyl alcohol on the koniocellular and magnocellular pathway of visual function and to investigate the relationship between such visual field changes and retrobulbar blood flow in healthy subjects.MethodsIn 12 healthy subjects (mean age 32 ± 4 years), color Doppler imaging, short-wavelength automated perimetry, and frequency doubling perimetry was performed before and 60 minutes after oral intake of 80 mL of 40 vol% ethanol. Mean and pattern standard deviations for short-wavelength automated and frequency doubling perimetry were assessed. End diastolic velocity (EDV) and peak systolic velocity (PSV) were measured in the central retinal and ophthalmic arteries using color Doppler imaging. Systemic blood pressure, heart rate, intraocular pressure, and blood alcohol concentration were determined.ResultsMean PSV and EDV in the central retinal artery showed a significant increase after alcohol intake (P = 0.03 and P = 0.02, respectively). Similarly, we found a significant acceleration of blood flow velocity in the ophthalmic artery (P = 0.02 for PSV; P = 0.04 for EDV). Mean intraocular pressure decreased by 1.0 mmHg after alcohol ingestion (P = 0.01). Retinal sensitivity in short-wavelength automated perimetry did not alter, whereas in frequency doubling perimetry, the mean deviation decreased significantly. Systolic and diastolic blood pressure did not change significantly. Mean blood alcohol concentration was 0.38 ± 0.16 g/L.ConclusionAlthough ethanol is known to cause peripheral vasodilation, our subjects had no significant drop in systemic blood pressure. However, a significant increase of blood flow velocity was seen in the retrobulbar vessels. Regarding visual function, moderate alcohol consumption led to reduced performance in the magnocellular visual system tested by frequency doubling perimetry, but had no effect on short-wavelength automated perimetry.

Hyperglycaemia emerging during general anaesthesia induces rat acute kidney injury via impaired microcirculation, augmented apoptosis and inhibited cell proliferation

Major surgery under general anaesthesia frequently triggers acute kidney injury by yet unknown mechanisms. We investigated the role of anaesthesia-triggered systemic hyperglycaemia in impairment of renal functioning, renal tissue injury, intra-renal Angiotensin-II synthesis and endogenous insulin production in anaesthetized rats. Eighty-eight Sprague-Dawley rats underwent general anaesthesia for 1 h by different anaesthetic compounds. Some of the animals were either injected with high glucose, or received insulin prior to anaesthesia. Blood pressure, renal functioning estimated by cystatin-C and urea, renal perfusion evaluated by laser Doppler technique, blood glucose and insulin were surveyed. Subsequently, rat kidneys were excised, to be used for immunohistochemical examinations or preparation of renal extracts for intra-renal Angiotensin-II measurements. Elevated blood sugar was observed 5 min following induction of anaesthesia, concurrently with deterioration of renal functioning, drop of systemic blood pressure and decreased renal blood flow. Blood insulin concentrations positively correlated with glucose levels. Intra-renal Angiotensin-II was significantly augmented. Immunohistochemical examinations demonstrated enhanced staining for pro-apoptotic proteins and negligible cell proliferation in tubular tissues. Renal damage resultant from anaesthesia-induced hyperglycaemia could be attenuated by insulin injections. Rats challenged with glucose prior to anaesthesia demonstrated cumulative hyperglycaemia, further increase in insulin secretion, drop of renal blood flow and increased apoptosis. The effects were specific, since they could not be mimicked by replacing glucose with mannose. Anaesthesia-induced hyperglycaemia affects intra-renal auto-regulation via decreased renal perfusion, thus triggering renal function deterioration and tubular injury. Increased intra-renal Angiotensin-II aggravates the damage. Tight hypoglycaemic control might prevent or, at least, attenuate anaesthesia-induced renal injury.

An acutely confused young woman

In September, 2009, a 20-year-old previously healthy woman presented to our emergency department with altered mental status, right arm tingling and numbness, and a bilateral pulsating frontotemporal headache. Her symptoms had started several hours earlier with transient loss of consciousness. On examination, she was alert, with reduced concentration, incoherent thoughts, and poor recall for recent events. There was no evidence of localising neurological signs or neck stiff ness. Her temperature, blood pressure, and vital signs were normal. Abuse of alcohol or illicit substances was denied by a friend who accompanied the patient. Her personal and family history was negative for seizure disorders, migraine, and vascular risk factors. CT of the brain and haematological, biochemical, and cerebrospinal fl uid examination were normal. MRI of the brain, 20 h after the onset of her symptoms, showed multiple confl uent areas of abnormal high signal intensity on T2-weighted scans, symmetrically involving juxtacortical white matter of the frontal, parietal, occipital, and temporal lobes. In these areas, diff usion coeffi cient maps, generated by diff usion-weighted imaging, showed an elevated diff usion suggestive of vasogenic oedema (fi gure A, C, and webappen dix). A diagnosis of posterior reversible enceph alopathy syndrome (PRES) was suspected, and confi rmed by the almost complete disappearance of MRI abnormalities a week later. PRES is clinically characterised by confusion, headache, altered consciousness, seizures, and visual disturbance, with MRI changes of often widespread vasogenic oedema typically predominating in the occipitoparietal regions. PRES is commonly associated with hypertensive encephalopathy, eclampsia, kidney disease, hypercal caemic crisis, autoimmune disorders, transplantation, sepsis, and immunosuppressive treatment or chemo therapy. The pathophysiology is poorly understood, although the ultimate underlying process seems to be an increase in capillary hydrostatic pressure or endothelial dysfunction with a breakdown of the blood–brain barrier triggered by diff erent systemic conditions. Surprisingly, our patient’s history and examinations did not identify any known cause of PRES. However, when suffi ciently recovered for an in-depth interview, she reported sniffi ng an unknown dose of “poppers” (nitrite inhalants) for the fi rst time, just before the onset of symptoms. The close temporal association between inhalation and the onset of the neurological features suggested a causal relation. Over the next 24 h she progressively and spontaneously recovered, returning to normal within a day. In October, 2009, at fi nal follow up MRI was normal (fi gure B, D). Nitrite inhalants act through generation of nitric oxide, which activates soluble guanylyl cyclase, stimulating the production of cyclic guanosine monophosphate (cGMP), which leads to vasorelaxation via cGMP-dependent protein kinases. Vasodilation can cause the common adverse eff ects—a drop in systemic blood pressure, increased heart rate, headache, and fainting. Donors of nitric oxide are well known to cause headache and trigger migraine attacks in people who have migraines. However, PRES has not been previously described as a consequence of use of nitrite inhalers, despite their widespread use as therapeutic, diagnostic, or recreational agents. Glyceryl trinitrate was reported to aggravate pre-eclamptic PRES in one case. Nitric oxide donors dilate veins and arteries, modifying intracranial haemodynamics and resulting in an imbalance between forces that govern fl uid motion into and out of the microvasculature. We suggest in our patient’s case, that this intense vasodilation might have promoted vascular instability, breakdown of the blood–brain barrier, and fl uid extravasation. Club-drug toxic eff ects should be considered in the diff erential diagnosis when a previously healthy individual (typically a young adult) presents with an acute change in mental status. Accurate drug history and a good knowledge of adverse eff ects of individual street drugs is important for the generalist clinician to eff ectively face the diagnostic and therapeutic challenges they pose. The growing list of causes of PRES should perhaps include nitrite inhalants.

Abstract 3520: The use of vasodilators to enhance efficacy of hypoxia or acid activated prodrugs in pancreatic cancers

Abstract The vasculature of tumors is torturous and immature and in many cases lacks tone (the ability to self-regulate pressure). The administration of vasodilating agents induces a drop in systemic blood pressure which is not matched in the tumor, resulting in decreased intratumoral perfusion due to the “steal phenomenon”. This research uses this phenomenon to induce decreased tumor perfusion which results in increased tumor acidity and hypoxia. We hypothesize that this change in the tumor microenvironment can be used in combination with hypoxia- and acid-activated prodrugs (HAPs and AAPs) to enhance their efficacy, by increasing both the depth and distribution of hypoxia or acidosis within the tumor. Specifically, we have investigated the administration of hydralazine in several pancreatic xenograft tumors and used a needle microelectrode to measure decreases in pH as a result of decreased perfusion. We have also employed a computational math model to investigate the timing of the delivery of both hydralazine and HAPs to optimize the cell death. Preliminary computational results suggest that multiple rounds of vasodilators may be given with a single round of HAPs, depending on several factors including duration of vasodilation effect and half-life of the HAP. The pH investigation showed a substantial pH drop in one tumor type (MiaPaca2), but no change in two others (HS766t and SU8686), suggesting that the ‘steal’ phenomenon is not universal. Preliminary data suggest that combination therapy in the ‘steal’-sensitive models will increase efficacy. We are continuing research with the combination therapy, employing the timing strategies suggested by the computational models. We are also investigating different imaging modalities to monitor the effects of the steal phenomenon, including Ultrasound (for perfusion) and MRI (for bulk tumor changes and monitoring pH). In conclusion, the preliminary data supports the hypothesis that vasodilatation agents may be used to induce increases in acidosis and hypoxia within the microenvironment of some (but not all) tumors. These effects can be taken advantage of through combination with HAPs or AAPs to enhance antitumor effects. Further, computational math models can be employed to help determine the best timing for the combination therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3520. doi:10.1158/1538-7445.AM2011-3520

There is no place (yet) for routine administration of sildenafil to patients with ARDS

Dear editor: We thank Namendys and colleagues for their comments and would like to respond here. We do not concur with their statement that sildenafil should not be administered to patients with ARDS and would like to elucidate our point of view. We are under the impression that Namendys and coworkers feel that the results may have been different if only patients meeting the current definition of pulmonary artery hypertension had been included [1]. We need to emphasize that the study we recently reported on in this journal [2] was performed in patients meeting the NAECC criteria for ARDS [3], but not necessarily meeting the criteria of pulmonary arterial hypertension (PAH) [1]. In only five out of the ten patients, MPAP was >25 mmHg, PAOP was ≤15 mmHg, and PVR was >3 Wood units (240 dyne × s/cm5). Our hypothesis was that by selectively reducing the pulmonary vascular tone in ARDS by means of sildenafil, the shunt fraction would decrease, and oxygenation would thereby improve. This hypothesis, however, was only in part supported by our results: pulmonary vascular tone decreased; oxygenation and shunt fraction did not improve. An important cause for these findings may have been sepsis. NO-mediated systemic (and pulmonary) vasodilation may have been enhanced by sildenafil as an intrinsic consequence of its mode of action. Due to the pronounced drop in systemic blood pressure, preferential vasodilation was not reached, explaining the deterioration in oxygenation and shunt fraction. Sepsis, or other inflammatory conditions requiring vasopressive support, frequently coincide with ARDS, thereby potentially rendering the treatment of pulmonary hypertension more complicated in patients suffering from ARDS as compared to ambulatory patients. However, in a recent study assessing the hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension, the effects of sildenafil were much alike [4]. Sildenafil improved pulmonary hemodynamics at rest and during exercise, but also decreased systemic arterial blood pressure and led to a deterioration of arterial oxygenation, which was ascribed to inhibition of hypoxic pulmonary vasoconstriction. The improvement in exercise capacity of sildenafil in ambulatory patients with PAH may be primarily the consequence of hemodynamic and not of ventilatory effects [5]. In ARDS, it remains to be questioned whether therapy should be targeted on oxygenation, since levels of PaO2 have not been associated with adverse outcome in ARDS. The beneficial effect of sildenafil on right ventricular performance may be of additional value besides other strategies (e.g., ventilation in prone position) in patients with severe PAH who do not have arterial hypotension. Namendys and colleagues further suggest that the approved dosage of sildenafil in PAH is 20 mg three times daily, and the 50 mg administered as a single dose in our study may have been too much. Yet, in ambulatory patients with COPD and PAH, there was no significant difference in hemodynamic effects between a 20- and 40-mg dose [4]. Finally, we emphasize our study was designed as a “proof of concept study” and to obtain physiologic information. It was underpowered to make a statement on the effect of sildenafil on the outcome in patients suffering from ARDS. Therefore, until a large, sufficiently powered and well-designed trial determines this effect, sildenafil should be considered potentially useful in selected patients with stable hemodynamics and life-threatening ARDS.

Vasovagal fainting as an evolutionary remnant of the fight against hemorrhage

Major bleeding is one of the most frequently occurring medical conditions that require the attention of physicians and surgeons. The most frequent causes of major bleeding in most hospitals are trauma, peri-operative bleeding (which can in fact be viewed as a variant of trauma), gastro-intestinal disease, and bleeding due to the use of anticoagulant agents [6]. Severe hemorrhage leads to an insufficient circulation and an inadequate supply of oxygen to tissue. Patients with serious bleeding often present with circulatory shock and collapse. Impaired brain perfusion and subsequent syncope seems an understandable sequence of events following a severe drop in systemic blood pressure as a consequence of acute blood loss. However, it is intriguing to speculate whether syncope may not only be a logical consequence of major hemorrhage but can rather be viewed as a response with distinct protective effects for the organism and as such has been carefully preserved as a beneficial mechanism throughout the evolution. In this issue of Clinical Autonomic Research, Dr. Diehl proposes an interesting explanation for the occurrence of vasovagal syncope, as a mechanism that was originally developed as a protective strategy against exsanguination upon major bleeding in mammals [3]. Dr. Diehl hypothesizes that low blood pressure and bradycardia that is associated with vasovagal syncope is beneficial for the organism that is threatened by ongoing major blood loss,when the initial physiological and compensatory responses, such as vasoconstriction and tachycardia, have failed. Indeed, a low blood pressure is likely to result in reduced blood loss during major hemorrhage and clinical studies indeed suggest that to strive for normalization of blood pressure in patients with trauma and serious bleeding by large volume intravenous infusion may do more harm than good [7]. Based on this notion, strategies that employ permissive hypotension awaiting further medical intervention are currently being investigated [8]. Dr. Diehl’s hypothesis is interesting and thought-provoking and is indeed supported by various physiological and clinical observations. As the author himself indicates, the hypothesis can be challenged by experimental studies in bleeding animals. In addition to this, we must also identify a mechanism by which fainting would not only be beneficial to slow the rate of bleeding but may be helpful in arresting the blood loss. The answer to this question may be found in the response of the coagulation system to circulatory collapse. Fainting leads to an immediate and marked increase in von Willebrand factor (and associated factor VIII), presumably due to release from Weibel Palade bodies in endothelial cells of the vessel wall [2]. Interestingly, post-fainting blood not only has a four-fold higher concentration of von Willebrand factor, but also the released von Willebrand factor occurs in unusually large multimers, which are known to be hemostatically much more potent than normal von Willebrand factor multimers. Under normal circumstances the constitutive release of large von Willebrand factor multimers is followed by enzymatic degradation by the von Willebrand factor cleaving protease (ADAMTS-13) [9]. It may be hypothesized that the immediate release of large amounts of von Willebrand factor as induced by fainting does not allow this cleaving protease to act properly, leaving the large multimers for C A R 52 M. Levi, MD ( ) Dept. Internal Medicine (F-4) Academic Medical Centre University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam, The Netherlands Tel.: +31-20/5662171 Fax: +31-20/6919658 E-Mail: m.m.levi@amc.uva.nl

Angiotensin Converting Enzyme Inhibitors: Should They be Used Early Post Myocardial Infarction?

Angiotensin II (ATII) levels are elevated in the myocardium after myocardial damage independent of serum levels [1]. ATII results in an increase NAD(P)H vascular oxidase, the most important vascular source of reactive oxygen species (ROS); destruction of nitric oxide (NO); endothelial dysfunction; vascular inflammation; vascular remodeling; myocardial hypertrophy and collagen formation; the progression of atherosclerosis; atherosclerotic plaque instability; thrombosis and impaired fibrinolysis. All of the adverse effects of ATII appear to be mediated through the AT1 receptor and can be prevented by angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor antagonists (ARB’s) providing a strong scientific basis for the clinical use of ACE-I or ARB’s in patients with acute myocardial infarction (MI). A meta analysis of all randomized trials of ACE-Is post MI [2] suggests that a relatively uniform beneficial effect on mortality/morbidity occurs in all subgroups including age, gender, baseline use of aspirin, beta blockers, and reperfusion status. The valiant trial [3] comparing the ACE-I captopril to the ARB valsartan showed that blocking the AT1 receptor by valsartan was as effective as inhibiting the conversion of Angiotensin I to ATII by captopril. Inhibition or blockade of ATII post MI has been suggested to be beneficial regardless of the extent of myocardial damage and the time from onset of MI, although the benefits appear greater in those early post MI with signs of heart failure and or a reduced left ventricular ejection fraction (LVEF) [2]. It is therefore surprising, that Voors et al. [4] in a pooled analysis of three randomized placebo controlled trials of ACE-I use within 9 hours of onset of mainly a first anterior MI find that although ACE-I reduce the 3 month incidence of hospitalization for HF they double the 3 month re-infarction rate from 3.6 to 7.0%, p = 0.032. In those with a relatively large MI and a reduced LVEF the favorable effects of ACE-Is on ventricular remodeling appear to outweigh the risks of reinfarction. However, in those with a relatively small MI the risk or re-infarction appears to outweigh the benefits such that the net effect is unfavorable. Of interest was their observation that the incidence of reinfarction post MI was related to ACE-I induced hypotension. Hypotension post MI could trigger ischemia, platelet activation, and thrombosis. Patients with relatively small MIs often have multiple areas of jeopardized myocardium aside from their infarct related artery. These areas of jeopardized myocardium are served by narrowed arteries or collateral vessels. Perfusion pressure beyond the narrowed artery or collateral vessel is lower than systemic blood pressure. A drop in systemic blood pressure of only a few mmHg could therefore trigger myocardial ischemia with all of its adverse consequences including re-infarction and possibly sudden cardiac death. Hypotension might also explain the failure of valsartan to add to the benefical effects of captopril post MI in the valiant trial [3]. Thus, the observation that ACE-Is increase the incidence of re-infarction when given early post MI is scientifically plausible and could have an important impact upon our current approach to treating patients early post MI. However, before altering our current approach it might be useful to carefully review the basis for the findings of Voors et al. [4]. The definition of re-infarction in the studies they reviewed was not prospectively determined but left to individual investigators. One would have hoped for a prospectively defined definition based upon a re-elevation of troponin. Thus, while scientifically plausible the authors observations will require further confirmation by a prospective randomized study before their hypothesis is proven. However, while I will continue to use an ACE-I or an ARB in the early hours post MI, especially in patients with evidence of HF and or a low LVEF, I will be more cautious and would start with a low dose of captopril, especially in patients with a borderline systemic blood pressure and in those with a relatively small MI, and only up-titrate to target doses of captopril or switch to a longer acting ACE-I or ARB if blood pressure is maintained over the first 24–48 hours. The observations of Voors et al. [4] also suggest careful attention to the effect of any therapeutic agent on blood pressure considered for use during the early hours post MI.

Historical Perspectives

“The experimental hypothesis, in short, must always be based on prior observation.”—Claude Bernard (1) Modern adult intensive care started in Denmark in 1952 in response to the high mortality from the respiratory complications seen with a devastating epidemic of poliomyelitis. Anesthetists and physiologists created a new discipline when they collaborated to make sequential measurements of cardiorespiratory variables, then aggressively corrected abnormal conditions. (2) When modern neonatal intensive care emerged a decade later, it followed the same philosophy. The start of modern neonatology was stimulated in large part by an expanding understanding of: 1) the circulatory and respiratory physiology of adaptation to extrauterine life, 2) how those adjustments could fail, and 3) the pathophysiology of hyaline membrane disease. (3)(4)(5)(6)(7)(8)(9)(10) (The monograph by Dawes (3) gives an excellent overview of the relevant animal research). This research had reached a point where it could be applied to clinical care if the necessary physiologic measurements could be made in newborns. To this end, investigators began to catheterize the umbilical arteries of newborns to measure blood gas tensions and pH, with several investigators also measuring aortic pressures. (9)(11)(12)(13) Such invasive techniques were highly controversial initially, but they gradually became the accepted methodology for monitoring the sick neonate. (12) The use of oxygen in preterm infants who had cardiorespiratory distress was an important component of this change in approach to the sick infant. The standard had been to use no more than 40% oxygen to prevent retrolental fibroplasia (retinopathy of prematurity). However, it was obvious that this approach would be insufficient to relieve hypoxia in some infants and would produce hyperoxia in others. Avery and Oppenheimer (13) observed an increase in deaths due to …

Somatostatin attenuates the hyperdynamic circulatory state in the gastric mucosa of rats with portal hypertension.

Portal hypertensive gastropathy is characterized by a hyperdynamic circulatory state in the gastric mucosa. We assessed the effect of bolus injection of somatostatin on gastric mucosal perfusion in a rat model of portal hypertension. We tested the hypothesis that somatostatin will reduce gastric mucosal perfusion in portal hypertension. Portal hypertension was induced by two-stage portal vein ligation (PVL). Two weeks after PVL significant elevation of portal venous pressure was demonstrated. Gastric mucosal hemodynamic changes were measured by reflectance spectrophotometry, which records the indexes of mucosal hemoglobin oxygen saturation (ISO2) and mucosal hemoglobin concentration (IHB). After an intravenous bolus of 1 microgram somatostatin significant reductions of ISO2 and IHB were demonstrated in the rats with PVL (ISO2, -34 +/- 5%; IHB, -15 +/- 2%) and the controls (ISO2, -26 +/- 4%; IHB, -15 +/- 2%). A dose-response relationship was shown by using 0.01, 0.1, and 1 microgram of somatostatin. Somatostatin did not induce other hemodynamic changes except a transient drop in systemic blood pressure of 8-10%. The significant reductions of gastric mucosal ISO2 and IHB by somatostatin support the hypothesis that somatostatin is capable of attenuating the hyperdynamic circulatory state in the gastric mucosa of rats with portal hypertension and may have a beneficial effect on portal hypertensive gastropathy. This hypothesis deserves to be evaluated in clinical studies.

Study of the effector mechanism involved in the production of haemorrhagic necrosis of the small intestine in rat passive anaphylaxis

1. The effector mechanism of intestinal necrosis in rat anaphylaxis was studied following several complementary approaches: (i) the use of monoclonal antibodies (mAb) belonging to different classes (IgG1, IgG2b and IgE anti-DNP), (ii) the assay of mediators, and (iii) the use of pharmacological tools. 2. Lethality and haemorrhagic necrosis of the small intestine were observed in IgE-sensitized rats, whereas IgG mAb produced milder physiological disturbances. 3. Inhibition of leukotriene biosynthesis reduced the drop of systemic blood pressure (BP) and the extent of protein-rich plasma exudation but it did not influence the haemorrhagic component of intestinal necrosis. 4. The antihistamine, pyrilamine, partially diminished the haemorrhagic component of the intestinal necrosis. 5. The involvement of mediators related to platelet-activating factor (PAF) was studied by examining the pharmacological effects of these autacoids and of PAF-receptor antagonists (PCA4248, UR12460 and BB823). PAF induced intestinal lesions similar to those observed in IgE-sensitized rats and PAF-receptor antagonists markedly decreased haemorrhage in IgE-sensitized rats. 6. PAF levels were transiently increased after dinitrophenol (DNP)- bovine serum albumin (BSA) challenge in the small intestine of IgE-sensitized rats. 7. These data stress differences in the outcome of anaphylaxis related to the type of receptors for the Fc portion of immunoglobulins that are involved. IgE is the antibody class that elicits the most severe response due to the activation of mast cells via Fc epsilon RI (surface receptors that bind IgE antibodies with high affinity), and the only one able to produce intestinal haemorrhagic necrosis. 8. The mast-cell-derived mediators PAF/acyl-PAF and histamine, most probably associated with tumour necrosis factor alpha/cachectin (TNF-alpha), seem to play a central role in the production of the vascular changes required for the extravasation of erythrocytes in the small intestine mucosa.

Efficacy of inhaled nitric oxide in a porcine model of adult respiratory distress syndrome.

To assess the efficacy of inhaled nitric oxide (NO) in reducing pulmonary hypertension in a porcine model of adult respiratory distress syndrome. Nonrandomized, controlled experiment without blinding. Surgical research laboratory. Twelve pigs, matched equally for body weight. Acute lung injury was induced by intravenous injection of oleic acid. Animals were then divided into either a control group, for monitoring without any further intervention, or a NO-treatment group, in which NO was administered at concentrations of 10 to 80 ppm, with each step separated by a NO-free interval to assess duration of effect. Pulmonary artery pressure, systemic blood pressure, PaO2, intrapulmonary shunt fraction, and extravascular lung water. Nitrosylated hemoglobin, arterial methemoglobin, and plasma nitrite and nitrate concentrations. All animals responded to oleic acid injection with rapid development of pulmonary hypertension and deterioration of PaO2 and intrapulmonary shunt fraction. Inhaled NO reversed these changes in a concentration-dependent manner. Cessation of NO administration led to a prompt return of pulmonary hypertension. A small but significant drop in systemic blood pressure was observed only at the highest concentration of NO administered (80 ppm). Extravascular lung water almost doubled following oleic acid injury. This increase was sustained in all animals for the remainder of the experiment. Significant increases in circulating methemoglobin and plasma nitrite and nitrate concentrations were measured during NO inhalation. Inhaled NO appears to be a selective pulmonary vasodilator and may prove to be useful in improving gas exchange in adult respiratory distress syndrome.

Pulmonary circulation and respiration in hypoxic and circulatory hypoxias

The linear and volumetric blood flow velocity in left low-lobar pulmonary artery and vein, the balance between cardiac output of right and left ventricles, as well as the blood pressure in pulmonary and femoral arteries, respiratory movements of the chest in hypoxic (3-5% O2 in nitrogen) and circulatory (acute hemorrhage) hypoxia were studied by ultrasonic method in acute experiments in cats under nembutal narcosis. It was shown that under the influence of severe hypoxic hypoxia the blood pressure in the pulmonary artery and the pulmonary vascular resistance increased; in the majority of the experiments, respiratory standstill without transitional stages occurred within 3 to 20 minutes. In circulatory hypoxia, the development of respiratory disorders was gradual with the appearance of pathological types of respiration such as apneusis and gasping occurring with a drop of systemic blood pressure to 30-40 mmHg, lowered pulmonary AP and 3-10-fold increased pulmonary vascular resistance. In hypoxic hypoxia the cardiac output changed insignificantly, without changes in the balance between cardiac output of the right and left ventricles. Only in the general circulation was observed. In circulatory hypoxia with decreased cardiac output redistribution of the blood to the general circulation occurred from the very beginning of the hemorrhage. Reinfusion of the autoblood restored the balance between the cardiac output of the right and left ventricles. The index of the capillary perfusion in the lungs decreased in parallel with a decrease of the pulmonary blood pressure. The index of capillary perfusion in hemorrhage decreased in parallel with a decrease of the pulmonary AP.

Atherosclerosis, Peripheral Arterial Disease and the Vascular Response to Ketanserin

Platelet activation releases thromboxane A2 and serotonin, which acts on blood vessels through a specific, 5-hydroxytryptamine (5-HT2) receptor. The development of ketanserin, the selective 5HT2 receptor blocker, has made it possible to explore the role of serotonin in patients with advanced atherosclerotic disease. Ketanserin in low doses (3 to 30 micrograms/kg) was administered intra-arterially to 23 patients with symptomatic peripheral occlusive vascular disease during peripheral angiography: an additional seven patients received a placebo. The angiographic response was evaluated by coded reading and by computer-assisted measurement of arterial segments in four anatomical regions (pelvis, thigh, knee, and lower leg). Hemodynamic changes were assessed by mercury strain gauge plethysmography and Doppler pressure measurement. Unequivocal vasodilatation was observed in zero of seven placebo-treated patients and in 13 of 23 (57%) treated patients primarily at the level of collateral vessels. Dilation of the geniculate arteries, a major source of collaterals to the calf, was associated with a significant increase in the blood flow delivery to the calf. There was a moderate drop of systemic blood pressure in patients who failed to respond with peripheral vasodilatation. Ketanserin induces hemodynamically significant vasodilatation in some patients with peripheral vascular disease, suggesting that serotonin may contribute to ischemia in some patients with advanced atherosclerosis.

Toxicological evaluation of the cardiotonic isomazole in the dog

Acute, subchronic, and chronic toxicity studies were conducted in dogs with the new vasodilator/cardiotonic drug isomazole (IMZ) to support, in part, clinical investigations of this agent in humans. Single oral doses of IMZ of 25, 50, or 100 mg/kg given to English pointer dogs (2/dose) caused a marked drop in systemic blood pressure and reflex-induced increases in heart rate to values well over 200 beats per minute. These responses were maintained for 12 to 22 hr depending on the dose given. One of the dogs receiving 100 mg/kg died at 4.5 hr postdose. Results of subchronic (3 months) and chronic (1 year) studies in beagle dogs (4/sex/dose group), in which measurable plasma levels of the drug and its metabolites were found, indicated that IMZ did not produce any discernible adverse findings when given in doses up to 16 mg/kg, other than expected cardiotoxic effects. The plasma t 1 2 of IMZ at 16 mg/kg increased to between 4 and 8 hr from 2 hr noted at lower doses. In the 1-year study, at all doses and in both sexes, plasma levels of IMZ declined over the first month, stabilizing (at the 2 and 6 mg/kg doses) thereafter for the duration of the study. At the high dose of 16 mg/kg, after 1 year plasma levels of IMZ exceeded (females) or equaled (males) the 1-month values. At peak plasma levels of IMZ (2 hr postdose), plasma levels of parent drug increased linearly with the dose. The cardiotoxic effects consisted of substantial postdose increases in heart rate throughout the course of treatment (5 mg/kg and above), significant increases in heart weight (6 mg/kg and above), and multifocal myocardial fibrosis (6 mg/kg and above). There was a decline in basal heart rate at doses of 12.5 mg/kg and higher. The results of these studies demonstrated that repeated IMZ administration, as expected, was cardiotoxic to the dog, a species relatively sensitive to the pharmacological activity and hemodynamic changes induced by vasodilator/cardiotonic drugs. The no-effect dose level for cardiotoxicity in the repeated dose studies was considered to be 2 mg/kg, the lowest dose tested.

Toxicological Evaluation of the Cardiotonic Isomazole in the Dog

Acute, subchronic, and chronic toxicity studies were conducted in dogs with the new vasodilator/cardiotonic drug isomazole (IMZ) to support, in part, clinical investigations of this agent in humans. Single oral doses of IMZ of 25, 50, or 100 mg/kg given to English pointer dogs (2/dose) caused a marked drop in systemic blood pressure and reflex-induced increases in heart rate to values well over 200 beats per minute. These responses were maintained for 12 to 22 hr depending on the dose given. One of the dogs receiving 100 mg/kg died at 4.5 hr postdose. Results of subchronic (3 months) and chronic (1 year) studies in beagle dogs (4/sex/dose group), in which measurable plasma levels of the drug and its metabolites were found, indicated that IMZ did not produce any discernible adverse findings when given in doses up to 16 mg/kg, other than expected cardiotoxic effects. The plasma t1/2 of IMZ at 16 mg/kg increased to between 4 and 8 hr from 2 hr noted at lower doses. In the 1-year study, at all doses and in both sexes, plasma levels of IMZ declined over the first month, stabilizing (at the 2 and 6 mg/kg doses) thereafter for the duration of the study. At the high dose of 16 mg/kg, after 1 year plasma levels of IMZ exceeded (females) or equaled (males) the 1-month values. At peak plasma levels of IMZ (2 hr postdose), plasma levels of parent drug increased linearly with the dose. The cardiotoxic effects consisted of substantial postdose increases in heart rate throughout the course of treatment (5 mg/kg and above), significant increases in heart weight (6 mg/kg and above), and multifocal myocardial fibrosis (6 mg/kg and above). There was a decline in basal heart rate at doses of 12.5 mg/kg and higher. The results of these studies demonstrated that repeated IMZ administration, as expected, was cardiotoxic to the dog, a species relatively sensitive to the pharmacological activity and hemodynamic changes induced by vasodilator/cardiotonic drugs. The no-effect dose level for cardiotoxicity in the repeated dose studies was considered to be 2 mg/kg, the lowest dose tested.

Acute Hemodynamic Response to Intravenous Enoximone

In light of previous studies in adults, we considered that enoximone could be useful in treating children with therapy-resistant cardiovascular insufficiency. Prior to clinical administration, we investigated the cardiovascular properties of enoximone in anesthetized and ventilated piglets characterized by small stroke volume and high heart rate. Enoximone was administered intravenously in increasing doses (0.25, 0.5, and 1 mg/kg). The animals were monitored with heart rate, systemic and pulmonary arterial pressures, and continuous electromagnetic flow. Enoximone induced a dose-dependent flow increase, whereby heart rate and systemic arterial pressure changed only slightly. With regard to persistent pulmonary hypertension in newborns, enoximone was also used in piglets to investigate the effects on endotoxin-induced, dopamine-resistant pulmonary hypertension. Enoximone (1 mg/kg i.v.) was given immediately after E. coli endotoxin (1.5 micrograms/kg i.v.) and inhibited the endotoxin-induced, eicosanoid-mediated pulmonary hypertension, whereas during infusion of dopamine (2 mg/kg/h), no drop in systemic blood pressure could be observed. In the clinical study, six infants with post-cardiac surgery low output syndrome despite maximal catecholamine inotropic support were given enoximone (i.v. bolus of 0.2, 0.5, or 1 mg/kg followed by continuous infusion of 7.5-10 micrograms/kg/min). Continuously measured mixed-venous oxygen saturation increased in a dose-related manner. Cardiac output increased significantly by 28%, accompanied by a decrease of arteriovenous oxygen content difference and O2 utilization ratio. The preliminary results show that intravenous enoximone produces acute useful hemodynamic effects in infants, in particular allowing a weaning of vasoactive amines.

Effect of nimodipine-associated hypotension on recovery from acute spinal cord injury in cats

The effect of nimodipine on acute spinal cord trauma was studied in cats. Spinal evoked responses (SERs) were abolished after weight drop injury of 100 g-cm. All control animals showed spontaneous recovery of spinal cord function as measured by SERs. Treatment with a moderate intravenous dose of nimodipine resulted in a 32% drop in systemic blood pressure and delay in or failure of spinal cord recovery. We concluded that in this model, nimodipine treatment had deleterious effect on the spinal cord recovery due to the significant associated hypotension. It is likely that marked hypotension in the case of traumatic loss of autoregulation overrides the expected nimodipine-related increase in spinal cord blood flow with resultant additional ischemic damage.