Early Propranolol Research Articles

Systemic and cerebro-cardiac biomarkers following traumatic brain injury: an interim analysis of randomized controlled clinical trial of early administration of beta blockers

This is an interim analysis of the Beta-blocker (Propranolol) use in traumatic brain injury (TBI) based on the high-sensitive troponin status (BBTBBT) study. The BBTBBT is an ongoing double-blind placebo-controlled randomized clinical trial with a target sample size of 771 patients with TBI. We sought, after attaining 50% of the sample size, to explore the impact of early administration of beta-blockers (BBs) on the adrenergic surge, pro-inflammatory cytokines, and the TBI biomarkers linked to the status of high-sensitivity troponin T (HsTnT). Patients were stratified based on the severity of TBI using the Glasgow coma scale (GCS) and HsTnT status (positive vs negative) before randomization. Patients with positive HsTnT (non-randomized) received propranolol (Group-1; n = 110), and those with negative test were randomized to receive propranolol (Group-2; n = 129) or placebo (Group-3; n = 111). Propranolol was administered within 24 h of injury for 6 days, guided by the heart rate (> 60 bpm), systolic blood pressure (≥ 100 mmHg), or mean arterial pressure (> 70 mmHg). Luminex and ELISA-based immunoassays were used to quantify the serum levels of pro-inflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, and IL-18), TBI biomarkers [S100B, Neuron-Specific Enolase (NSE), and epinephrine]. Three hundred and fifty patients with comparable age (mean 34.8 ± 9.9 years) and gender were enrolled in the interim analysis. Group 1 had significantly higher baseline levels of IL-6, IL-1B, S100B, lactate, and base deficit than the randomized groups (p = 0.001). Group 1 showed a significant temporal reduction in serum IL-6, IL-1β, epinephrine, and NSE levels from baseline to 48 h post-injury (p = 0.001). Patients with severe head injuries had higher baseline levels of IL-6, IL-1B, S100B, and HsTnT than mild and moderate TBI (p = 0.01). HsTnT levels significantly correlated with the Injury Severity Score (ISS) (r = 0.275, p = 0.001), GCS (r = − 0.125, p = 0.02), and serum S100B (r = 0.205, p = 0.001). Early Propranolol administration showed a significant reduction in cytokine levels and TBI biomarkers from baseline to 48 h post-injury, particularly among patients with positive HsTnT, indicating the potential role in modulating inflammation post-TBI.Trial registration: ClinicalTrials.gov NCT04508244. It was registered first on 11/08/2020. Recruitment started on 29 December 2020 and is ongoing. The study was partly presented at the 23rd European Congress of Trauma and Emergency Surgery (ECTES), April 28–30, 2024, in Estoril, Lisbon, Portugal.

Early propranolol treatment of infantile hemangiomas improves outcome

BackgroundInfantile hemangiomas (IH) are the most common soft tissue tumors of childhood. Although most of these tumors are not worrisome, some IH may be life or function-threatening, can lead to permanent disfigurement, or have associated structural congenital anomalies, requiring early recognition and referral to specialists for treatment consideration. Since 2008, oral propranolol has been widely considered to be the first-line treatment for IH. ObjectivesTo evaluate aesthetic and functional outcome in propranolol-treated infantile hemangiomas according to the age of treatment onset. MethodsRetrospective, observational study of infantile hemangioma patients under 4 years of age at the time of diagnosis, treated with oral propranolol. Evaluated parameters included: pre and post-treatment morphologic/aesthetic aspects of the hemangioma, total resolution rate, degree of functional compromise of affected areas and its evolution. Two independent pediatric dermatologists evaluated all cases reviewing clinical data from medical records and comparing clinical photographs taken at initiation and at the end of treatment of each patient. Data were analyzed with STATA 13.0 program. ResultsThe cohort included 138 patients, with a female predominance. The median age at therapy onset was 3 months. The morphological/aesthetic improvement rate was 99% (95% CI 96‒99), the total resolution rate was 48% (95% CI 44‒60) and the functional improvement rate reached 100%. When comparing total resolution outcome versus age when treatment started, the improvement was larger in younger patients (3.5 vs. 4.9 months, p = 0.01). When comparing the total resolution rate in those younger or older than 3 months at treatment initiation, the percentage of total resolution in the younger group was 57% vs. 40% in the older one (p = 0.05). Study limitationsRetrospective design; patients photographs were the sole indicators used to measure regression rates. Visual assessment is subjective. ConclusionThe present results strongly suggest that early (before 3 months of age) initiation of treatment of infantile hemangiomas with propranolol results in significantly higher aesthetic and functional improvement rates and a higher percentage of total resolution.

Beta blocker use in traumatic brain injury based on the high-sensitive troponin status (BBTBBT): methodology and protocol implementation of a double-blind randomized controlled clinical trial

BackgroundBeta-adrenergic receptor blockers (BB) play an important role in the protection of organs that are susceptible for secondary injury due to stress-induced adrenergic surge. However, the use of BB in traumatic brain injury (TBI) patients is not yet the standard of care which necessitates clear scientific evidence to be used. The BBTBBT study aims to determine whether early administration of propranolol based on the high-sensitive troponin T(HsTnT) status will improve the outcome of TBI patients. We hypothesized that early propranolol use is effective in reducing 10- and 30-day mortality in TBI patients. Secondary outcomes will include correlation between serum biomarkers (troponin, epinephrine, cytokines, enolase, S100 calcium binding protein B) and the severity of injury and the impact of BB use on the duration of hospital stay and functional status at a 3-month period.MethodsThe BBTBBT study is a prospective, randomized, double-blinded, placebo-controlled three-arm trial of BB use in mild-to-severe TBI patients based on the HsTnT status. All enrolled patients will be tested for HsTnT at the first 4 and 6 h post-injury. Patients with positive HsTnT will receive BB if there is no contraindication (group 1). Patients with negative HsTnT will be randomized to receive either propranolol (group 2) or placebo (group 3). The time widow for receiving the study treatment is the first 24 h post-injury.DiscussionEarly BB use may reduce the catecholamine storm and subsequently the cascade of immune and inflammatory changes associated with TBI. HsTnT could be a useful fast diagnostic and prognostic tool in TBI patients. This study will be of great clinical interest to improve survival and functional outcomes of TBI patients.Trial registrationClinicalTrials.gov NCT04508244. Registered on 7 August 2020. Recruitment started on 29 December 2020 and is ongoing.

Early Propranolol Is Associated With Lower Risk of Venous Thromboembolism After Traumatic Brain Injury.

Traumatic brain injury (TBI) results in an elaborate systemic cascade of secondary injury elicited in part by an intrinsic catecholamine response, which ultimately leads to changes in inflammation and coagulopathy. Attenuation of this catecholamine response with agents such as propranolol confers a survival advantage. The related impact of propranolol on venous thromboembolism (VTE) after TBI is largely unknown. A single institution retrospective review was conducted of all TBI patients requiring intensive care unit (ICU) admission with an injury severity scale (ISS) ≥ 25 from January 2013 to May 2015. Patients who received at least one dose of propranolol within 24hours of admission (PROP) were compared to patients who did not receive any doses of propranolol (NPROP) during their hospitalization. Of the 131 patients analyzed, 31 (23.7%) patients received propranolol. The PROP cohort was more severely injured overall (ISS 29 vs 26.5, P = .02). While unadjusted VTE rates were similar (16.1% vs 19.0%, P = .72), the adjusted VTE rate was lower in the PROP cohort (AOR 0.20 (95% CI 0.04-0.97), adjusted P-value < .05). Propranolol use in TBI patients who have sustained critical injuries may mitigate the risk of VTE. The mechanism by which this outcome is achieved requires further investigation.

Role of Administration of Beta Receptor Blockers in the Management of Traumatic Brain Injury

Background: Severe traumatic brain injury (TBI) is associated with paroxysmal sympathetic hyperactivity (PSH), which is characterized by catecholamine surge. β-blockers can break this cycle by protecting β-receptor rich brain cells to decrease the cerebral oxygen demand, which may attenuate cerebral ischemia and secondary brain injury. In addition, β-blockers are beneficial to decrease hypermetabolism, lighten cardiac workload and ischemia, and lessen cerebral oxygen demand in head injury. Objective: The purpose of the study was to evaluate the effect of beta blockers (propranolol) on patients with acute TBI. Patients and methods: A total of 400 patients who were presented and admitted to Mansoura University Emergency Hospital (MUEH) surgical ICU with TBI were enrolled in this study. The enrolled patients were divided equally and randomly into 2 groups: Propranolol group (200 patients) who received IV propranolol and control group (200 patients) who received the standard medical and surgical care without propranolol. Results: The clinical outcome of the studied cases were obviously better in propranolol group (P <0.05). The neurologic examination; according to GCS; was improved in 34% vs. 27.5%. The cardiac examination; according to ECG showed changes in 12% vs. 26.5% in propranolol and control groups respectively. Also, the secondary outcome assessment parameters including ICU length of stay (LOS), ward LOS, mechanical ventilation, ventilation periods, survival rate and unfavorable GOS were better in propranolol group (P <0.05). Conclusion: Early propranolol administration is associated with post-head injury cardioprotective and neuroprotective effects, lower hospital resources use and better functional outcome.

Large Infantile Hemangioma on the Face: Let’s ‘PHACE’ It

Background: Infantile hemangiomas (IH) are the most common benign (vascular) tumors in infancy but due to their natural self-limiting course do not necessarily need treatment; in case of ulceration, bleeding or potential deformity, treatment is necessary. Large segmental facial hemangiomas may be associated with PHACE syndrome. Case presentation: We present a case of a boy with a large segmental facial IH. Ulceration, size and location were indications for starting propranolol up to a dose of 3 mg/kg/day in three doses, eleven days after birth. Because of the location and distribution, PHACE syndrome had to be excluded: the patient was checked for possible brain, cardiac and vascular malformations and visual impairment. The IH improved. At the age of nine months, there were no adverse effects or IH progression. Discussion: Propranolol is a beta-blocker effective in treating IH. Its working mechanism has not been completely clarified. We provide a thorough description of our approach to the early propranolol treatment of this large segmental facial IH. Conclusion: Complicated IH like the one described here can be treated safely and effectively with propranolol; very early treatment initiation is recommended to prevent the development of anatomic deformities. Our patient was treated with propranolol 3 mg/kg/day in three doses in order to prevent future disfigurement when it is located in a high-risk area like the face. Further research is needed to create a uniform approach and universal guideline for the treatment of IH with propranolol.

Early propranolol treatment ameliorates endothelial dysfunction in experimental septic lung.

Recent reports have indicated an improved prognosis in sepsis with β-blocker agents; however, the underlying action mechanism is still under debate. The aim of this study was to investigate the potential effect of propranolol on endothelial dysfunction in septic rats. The cecal ligation and puncture model (CLP) was used to generate sepsis. Adult male Wistar-Albino rats were divided into 4 groups: group 1 was a sham group, group 2 received sterile saline, group 3 received 10 mg/kg of propranolol 3 days before the intervention, and group 4 received 10 mg/kg of propranolol 30 min after CLP. Six rats from each group were sacrificed 24 h postoperatively. The remaining rats were followed for survival. We have also evaluated the effects on systemic inflammation, coagulation and the lung tissue with immunohistochemical and electron microscopic evaluation. Serum tumor necrosis factor alpha (TNF-α) and plasminogen activator inhibitor-1 (PAI-1) levels, as well as tissue TNF-α scores were elevated in septic rats. Electron microscopic examination of the lung tissue showed endothelial dysfunction in the sepsis group. Pretreatment significantly improved survival. Moreover, pre-treatment altered serum vascular endothelial growth factor receptor-1 (VEGFR-1) levels and post-treatment reduced serum PAI-1 and VEGFR-1 levels. In both the preand post-treatment groups, electron microscopic examination revealed improvement of the destroyed lung endothelium and showed only mild alterations in the cytoplasmic organelles, especially in the mitochondria of the endothelial cells. These results suggest that the improved outcome with β-blockers in sepsis may be due to the ameliorated endothelial dysfunction. Further studies focusing on the potential effect of β-blockers on the endothelium may lead to a better understanding of sepsis.

Role of early propranolol in weaning from mechanical ventilator in severe traumatic brain injury patients

Background Traumatic brain injury (TBI) is responsible for up to 30% of all injury-related deaths. The majority of patients with severe TBI require mechanical ventilation (MV). To date, no pharmacologic agent has been developed to improve outcomes in TBI. The primary aim of this prospective study was to investigate whether early use of low-dose propranolol within 24 h in patients with severe TBI can affect their weaning from MV or not. Patients and methods This study was carried out on 340 adult patients with severe TBI randomly assigned to two groups. The early propranolol after traumatic brain injury (EPAT) group (102) received propranolol 40 mg twice daily within 24 h from admission. The non-EPAT group (238) did not receive any β blockers. Results EPAT patients showed lower duration of MV (7.74 vs. 11.14 days, P=0.0013). The length of stay in ICU was lower in the EPAT group (10.62 vs. 14.13 days, P=0.003), but there was no statistically significant difference in mortality between the two groups studied (P=0.392). Conclusion Early use of propranolol does not increase episodes of bradycardia or hypotension. Early propranolol after TBI can be used safely and may be associated with decreased days on MV and ICU length of stay.

Early propranolol after traumatic brain injury is associated with lower mortality.

β-Adrenergic receptor blockers (BBs) administered after trauma blunt the cascade of immune and inflammatory changes associated with injury. BBs are associated with improved outcomes after traumatic brain injury (TBI). Propranolol may be an ideal BB because of its nonselective inhibition and ability to cross the blood-brain barrier. We determined if early administration of propranolol after TBI is associated with lower mortality. All adults (age ≥ 18 years) with moderate-to-severe TBI (head Abbreviated Injury Scale [AIS] score, 3-5) requiring intensive care unit (ICU) admission at a Level I trauma center from January 1, 2013, to May 31, 2015, were prospectively entered into a database. Administration of early propranolol was dosed within 24 hours of admission at 1 mg intravenous every 6 hours. Patients who received early propranolol after TBI (EPAT) were compared with those who did not (non-EPAT). Data including demographics, hospital length of stay (LOS), ICU LOS, and mortality were collected. Over 29 months, 440 patients with moderate-to-severe TBI met inclusion criteria. Early propranolol was administered to 25% (109 of 440) of the patients. The EPAT cohort was younger (49.6 years vs. 60.4 years, p < 0.001), had lower Glasgow Coma Scale (GCS) score (11.7 vs. 12.4, p = 0.003), had lower head AIS score (3.6 vs. 3.9, p = 0.001), had higher admission heart rate (95.8 beats/min vs. 88.4 beats/min, p = 0.002), and required more days on the ventilator (5.9 days vs. 2.6 days, p < 0.001). Similarities were noted in sex, Injury Severity Score (ISS), admission systolic blood pressure, hospital LOS, ICU LOS, and mortality rate. Multivariate regression showed that EPAT was independently associated with lower mortality (adjusted odds ratio, 0.25; p = 0.012). After adjusting for predictors of mortality, early administration of propranolol after TBI was associated with improved survival. Future studies are needed to identify additional benefits and optimal dosing regimens. Therapeutic study, level IV.

Prospective evaluation of early propranolol after traumatic brain injury

BackgroundAlthough beta-adrenergic receptor blockade may improve outcomes after traumatic brain injury (TBI), its early use is not routine. We hypothesize that judicious early low-dose propranolol after TBI (EPAT) will improve outcomes without altering bradycardia or hypotensive events. MethodsWe conducted a prospective, observational study on all patients who presented with moderate-to-severe TBI from March 2010–August 2013. Ten initial patients did not receive propranolol (control). Subsequent patients received propranolol at 1-mg intravenous every 6 h starting within 12 h of intensive care unit (ICU) admission (EPAT) for a minimum of 48 h. Heart rate and blood pressure were recorded hourly for the first 72 h. Bradycardia and hypotensive events, mortality, and length of stay (LOS) were compared between cohorts to determine significant differences. ResultsThirty-eight patients were enrolled; 10 control and 28 EPAT. The two cohorts were similar when compared by gender, emergency department (ED) systolic blood pressure, ED heart rate, and mortality. ED Glasgow coma scale was lower (4.2 versus 10.7, P < 0.01) and injury severity score higher in control. EPAT patients received a mean of 10 ± 14 doses of propranolol. Hypotensive events were similar between cohorts, whereas bradycardia events were higher in control (5.8 versus 1.6, P = 0.05). ICU LOS (15.4 versus 30.4 d, P = 0.02) and hospital LOS (10 versus 19.1 d, P = 0.05) were lower in EPAT. Mortality rates were similar between groups (10% versus 10.7%, P = 0.9). The administration of propranolol led to no recorded complications. ConclusionsAlthough bradycardia and hypotensive events occur early after TBI, low-dose intravenous propranolol does not increase their number or severity. Early use of propranolol after TBI appears to be safe and may be associated with decreased ICU and hospital LOS.

Early propranolol administration to severely injured patients can improve bone marrow dysfunction.

Bone marrow (BM) dysfunction is common in severely injured trauma patients, resulting from elevated catecholamines and plasma granulocyte colony-stimulating factor (G-CSF) as well as prolonged mobilization of hematopoietic progenitor cells (HPCs). We have previously shown that propranolol (β-blocker [BB]) reduces HPC mobilization in a rodent model of injury and hemorrhagic shock. We hypothesize that BB would prevent BM dysfunction in humans following severe injury. Forty-five severely injured trauma patients were studied in a prospective, randomized pilot trial. Twenty-five patients received BB, and 20 served as untreated controls. The dose of propranolol was adjusted to decrease the heart rate by 10% to 20% from baseline. Blood was analyzed for the presence of HPC (blast-forming unit erythroid cells [BFU-E] and colony-forming unit erythroid cells) and G-CSF. Demographic data, Injury Severity Score (ISS), hemoglobin, reticulocyte number, and outcome data were obtained. The mean age of the study population was 33 years; 87% were male, with a mean ISS of 29. There is a significant increase in BFU-E in peripheral blood immediately following traumatic injury, and this mobilization persists for 30 days. The use of BB significantly decreases BFU-E and colony-forming unit erythroid cells at all time points. G-CSF is significantly elevated in both groups on admission; the use of BB decreases G-CSF levels by 51% as compared with 37% for controls. The average hemoglobin is nearly 1 g higher on the day of discharge with propranolol treatment (BB, 9.9 ± 0.4 g/dL vs. no BB, 9.1 ± 0.6 g/dL). Following severe trauma, early treatment with propranolol following resuscitation is safe. The use of propranolol blunts early tachycardia, reduces HPC mobilization, and results in a faster return to baseline of the G-CSF peak seen after injury. There is also a trend toward faster recovery and resolution of anemia. Propranolol may be the first therapeutic agent to show improved BM function after severe injury. Therapeutic study, level III.

Early propranolol treatment induces lung heme-oxygenase-1, attenuates metabolic dysfunction, and improves survival following experimental sepsis

IntroductionPharmacological agents that block beta-adrenergic receptors have been associated with improved outcome in burn injury. It has been hypothesized that injuries leading to a hypermetabolic state, such as septic shock, may also benefit from beta-blockade; however, outcome data in experimental models have been contradictory. Thus, we investigated the effect of beta-blockade with propranolol on survival, hemodynamics, lung heat shock protein (HSP) expression, metabolism and inflammatory markers in a rat cecal ligation and puncture (CLP) model of sepsis.MethodsSprague-Dawley rats receiving either repeated doses (30 minutes pre-CLP and every 8 hours for 24 hours postoperatively) of propranolol or control (normal saline), underwent CLP and were monitored for survival. Additionally, lung and blood samples were collected at 6 and 24 hours for analysis. Animals also underwent monitoring to evaluate global hemodynamics.ResultsSeven days following CLP, propranolol improved survival versus control (P < 0.01). Heart rates in the propranolol-treated rats were approximately 23% lower than control rats (P < 0.05) over the first 24 hours, but the mean arterial blood pressure was not different between groups. Metabolic analysis of lung tissue demonstrated an increase in lung ATP/ADP ratio and NAD+ content and a decreased ratio of polyunsaturated fatty acids to monounsaturated fatty acids (PUFA/MUFA). Cytokine analysis of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) demonstrated decreased expression of TNF-alpha in both lung and plasma at 24 hours post CLP induced sepsis. Finally, propranolol led to a significant increase in lung hemeoxygenase-1 expression, a key cellular protective heat shock protein (HSP) in the lung. Other lung HSP expression was unchanged.ConclusionsThese results suggest that propranolol treatment may decrease mortality during sepsis potentially via a combination of improving metabolism, suppressing aspects of the inflammatory response and enhancing tissue protection.

The efficacy of early propranolol administration at reducing PTSD symptoms in pediatric injury patients: A pilot study

Initial research supports the use of propranolol to prevent posttraumatic stress disorder (PTSD); research has not examined pharmacological prevention for children. Twenty-nine injury patients (ages 10-18 years old) at risk for PTSD were randomized to a double-blind 10-day trial of propranolol or placebo initiated within 12 hours postadmission. Six-week PTSD symptoms and heart rate were assessed. Although intent-to-treat analyses revealed no group differences, findings supported a significant interaction between gender and treatment in medication-adherent participants, Delta R(2) = .21. Whereas girls receiving propranolol reported more PTSD symptoms relative to girls receiving placebo, Delta R(2) = .44, boys receiving propranolol showed a nonsignificant trend toward fewer PTSD symptoms than boys receiving placebo, Delta R(2) = .32. Findings inform gender differences regarding pharmacological PTSD prevention in youth.

Effect of early propranolol administration on portal hypertensive gastropathy in cirrhotic rats.

To investigate any protective effect of early propranolol administration in the development of portal hypertensive gastropathy in cirrhotic rats. For the development of liver cirrhosis and portal hypertensive gastropathy, 60 rats underwent ligation of the left adrenal vein and complete devascularization of the left renal vein, followed by phenobarbital and carbon tetrachloride (CCl(4)) administration. After two weeks of CCl(4) administration, the rats were randomly separated into two groups. In group A, propranolol was continuously administered intragastrically throughout the study, whereas in group B normal saline (placebo) was administered instead. Hemodynamic studies and vascular morphometric analysis of gastric sections were performed after complete induction of cirrhosis. Vascular morphometric studies showed higher numbers of vessels in all mucosal layers in the control group. Statistical analysis revealed a significantly higher total vascular surface in the control group compared to the propranolol group, but with no statistically significant difference between the mean vascular surfaces between the groups. Our study clearly shows that the increased mucosal blood flow is manifested by a marked increase of vessel count. Early propranolol's administration in portal hypertensive cirrhotic rats seems to prevent intense gastric vascular congestion that characterizes portal hypertensive gastropathy.

Early Propranolol Administration Does Not Prevent Development of Esophageal Varices in Cirrhotic Rats

Background and Aims: Variceal bleeding is the most serious complication of portal hypertension associated with high mortality. This study was conducted to investigate any protective effect of early propranolol administration in the development and degree of esophageal varices in cirrhotic rats with portal hypertension. This topic is controversial in the literature. Methods: For the development of liver cirrhosis and esophageal varices, 60 rats underwent ligation of the left adrenal vein and complete devascularization of the left renal vein, followed by phenobarbital and carbon tetrachloride (CCl₄) administration. This operation enhances the development of cephalad collaterals, responsible for the induction of esophageal varices. After 2 weeks of CCl₄ administration, the rats were randomly separated into 2 groups. In group I, propranolol was continuously administered intragastrically throughout the study, whereas in group II normal saline (placebo) was administered instead. Cirrhosis was detected clinically by ascites development. Hemodynamic studies and morphometric analysis of the lower esophagus were performed after complete induction of cirrhosis, measuring the following parameters: portal pressure, total number of submucosal veins, total submucosal vessel area, mean cross-sectional submucosal vessel area, relative submucosal area (percentage) occupied by vessels and area of the single most dilated submucosal vein. Results: The statistical analysis revealed no statistically important difference between the 2 groups for the morphometrically studied parameters. However, portal venous pressure was lower in group I. Conclusion: Early propranolol administration did not protect rats from developing esophageal varices, despite the fact that a significant decrease in portal pressure was detected.

Effect of early propranolol treatment in an animal model of congestive cardiomyopathy. II. beta-adrenergic receptors and left ventricular function.

Young turkeys inbred for congestive cardiomyopathy (CCM) were treated with propranolol prior to the development of cardiac enlargement. One-day-old inbred CCM and commercial turkeys received 2 mg X kg-1 X day-1 of propranolol for 1 month and were compared with untreated age matched inbred CCM and commercial turkeys. Heart weight, body weight, and binding characteristics of cardiac beta-adrenergic receptors, using (-)3H-dihydroalprenolol as a ligand, were determined at 10 and 28 days. Left ventricular shortening fraction was determined at 28 days and at 32 days, 4 days after propranolol was discontinued, in treated and untreated inbred CCM and commercial turkeys. Propranolol did not prevent the development of cardiac hypertrophy in inbred CCM turkeys at 28 days of age and did not effect body weight or heart weight in either inbred CCM or commercial turkeys at 10 or 28 days of age. In the inbred CCM turkeys, the maximum number of binding sites (Bmax) and the binding affinity (Kd) of beta-adrenergic receptors were not changed by propranolol treatment. In the propranolol-treated commercial turkeys, Bmax the of beta-receptors was increased at 28 days of age compared with untreated age matched controls, 382 vs 194 fmol X mg-1 (p less than 0.05). Untreated inbred CCM turkeys when compared with untreated age matched commercial turkeys show a significant reduction of binding affinity of beta-receptors at both 10 and 28 days of age, Kd = 10.4 vs 6.2 nmol X litre-1 at 10 days and 11.3 vs 5.2 nmol X litre-1 at 28 days (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of early propranolol treatment in an animal model of congestive cardiomyopathy: I Mortality and Ca2+ transport in sarcoplasmic reticulum.

Young turkeys inbred for congestive cardiomyopathy were treated with propranolol prior to the development of cardiac enlargement. One-day-old inbred and commercial turkeys received propranolol, 2 mg X kg-1 X day-1 for 1 month. Propranolol treated inbred birds showed a significantly reduced mortality from 5 to 15 days of age when compared with untreated inbred birds. However, by 28 days of age, cumulative mortality in the treated inbred birds was equal to that in the untreated inbred birds, 29 and 32%, respectively. Propranolol-treated and untreated commercial birds have a 28-day cumulative mortality of 5%. Ca2+ transport in isolated cardiac sarcoplasmic reticulum was studied at 10 and 28 days of age. At 10 days of age Ca2+ uptake and Ca2+ binding in propranolol-treated birds was reduced to 56% and 83%, respectively, of values in untreated inbred birds. By 28 days of age Ca2+ uptake and Ca2+ binding in treated and untreated inbred birds were similar. Ca2+-stimulated ATPase activity was significantly elevated in treated inbred birds compared with age-matched untreated inbred birds at 10 and 28 days of age. Ca2+ transport in isolated cardiac SR from propranolol-treated commercial control birds was not significantly different from the values in untreated commercial birds at 10 or 28 days of age. Improvement in early mortality may be due to the prevention of arrhythmias. Propranolol alters Ca2+ transport in isolated cardiac SR from inbred birds by uncoupling Ca2+-stimulated ATPase. Whether this is due to a direct effect of propranolol on the SR membrane or occurs from its beta-adrenergic blocking action is unclear.

363 ALTERED BEHAVIOURAL DEVELOPMENT AFTER EARLY PROPRANOLOL EXPOSURE

Studies on the rat indicate that, as suggested by human case reports, early propranolol exposure results in a growth deficit. Brain weight was significantly smaller in suckling rats given daily propranolol 50 mg/kg by gavage starting on day 4. Mean brain weight was 1.36±0.02g vs 1.45±0.01g in vehicle treated controls (p<0.01). To determine whether there was a functional deficit accompanying the anatomical one, behavioural studies were carried out when the rats were 50-60 days of age. Propranolol exposed animals required significantly more trials to reach criterion on a passive avoidance task. There was a trend toward decreased head dip response. Rats given propranolol 50 mg/kg but supplemented with triiodothyronine (T3) in a dose of 700 ng/kg performed normally on passive avoidance and were intermediate in head dip between PRO treated rats and vehicle controls.Conclusion: Early propranolol exposure produces an alteration in behavioural development. T3 supplementation protects against this effect of propranolol.