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Biomedical subjects

E Kirkman

Publications and source records attributed to E Kirkman.

At least 19 recordsLinked to original sources
PubMed2002

The effects of primary thoracic blast injury and morphine on the response to haemorrhage in the anaesthetised rat.

Primary thoracic blast injury causes a triad of bradycardia, hypotension and apnoea mediated in part via a vagal reflex. Blast casualties may also suffer blood loss, and the response to progressive simple haemorrhage is biphasic: an initial tachycardia followed by a vagally mediated reflex bradycardia which can be attenuated by micro opioid agonists. The aims of this study were to determine the effects of thoracic blast injury on the response to subsequent haemorrhage, and the effects of morphine, administered after blast, on the response to blood loss. Male Wistar rats, terminally anaesthetised with alphadolone-alphaxolone (19-21 mg x kg(-1) h(-1) I.V.), were allocated randomly to one of three groups: Group I, sham blast; Group II, thoracic blast; Group III, thoracic blast plus morphine (0.5 mg x kg(-1) I.V. given 5 min after blast). Blast (Groups II and III) resulted in significant (P < 0.05, ANOVA) bradycardia, hypotension and apnoea. Sham blast (Group I) had no effect. Ten minutes later, haemorrhage (40 % of the estimated total blood volume (BV)) in Group I produced a biphasic response comprising a tachycardia followed by a peak bradycardia after the loss of 33 % BV. Arterial blood pressure did not fall significantly until the loss of 13.3 % BV. In Group II the haemorrhage-induced tachycardia was absent and the bradycardia was augmented: peak bradycardia was seen after the loss of 23 % BV. Mean arterial blood pressure (MBP) began to fall as soon as haemorrhage commenced and was significant after the loss of 10 % BV. Morphine (Group III) prevented the haemorrhage-induced bradycardia and delayed the significant fall in MBP until the loss of 30 % BV. It is concluded that the response to thoracic blast injury augments the depressor response to haemorrhage while morphine attenuates this response.

Anesthesia↗
PubMed2001

Reflex nature of the cardiorespiratory response to primary thoracic blast injury in the anaesthetised rat.

Blast injuries represent a problem for civilian and military populations. Primary thoracic blast injury causes a triad of bradycardia, hypotension and apnoea. The objective of this study was to investigate the reflex nature of this response and its modulation by vagotomy or administration of atropine. The study was conducted on terminally anaesthetised (alphadolone/alphaxalone, 18-24 mg x kg x h(-1), I.V.) male Wistar rats randomly allocated to the groups indicated below. Blast injuries were produced with compressed air while sham blast involved the sound of a blast only. Primary blast injury to the thorax resulted in a bradycardia (measured as an increase in the interval between beats, or heart period (HP) to 489 +/- 37 ms from 133 +/- 3 ms with a latency of onset of 4.3 +/- 0.3 s, mean +/- S.E.M.), hypotension (fall in mean arterial blood pressure (MBP) from 128.1 +/- 3.7 mmHg to 34.8 +/- 4.1 mmHg, latency of onset 2.0 +/- 0.1 s) and apnoea lasting 28.3 +/- 2.3 s. Sham blast had no effect. The bradycardia and apnoea following thoracic blast were abolished by cervical vagotomy while the hypotension was attenuated. Atropine (0.3 mg x kg(-1), I.V.) caused a significant reduction in the bradycardia (HP increasing from 124 +/- 3 ms to 142 +/- 4 ms) but did not modulate either the hypotension or apnoea. It is concluded that a reflex involving the vagus nerve mediates the bradycardia, apnoea and a component of the hypotension associated with thoracic blast. The pattern of this response is similar to effects that follow stimulation of the pulmonary afferent C-fibres.

Anesthesia↗
PubMed2001

Cardiovascular response to graded lower body negative pressure in young and elderly man.

Lower body negative pressure (LBNP) reduces central venous pressure (CVP) and cardiac output. The elderly are reported to have a limited capacity to increase cardiac output by increasing heart rate (HR), are especially dependent on end diastolic volume to maintain stroke volume and therefore should be especially vulnerable to LBNP. The present study compared the effects of LBNP in the young and old. Stroke volume was assessed non-invasively as stroke distance (SD) by aortovelography. Two groups of healthy male volunteers were studied: eight young (29.7 +/- 2.0 years, mean +/- S.E.M.) and nine old (70.1 +/- 0.9 years). LBNP was applied progressively at 17.5, 35 and 50 mmHg in 20 min steps, with measurements taken during each steady state. There were similar, significant, falls in CVP in both groups. SD fell significantly in both groups from respective control values of 24.8 +/- 1.6 and 16.6 +/- 0.9 cm to 12.5 +/- 1.3 and 8.9 +/- 0.4 cm at a LBNP of 50 mmHg. Although SD in the elderly was significantly lower than in the young, the LBNP-induced changes were not different between groups. Both groups produced similar significant increases in vascular resistance, HR, plasma vasopressin (AVP) and noradrenaline. Mean arterial blood pressure (MBP) and plasma adrenaline did not change significantly. Therefore healthy old men respond to LBNP in a similar manner to the young, although MBP and SD are regulated around different baselines in the two groups.

Adult↗
PubMed2000

Gender-dependent IL-12 secretion by APC is regulated by IL-10.

Female SJL mice preferentially mount Th1-immune responses and are susceptible to the active induction of experimental allergic encephalomyelitis. By contrast, young adult male SJL are resistant to experimental allergic encephalomyelitis due to an APC-dependent induction of Th2 cells. The basis for this gender-dependent differential T cell induction was examined by analysis of macrophage APC cytokine secretion during T cell activation. APC derived from females secrete IL-12, but not IL-10, during T cell activation. By contrast, APC derived from males secrete IL-10, but not IL-12, during T cell activation. Activation of T cells with APC derived from the opposite sex demonstrated that these cytokines were derived from the respective APC populations. Furthermore, inhibition of IL-10, but not TGF-beta, during T cell activation resulted in the secretion of IL-12 by male-derived APC. APC from naive male mice, in which IL-10 was reduced in vivo before isolation, also secrete IL-12, demonstrating altered APC cytokine secretion was due to an environment high in IL-10 before Ag encounter. Finally, APC derived from castrated male mice preferentially secrete IL-12 during T cell activation. These data demonstrate a link between gonadal hormones and APC activity and suggest that these hormones alter the APC, thereby influencing cytokine secretion during initial T cell activation.

Animals↗
PubMed1999

Modification of the cardiovascular response to hemorrhage by somatic afferent nerve stimulation with special reference to gut and skeletal muscle blood flow.

BACKGROUND: Tissue injury modifies heart rate and blood pressure responses to hemorrhage. The effect of concomitant injury on the hemorrhage-induced redistribution of cardiac output is much less clear. However, if injury elicits the visceral alerting response of the defense reaction, then a change in this redistribution of peripheral blood flow might be expected. If such a change compromised the gut circulation, then it might explain the deleterious effects of injury on the ability to withstand hemorrhage. METHODS: Immature pigs anesthetized with Saffan were bled 30% of blood volume with or without concomitant somatic afferent (brachial) nerve stimulation (to mimic injury). In addition to global cardiovascular and oxygen transport variables, blood flow was measured in the cranial mesenteric (gut) and right femoral (skeletal muscle) arteries after a 60-minute stabilization period after surgery, at the end of the 30-minute hemorrhage, and after a 30-minute shock period. RESULTS: Hemorrhage induced the expected cardiovascular and oxygen transport changes accompanied by a reduction in skeletal muscle blood flow and a 55% increase in skeletal muscle vascular resistance, but gut blood flow and vascular resistance were unchanged. However, in the presence of brachial nerve stimulation, the pattern of response to hemorrhage was modified, such that gut blood flow was now reduced and gut vascular resistance increased. CONCLUSION: The sparing of the gut circulation after hemorrhage was abolished in the presence of "injury." This finding is consistent with injury eliciting the defense reaction and may help explain the deleterious effects of injury on resistance to hypovolemia.

Analysis of Variance↗
PubMed1999

Are the motility abnormalities of achalasia reversible? An experimental outflow obstruction in the feline model.

BACKGROUND: Experimental and clinical evidence suggests that the loss of esophageal body function in achalasia may be a result of the outflow obstruction of a nonrelaxing, hypertensive lower esophageal sphincter. The reversibility of such abnormalities has implications to the timing of therapeutic interventions. This study was designed to evaluate the evolution and reversibility of motility abnormalities resulting from esophageal outflow obstruction in cats. METHODS: Twenty adult cats were divided into 2 groups. Group 1 consisted of 4 cats that underwent laparotomy as a sham procedure. Group 2 consisted of 16 cats that underwent surgical placement of a loose Gore-tex expanded polytetrafluoroethylene (W. L. Gore, Elkton, Md) band calibrated to 110% of the circumference of the gastroesophageal junction. The band was removed from 4 randomly selected cats each at 1, 2, 4, and 6 weeks after placement. Esophageal manometry was performed before placement of the band, at weekly intervals after placement of the band, and after removal of the band. The resting pressure and percent relaxation of the lower esophageal sphincter (LES), in addition to amplitude, duration, and propagation of esophageal body contractions, were measured at each interval. Data are expressed as median and interquartile range and compared with use of the Mann-Whitney U test for independent samples. RESULTS: The LES resting pressure remained unchanged after placement of the band, but sphincter compliance was reduced, as manifested by a significant reduction in the percent of sphincter relaxation (98% prebanding, 65% postbanding, P < .05). The median amplitude of esophageal contraction decreased significantly after banding. By 6 weeks after banding the esophagus was markedly dilated and exhibited aperistaltic, low-amplitude esophageal motility typical of that seen in clinical achalasia. Importantly, removal of the bands resulted in a prompt return of both peristalsis and amplitude of contraction. CONCLUSIONS: Loss of compliance of the lower esophageal sphincter produces outflow obstruction with the resultant loss of esophageal contraction amplitude and peristaltic waveform typical of achalasia in humans. These abnormalities were reversible after relief of obstruction in the feline model and may indicate that early relief of outflow obstruction in clinical achalasia may preserve esophageal function in patients.

Animals↗
PubMed1998

Cerebrovascular accumulation and increased blood-brain barrier permeability to circulating Alzheimer's amyloid beta peptide in aged squirrel monkey with cerebral amyloid angiopathy.

Senescent squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Cerebrovascular sequestration and blood-brain barrier (BBB) permeability to 121I-amyloid beta(1-40) synthetic peptide (sA beta(1-40)) were studied in adult versus aged squirrel monkey 1 h after a single intravenous injection. In aged monkey, the half-time of elimination of sA beta(1-40), t(1/2)e, was prolonged by 0.6 h, the systemic clearance, ClSS, was reduced from 1.8 to 1.1 ml/min/kg, and the mean residence time of intact peptide in the circulation was increased by 1 h (45%). In adult monkey, cerebrovascular sequestration of intact sA beta(1-40) was significant, and the BBB permeability was 18.6-fold higher than for inulin. In aged monkey, the sequestration of intact sA beta(1-40) by cortical and leptomeningeal microvessels and the BBB permeability were increased by 5.9, 1.8-, and 2.1-fold, respectively, in the presence of an unchanged barrier to inulin. In brain parenchyma of aged animals, 76.1% of circulating sA beta(1-40) remained intact versus 45.7% in adult. We conclude that multiple age-related systemic effects, i.e., reduced body elimination and systemic clearance of sA beta(1-40), and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendothelial transport and microvascular accumulation of blood-borne sA beta(1-40), and reduced brain metabolism to enhance the development of CAA.

Aging↗
PubMed1998

Use of stroke distance in the early detection of simulated blood loss.

OBJECTIVES: To compare the effects of simulated and mild actual hemorrhage on parameters used traditionally to assess hemorrhaging patients: heart rate (HR), blood pressure (BP), and Shock Index (SI = HR/systolic BP), with stroke distance (SD) measured ultrasonically as an index of cardiac stroke volume. MATERIALS AND METHODS: Hemorrhage was simulated in 19 healthy volunteers by the application of graded lower-body negative pressure (LBNP) (0, -20, -40, and -60 mm Hg) to pool blood in the lower body and reduce venous return. Measurements were also made before and after a standard blood donation (450 mL) in nine healthy volunteers. MEASUREMENTS AND MAIN RESULTS: SD decreased significantly and progressively from the baseline level of 23.8+/-5.7 cm (mean+/-SD) at each level of LBNP: by 3.4+/-1.9, 7.4+/-2.5, and 11.8+/-3.2 cm at LBNP of -20, -40, and -60 mm Hg, respectively. Neither HR nor SI changed significantly at the lowest level of LBNP (-20 mm Hg), but they showed progressive, significant increases thereafter. Mean BP did not change significantly at any level of LBNP. Similarly, after a controlled hemorrhage of 450 mL, SD decreased significantly by 3.3+/-1.6 cm from 22.2+/-2.8 cm, whereas HR and SI remained unchanged and mean BP increased slightly. CONCLUSION: Changes in SD may provide an earlier indication of progressive blood loss than either HR or BP alone or in combination.

Adult↗
PubMed1998

Physiologic responses to primary blast.

BACKGROUND: Primary blast injuries are produced by the blast shock wave. The critical determinant of survival is pulmonary injury, but acute cardiorespiratory responses to blast exposure are not well understood. The aim of this study was to investigate these changes. METHODS: Twenty anesthetized rats were exposed to moderate blast overpressure, 10 animals receiving thoracic and 10 receiving abdominal exposure. Another 9 animals acted as controls. Respiration, heart rate, and blood pressure were recorded continuously before, during, and for 6 hours after blast exposure. RESULTS: All animals exposed to thoracic blast demonstrated apnea, bradycardia, and hypotension after blast exposure, followed by a return to preblast values. No significant cardiovascular or respiratory changes were seen in animals in the other groups. CONCLUSION: Moderate thoracic blast injury produces a reflex triad of apnea, bradycardia, and hypotension that is not present after abdominal blast. These observations may have important implications for the immediate management of patients with blast injuries.

Abdominal Injuries↗
PubMed1998

Bradycardia and hypotension associated with severe hemorrhage are reversed by morphine given centrally or peripherally in anesthetized rats.

BACKGROUND: Severe simple hemorrhage (blood loss in the absence of tissue damage and nociception) leads to a reflex bradycardia and hypotension. Earlier studies showed that this reflex can be attenuated by prior administration of morphine. However, some patients may receive morphine, e.g., for analgesia after they have suffered severe hemorrhage. The aim of this study was to determine whether an established bradycardia and hypotension could be reversed by morphine. METHODS: Four groups of male Wistar rats (236-258 g) were anesthetized with alphadolone/alphaxalone (16-19 mg x hg x h(-1) intravenously). All groups received a hemorrhage of 40% total blood volume (BV) at 2% BV x min(-1). After the loss of 27% BV, bradycardia and hypotension were established equally in groups I and II and III and IV. Groups I (n=8) and III (n=10) received 0.9% saline (20 microL intracerebroventricularly or 1 mL x kg(-1) intravenously, respectively), whereas groups II (n=10) and IV (n=10) received morphine (10 microg intracerebroventricularly or 0.5 mg x kg(-1) intravenously, respectively). RESULTS: In groups I and III, heart rate and mean arterial blood pressure continued to fall, whereas the bradycardia was completely reversed and the hypotension partly reversed in groups II and IV after treatment with morphine. CONCLUSION: Morphine, administered centrally or peripherally, can reverse the bradycardia and markedly can attenuate the hypotension associated with severe hemorrhage. However, any benefit may be more apparent than real because other studies suggest that mortality may be increased.

Acid-Base Equilibrium↗
PubMed1998

Prediction of hemorrhagic blood loss with a genetic algorithm neural network.

There is no established method for accurately predicting how much blood loss has occurred during hemorrhage. In the present study, we examine whether a genetic algorithm neural network (GANN) can predict volume of hemorrhage in an experimental model in rats and we compare its accuracy to stepwise linear regression (SLR). Serial measurements of heart period; diastolic, systolic, and mean blood pressures; hemoglobin; pH; arterial PO2; arterial PCO2; bicarbonate; base deficit; and blood loss as percent of total estimated blood volume were made in 33 male Wistar rats during a stepwise hemorrhage. The GANN and SLR used a randomly assigned training set to predict actual volume of hemorrhage in a test set. Diastolic blood pressure, arterial PO2, and base deficit were selected by the GANN as the optimal predictors set. Root mean square error in prediction of estimated blood volume by GANN was significantly lower than by SLR (2.63%, SD 1.44, and 4.22%, SD 3.48, respectively; P < 0.001). A GANN can predict highly accurately and significantly better than SLR volume of hemorrhage without knowledge of prehemorrhage status, rate of blood loss, or trend in physiological variables.

Algorithms↗
PubMed1997

Morphine blocks the bradycardia associated with severe hemorrhage in the anesthetized rat.

Progressive hemorrhage in the absence of tissue injury produces a biphasic response: an initial tachycardia, vasoconstriction and maintenance of arterial blood pressure by the baroreflex, followed by bradycardia, vasodilatation and hypotension due to the activation of a second 'depressor' reflex. The present study has investigated the effect of morphine (a mu-opioid receptor agonist) on the cardiac chronotropic response to a progressive hemorrhage at 2% total estimated blood volume (BV) min(-1) in the anesthetized rat. In control rats (20 microl saline intracerebroventricularly, i.c.v.) heart period initially decreased significantly (P < 0.05) by a maximum of 5.4 +/- 0.8 ms from a baseline of 147.3 +/- 2.2 ms after a blood loss of 8.3 +/- 1.5% BV, and then increased significantly by a maximum of 43.0 +/- 5.5 ms above the baseline after the loss of 34.5 +/- 1.6% BV. Blood pressure was initially maintained and then fell during the hemorrhage. The increase in heart period was prevented by treatment with morphine (10 microg i.c.v.), and the fall in blood pressure delayed significantly. These effects of morphine were prevented by pretreatment with naloxone (20 microg i.c.v.). Intravenous (i.v.) administration of morphine (10 microg) had no effect on the response to hemorrhage. However, a clinically relevant dose of 0.5 mg x kg(-1) morphine (i.v.) abolished the bradycardia and delayed the fall in blood pressure associated with hemorrhage. These results indicate that morphine, acting on central nervous opioid receptors, can abolish the bradycardia and delay the hypotension associated with progressive hemorrhage, a pattern of response reminiscent of the effects of musculo-skeletal injury on the response to blood loss.

Anesthesia↗
PubMed1996

Nociceptive somatic nerve stimulation and skeletal muscle injury modify systemic hemodynamics and oxygen transport and utilization after resuscitation from hemorrhage.

OBJECTIVE: To examine if either nociceptive somatic nerve stimulation or skeletal muscle injury modified systemic hemodynamics and oxygen transport and utilization after resuscitation from hemorrhage in anesthetized pigs. DESIGN: Prospective, randomized, controlled laboratory study. SETTING: Animal laboratory. SUBJECTS: Twenty isoflurane-anesthetized and mechanically ventilated large white pigs. INTERVENTIONS: Three groups of animals were instrumented with femoral arterial and thermodilution pulmonary artery catheters. One group of animals had bilateral brachial nerve electric stimulation before hemorrhage (brachial nerve stimulation + hemorrhage, n = 7). The second group of animals had bilateral hindlimbs skeletal muscle injury induced by firing a captive-bolt handgun with standard charges before hemorrhage (skeletal muscle injury + hemorrhage, n = 6). The third group had neither insult before hemorrhage (control, n = 7). Controlled bleeding was initiated to reduce the cardiac index and systemic oxygen delivery (Do2) by 50% in all animals. Animals were then left for 30 mins before resuscitation. All animals were resuscitated with 4.5% human serum albumin at 45 mL/kg and observed for 2 hrs. MEASUREMENTS AND MAIN RESULTS: Plasma volume, systemic hemodynamics, and oxygen transport variables were measured and calculated after resuscitation. Similar increases of plasma volume and supranormal cardiac index were observed in all groups immediately after resuscitation. The branchial nerve stimulation and hemorrhage group maintained higher heart rate, cardiac index, Do2, and oxygen consumption (Vo2) than the hemorrhage group. In contrast, the skeletal muscle injury and hemorrhage group had lower systemic mean arterial pressure and vascular resistance, and a tendency for decrease in Vo2, than the hemorrhage group, although heart rate, cardiac index, and Do2 were similar in both groups. Hemorrhage increased the arterial plasma lactate concentration, which was later normalized in all groups 60 mins after resuscitation. CONCLUSIONS: Neither nociceptive brachial nerve stimulation nor skeletal muscle injury attenuated the increase in plasma volume, cardiac index, or the repayment of systemic oxygen debt after resuscitation from hemorrhage. Brachial nerve stimulation was associated with augmented cardiac index, systemic Do2, and increased Vo2 requirements related to increased sympathetic nervous system activation. Skeletal muscle injury produced early systemic arterial hypotension and vasodilation, and a decrease in Vo2 that was suggestive of pathologic supply dependency on systemic Do2.

Animals↗
PubMed1995

Inhibition of ovarian-derived prorenin to angiotensin cascade in the treatment of ovarian hyperstimulation syndrome.

The purpose of this experiment was to determine whether use of the angiotensin-converting enzyme (ACE) inhibitor, enalapril, would prevent the occurrence of ovarian hyperstimulation syndrome (OHSS) in the rabbit model. A total of 20 adult female New Zealand white rabbits were studied. All rabbits received 75 IU of human menopausal gonadotrophin s.c. each day for 7 days. On day 8, all rabbits received 2500 IU of human chorionic gonadotrophin (HCG). Ten rabbits were randomly chosen to receive enalapril orally. Five received 1 mg/kg of enalapril and five received 2 mg/kg of enalapril twice daily. The remainder received placebo orally twice daily. On day 10, all rabbits underwent surgical exploration. Total body weight was found to increase significantly in the placebo group (by 293 g, P < 0.001) but not in either group receiving enalapril. Haematocrit also increased significantly in the placebo group (by 3%, P < 0.013) but not in the enalapril groups. Ovarian weights were highest for the 2 mg/kg enalapril group (5.80 +/- 0.52 g), followed by the 1 mg/kg enalapril group (3.64 +/- 0.45), and least for the placebo group (2.69 +/- 0.17). All 10 placebo rabbits met criteria for severe OHSS whereas only six in the enalapril groups did. We concluded that angiotensin II may play a significant role in the development of weight gain, third space fluid accumulation and intravascular fluid depletion in OHSS. ACE inhibition resulted in a 40% decrease in the incidence of OHSS in the rabbit model.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Effects of afferent neural stimulation on critical oxygen delivery: a hemodynamic explanation.

Injury and activation of somatic afferent nerve fibers may alter critical oxygen delivery (DO2C), the point at which oxygen consumption becomes dependent upon delivery, and hence reduce tolerance to hypovolemia. The present study investigated the mechanism of this. Anesthetized mongrel dogs were divided into two groups: control (n = 6) and those subject to brachial nerve stimulation (BNS; n = 5). Whole body oxygen delivery (DO2I) and consumption were initially similar in both groups. DO2I was reduced by cardiac tamponade to determine DO2C. DO2C was significantly higher in BNS compared with control (11.5: 11.0-16.7 vs. 7.5: 6.9-9.5 ml.min-1.kg-1; median: Q1 - Q3), whereas critical oxygen extraction ratios were lower (54.8: 39.7-61.2 vs. 78.3: 53.5-92.4%). At approximately DO2C, normalized femoral blood flow was lower than renal flow in control (renal-femoral difference 17.4: 8.7-40.0%) but not in BNS (-7.8: -14.8 to +11.8%). These results indicate that activation of somatic afferent nerve fibers elevates DO2C. This could be due to an impairment in peripheral oxygen extraction as a consequence of a redistribution of blood flow away from metabolically active vital organs toward relatively inactive skeletal muscle.

Afferent Pathways↗