Risk factors for postoperative delirium: An umbrella review of systematic reviews.

BACKGROUND: Postoperative delirium (POD) is associated with increased mortality, increased length of hospital stays and increased rates and severity of subsequent cognitive decline including dementia. A wide range of risk factors for POD have been suggested in the literature across multiple surgical specialities. However few are validated and no accurate prognostic models exist. We therefore aimed to map the existing evidence regarding risk factors for POD to help guide future research by undertaking an umbrella review of systematic reviews examining risk factors for POD in any context. MATERIALS AND METHODS: We systematically searched multiple medical databases for systematic reviews examining the risk factors for POD in adults undergoing any surgery. We then selected relevant reviews with minimal overlap in primary studies and extracted information about individual risk factors. RESULTS: Thirty-five relevant reviews were identified of which ten were in trauma and orthopaedic surgery patients (four exclusively examined hip fractures), five were in cardiac surgery patients, and four were in vascular surgery patients. Due to substantial overlap in reviews, eighteen reviews were analysed in detail finding the widely examined and consistent risk factors were increasing age, nursing home residency, pre-existing cognitive impairment, psychiatric disorders, cerebrovascular disease, end stage renal failure, low albumin, higher ASA score, and intra-operative blood transfusion. Many other risk factors were examined, but they were either not studied in multiple systematic reviews, or inconsistent either in results or in categorisation (which for many factors was heterogenous even within systematic reviews). There are also a large number of existing prognostic models, many of which remain unvalidated. CONCLUSION: Given the wealth of existing literature, future research should avoid simple risk factor evaluation except for novel candidates, validate existing prognostic models where possible, and instead focus on interventional research.

Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial.

OBJECTIVE: Central blood pressure (CBP) and carotid intima-media thickness (CIMT) are surrogate measures of cardiovascular risk. Allopurinol reduces serum uric acid and oxidative stress and improves endothelial function and may therefore reduce CBP and CIMT progression. This study sought to ascertain whether allopurinol reduces CBP, arterial stiffness and CIMT progression in patients with ischaemic stroke or transient ischaemic attack (TIA). METHODS: We performed a randomised, double-blind, placebo-controlled study, examining the effect of 1-year treatment with allopurinol (300 mg daily), on change in CBP, arterial stiffness and CIMT progression at 1 year and change in endothelial function and circulating inflammatory markers at 6 months. Patients aged over 18 years with recent ischaemic stroke or TIA were eligible. RESULTS: Eighty participants were recruited, mean age 67.8 years (SD 9.4). Systolic CBP [-6.6 mm Hg (95% CI -13.0 to -0.3), p=0.042] and augmentation index [-4.4% (95% CI -7.9 to -1.0), p=0.013] were each lower following allopurinol treatment compared with placebo at 12 months. Progression in mean common CIMT at 1 year was less in allopurinol-treated patients compared with placebo [between-group difference [-0.097 mm (95% CI -0.175 to -0.019), p=0.015]. No difference was observed for measures of endothelial function. CONCLUSIONS: Allopurinol lowered CBP and reduced CIMT progression at 1 year compared with placebo in patients with recent ischaemic stroke and TIA. This extends the evidence of sustained beneficial effects of allopurinol to these prognostically significant outcomes and to the stroke population, highlighting the potential for reduction in cardiovascular events with this treatment strategy. TRIAL REGISTRATION NUMBER: ISRCTN11970568.

The development and evaluation of options for improving future U.K. blood component labelling--outcome of the 2013 U.K. hospital survey.

BACKGROUND/OBJECTIVES: U.K. blood component labels have evolved to accommodate a plethora of information. Concern has, however, been expressed that current U.K. labelling is too 'cluttered', detracting from the clarity of critical information. This prompted a holistic review of labelling and available information technology (IT) with the aim of improving the situation. METHODS/MATERIALS: A survey was circulated requiring U.K. hospital participants to rank each item of information on the label according to its 'criticality' and assess three novel 'future' and one 'transition' prototype labels. Prototypes were based on applicable regulatory standards, best practice guidance, international benchmark data and U.K. expert input. The prototypes support steps towards 'full face' label printing and utilise 2D and quick response (QR) barcodes. RESULTS: Two-hundred eleven completed surveys were received identifying 110 contributing hospitals with 41% from clinical staff, 37% from transfusion laboratory staff and 22% from transfusion practitioners. There was excellent agreement between the three groups on the critical information, i.e., blood group, expiry date, blood component name, unique donation identification number (DIN) and blood component volume but far less on the other information, especially the various warning messages. Of the 'future' labels, option 3 (closest to the current 'quadrant model') was most popular. Option 1, with its additional inverted section replicating critical information was least popular and prompted significant safety concerns. CONCLUSION: The prototype labels correctly identified the critical items of information and extensive comments confirmed that this was more prominently and clearly displayed. Laboratory staff commented that the transition label was essential to enable IT systems to be adapted.

Autotransfusion in emergent operative trauma resuscitation.

PURPOSE: Autotransfusion of red cells is common in many surgical specialties. However, this technique is not uniformly used in abdominal trauma. The purpose of this paper is to study the outcomes of patients who were autotransfused during emergency trauma operations in which they sustained full-thickness hollow viscus injury (HVI). METHODS: A total of 179 patients in period 1999-2008 with penetrating and blunt abdominal trauma requiring intraoperative blood transfusion were evaluated. Recipients of autotransfusion and banked blood (autotransfused group) were compared with recipients of banked blood products only (control group). The t-test, Chi-squared, and Fisher's exact test were used to evaluate the data. Multivariate regression analysis evaluated the primary outcomes, survival and bloodstream infection (BSI). RESULTS: Of the 179 patients, 108 controls and 71 autotransfused patients were evaluated. The results showed no statistically significant difference between the control and autotransfusion groups regarding age, injury pattern/severity [Injury Severity Score (ISS)], length of stay, postoperative international normalized ratio (INR), and volume of banked blood products. Both groups were also proportional with colon injury. The estimated operative blood loss (EBL) was 2,472 ± 3,261 for controls and 4,056 ± 3,825 for the autotransfused group (p = 0.0001). The total volume of blood transfused was 2,792 and 5,513 for controls and patients in the autotransfusion group, respectively (p = 0.002). Ninety controls (84 %) and 53 autotransfused patients (76 %) survived to discharge (p = 0.21). Twenty controls (49 %) and 17 autotransfused patients (45 %) developed BSI (p = 0.72). Logistic regression analysis revealed that an ISS >25, systolic blood pressure <90, and EBL >2 L predicted mortality. There was also a trend towards decreased survival with age >50 years. CONCLUSION: We found no evidence that emergent autotransfusion worsens clinical outcomes in the setting of concomitant HVI.

Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor.

There is significant interest in treating cancers by blocking protein synthesis, to which hematological malignancies seem particularly sensitive. The translation elongation inhibitor homoharringtonine (Omacetaxine mepesuccinate) is undergoing clinical trials for chronic myeloid leukemia, whereas the translation initiation inhibitor silvestrol has shown promise in mouse models of cancer. Precisely how these compounds induce cell death is unclear, but reduction in Mcl-1, a labile pro-survival Bcl-2 family member, has been proposed to constitute the critical event. Moreover, the contribution of translation inhibitors to neutropenia and lymphopenia has not been precisely defined. Herein, we demonstrate that primary B cells and neutrophils are highly sensitive to translation inhibitors, which trigger the Bax/Bak-mediated apoptotic pathway. However, contrary to expectations, reduction of Mcl-1 did not significantly enhance cytotoxicity of these compounds, suggesting that it does not have a principal role and cautions that strong correlations do not always signify causality. On the other hand, the killing of T lymphocytes was less dependent on Bax and Bak, indicating that translation inhibitors can also induce cell death via alternative mechanisms. Indeed, loss of clonogenic survival proved to be independent of the Bax/Bak-mediated apoptosis altogether. Our findings warn of potential toxicity as these translation inhibitors are cytotoxic to many differentiated non-cycling cells.

Spatial and temporal characteristics of vestibular convergence.

In all species studied, afferents from semicircular canals and otolith organs converge on central neurons in the brainstem. However, the spatial and temporal relationships between converging inputs and how these contribute to vestibular behaviors is not well understood. In the current study, we used discrete rotational and translational motion stimuli to characterize canal- and otolith-driven response components of convergent non-eye movement (NEM) neurons in the vestibular nuclear complex of alert pigeons. When compared to afferent responses, convergent canal signals had similar gain and phase ranges but exhibited greater spatial variability in their axes of preferred rotation. Convergent otolith signals also had similar mean gain and phase values to the afferent population but were spatially well-matched with the corresponding canal signals, cell-by-cell. However, neither response component alone nor a simple linear combination of these components was sufficient to predict actual net responses during combined canal-otolith stimulation. We discuss these findings in the context of previous studies of pigeon vestibular behaviors, and we compare our findings to similar studies in other species.

Radial artery hypertrophy occurs in coronary atherosclerosis and is independent of blood pressure.

Endothelial dysfunction, believed to underlie the structural changes of atherosclerosis, is a systemic phenomenon. Despite this, the radial artery has been considered as devoid of atherosclerosis and is commonly used as a conduit in coronary artery bypass grafting (CABG). Recently, histological study has shown intimal hyperplasia and other structural changes consistent with early atherosclerosis in the radial artery. The objective of the present study was to determine if structural changes in the radial artery could be detected in vivo in patients with coronary atherosclerosis. Using high resolution echo-tracking, measurements of radial artery internal diameter, wall thickness and wall cross-sectional area were made in 25 patients awaiting CABG and in 20 controls. Digital and brachial blood pressures were also recorded. Mean arterial pressures did not differ between the patient and control groups. All measures of wall thickness were greater in the patient than the control group. Neither current arterial pressures nor past history of hypertension correlated with wall thickness. Using a model of analysis of covariance, coronary artery disease was the best single predictor of intima-media thickness, R(2)=48%, n=44, P<0.0005. We concluded that increased radial artery wall thickness can be demonstrated in vivo in patients with coronary atherosclerosis. This is a novel observation which seems to be independent of blood pressure, and is consistent both with the hypothesis of systemic endothelial dysfunction leading to systemic structural changes and also to the recent histological evidence for atherosclerotic changes in this vessel.

Pharmacological characterisation of endothelium-dependent relaxation in human radial artery: comparison with internal thoracic artery.

OBJECTIVE: The aim of this study was to investigate the contribution of nitric oxide/prostanoid-independent pathways to endothelium-dependent vasorelaxation in human conduit arteries. METHODS: Rings of internal thoracic artery (ITA) and radial artery (RA) taken from patients undergoing coronary artery bypass graft surgery were suspended in 10-ml organ baths and relaxation to carbachol and bradykinin studied in the presence and absence of nitric oxide synthase (NOS) inhibitors and potassium channel blockers. RESULTS: No significant relaxation to carbachol or bradykinin was observed in ITA after NOS inhibition. In contrast, in RA less than 40% attenuation of relaxation to carbachol or bradykinin was achieved with any of the NOS inhibitors. In the presence of 20 mM K+ relaxation to carbachol and bradykinin was inhibited by 28 +/- 9% and 42 +/- 9% while in the presence of L-NAME 200 microM + 20 mM K+ relaxation was inhibited by 66 +/- 6% and 70 +/- 4% respectively in this artery. Tetraethylammonium, glibenclamide, apamin and iberiotoxin had little effect on relaxation to carbachol but charybdotoxin alone and charybdotoxin plus apamin attenuated relaxation to carbachol by 23 +/- 4% and 49 +/- 9% in RA. In the presence of L-NAME 200 microM attenuation of these relaxations were increased to 60 +/- 4% and 78 +/- 4%. CONCLUSION: In ITA relaxations to carbachol and bradykinin were mediated via nitric oxide. In contrast in RA, a conduit vessel of similar diameter, both nitric oxide-dependent and independent pathways appeared to contribute to vascular relaxation. This nitric oxide-independent relaxation involved opening of Ca2+ activated potassium channel(s). The existence of alternative pathways mediating endothelium-independent relaxation could be important under pathological conditions and may contribute to the long term survival of radial artery grafts.

Does potassium channel opening contribute to endothelium-dependent relaxation in human internal thoracic artery?

Opening of potassium channels can cause hyperpolarization and relaxation of vascular smooth muscle cells. The aim of this work was to investigate the contribution of potassium channel activation to vasorelaxation in internal thoracic artery taken from patients undergoing coronary artery bypass graft surgery. Relaxations to carbachol and sodium nitroprusside were studied in isolated rings of internal thoracic artery in the absence and presence of nitric oxide synthase inhibitors and potassium channel blockers. The nitric oxide synthase inhibitors Nomega-nitro-L-arginine methyl ester and NG-monomethyl-L-arginine abolished relaxations to carbachol. Relaxations to both carbachol and sodium nitroprusside were attenuated in the presence of raised extracellular potassium and the potassium channel blockers charybdotoxin, iberiotoxin and tetraethylammonium. Neither apamin nor glibenclamide modified relaxation. ODQ (1H-[1,2,4]oxadiazolol-[4,3a] quinoxalin-1-one), an inhibitor of soluble guanylate cyclase, abolished relaxation to carbachol in rings from some but not all subjects. These results suggest that potassium channel opening may make a small contribution to endothelium-dependent vasorelaxation in internal thoracic artery. The potassium channels had characteristics consistent with those of large-conductance calcium-dependent potassium channels.

The Toronto Tri-Hospital Gestational Diabetes Project. A preliminary review.

In this study, we assessed maternal-fetal outcomes in untreated patients with increasing carbohydrate intolerance not meeting the current criteria for the diagnosis of gestational diabetes mellitus (GDM), examined the relationship between birth weight and mode of delivery among women with untreated borderline GDM, treated overt GDM, and normoglycemia, and established more efficient screening strategies for detection of GDM. This was a prospective analytic cohort study in which nondiabetic women aged > or = 24 years were eligible for enrollment. A 50-g glucose challenge test (GCT) and a 100-g oral glucose tolerance test (OGTT) were administered at 26 and 28 weeks gestational age, respectively. Risk factors for unfavorable maternal-fetal outcomes were recorded. Time since the last meal prior to the screening test was recorded, as well. Caregivers and patients were blinded to glucose values except when test results met the National Diabetes Data Group criteria for GDM. Maternal and fetal outcomes, including the mode of the delivery, were recorded in the postpartum period. Of 4,274 patients screened, 3,836 (90%) continued to the diagnostic oral glucose tolerance test. GDM was seen in 145 women. Increasing carbohydrate intolerance in women without overt gestational diabetes was associated with a significantly increased incidence of cesarean section, preeclampsia, macrosomia, and need for phototherapy, as well as an increased length of maternal and neonatal hospital stay. Multivariate analysis showed that increasing carbohydrate intolerance remained an independent predictor for various unfavorable outcomes, but the strength of the associations was diminished. Compared with normoglycemic control subjects, the untreated borderline GDM group had increased rates of macrosomia (28.7 vs. 13.7%, P < 0.001) and cesarean delivery (29.6 vs. 20.2%, P = 0.03). Usual care of known GDM patients normalized birth weights, but the cesarean delivery rate was about 33%, whether macrosomia was present or absent. An increased risk of cesarean delivery among treated patients compared with normoglycemic control subjects persisted after adjustment for multiple maternal risk factors. As for the screening tests, time since the last meal had a marked effect on mean plasma glucose. Receiver operating characteristic curve analysis allowed the selection of the most efficient cut points for the GCT based on the time since the last meal. These cut points were 8.2, 7.9, and 8.3 mmol/l (1 mmol/l = 18.015 mg/dl) for elapsed postprandial time of < 2, 2-3, and > 3 h, respectively. With this change from the current threshold of 7.8 mmol/l, the number of patients with a positive screening test dropped from 18.5 to 13.7%. There was an increase in positive predictive value from 14.4 to 18.7%. The overall rate of patient misclassification fell from 18.0 to 13.1%. In conclusion, increasing maternal carbohydrate intolerance in pregnant women without GDM is associated with a graded increase in adverse maternal and fetal outcomes. Infant macrosomia is an important factor in high cesarean delivery rates for women with untreated borderline GDM. Although detection and treatment of GDM normalizes birth weights, rates of cesarean delivery remain inexplicably high. Recognition of GDM may lead to a lower threshold for surgical delivery. The efficiency of screening for GDM can be enhanced by adjusting the current GCT threshold of 7.8 mmol/l to new values related to time since the last meal before screening. Further analyses are underway to elucidate whether maternal risk factors can be used to achieve additional efficiency gains in screening.

Laparotomy and proximal gastric vagotomy in Zollinger-Ellison syndrome: results of a 16-year prospective study.

OBJECTIVE: Pharmacological control of gastric acid hypersecretion in the Zollinger-Ellison syndrome has steadily improved, but medical treatment does not address the underlying tumor. The objective of this study was to evaluate the long-term effectiveness of a surgical approach to both tumor and acid hypersecretion in 22 patients with the Zollinger-Ellison syndrome. METHODS: Patients underwent laparotomy to resect tumors, combined with vagotomy to reduce acid secretion, followed by postoperative antisecretory therapy, if necessary. RESULTS: No surgical mortality or serious morbidity occurred. Tumor was found at laparotomy in nine patients (41%) and during long-term follow-up in an additional two patients (9%). Ten-year survival is 81%, with a long-term cure rate of at least 14%. Most patients (86%) have had long-term inhibition of acid secretion. Eight patients have discontinued regular use of acid-inhibiting medications. Patients requiring medication need less of it, and they have an improved acid inhibitory response to medication for up to 16 yr after surgery. CONCLUSION: Cure of the Zollinger-Ellison syndrome is possible in a minority of patients. Acid secretion can be safely reduced in almost all patients with laparotomy/vagotomy, usually allowing discontinuation, or reduced dose, of acid-inhibiting drugs. Long-term survival and quality of life are generally excellent.

Effects of aging and gastritis on gastric acid and pepsin secretion in humans: a prospective study.

BACKGROUND & AIMS: Recent studies suggesting that gastric secretion does not decrease with aging included few elderly individuals and measured only acid secretion. The aims of this study were to measure gastric acid and pepsin output in 206 health Americans (age range, 18-98 years) and to compare secretion rates with gastric histology. METHODS: Immediately after basal and pentagastrin-stimulated acid and pepsin outputs were measured, oxyntic biopsy samples were obtained. RESULTS: Gastric acid and pepsin output rates were similar in young (age range, 18-34 years) and middle-aged (age range, 35-64 years) groups. Stimulated acid output was reduced approximately 30% in the elderly (age range, 65-98 years). However, after adjustment for histology, Helicobacter pylori infection, and other variables, age had no independent effect on acid output. The decline in acid secretion in the elderly was primarily related to a higher prevalence of chronic atrophic gastritis and a lower prevalence of smoking. Pepsin output was reduced by approximately 40% in the elderly. After adjustment for other variables, age remained a robust predictor of reduced pepsin output. CONCLUSION: Although advancing age has no independent effect on gastric acid secretion, it is associated with reduced pepsin output independent of atrophic gastritis, H. pylori infection, and smoking.

Review article: drug-induced pancreatitis.

Drugs are a relatively uncommon cause of pancreatitis in adult patients, but should be considered when other reasonable causes of pancreatitis are not present. A wide variety of drugs have been reported to cause pancreatitis. Drug-induced pancreatitis is almost always acute and may be mild to fatal in severity. Definite proof that a drug causes pancreatitis requires that pancreatitis develops during treatment with the drug, that other likely causes of pancreatitis are not present, that pancreatitis resolves upon discontinuing the drug, and that pancreatitis usually recurs upon readministration of the drug. For ethical reasons, rechallenge with the suspect drug can be done only if the drug is necessary to treat a serious condition; thus this highly convincing piece of evidence relating the drug to pancreatitis may not be available. Information about drug-related pancreatitis is often not readily available, particularly for newer drugs. Clinicians should consider obtaining information directly from regulatory agencies and manufacturers as well as the literature.

Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes. The Toronto Tri-Hospital Gestational Diabetes Project.

OBJECTIVE: Our purpose was to assess maternal-fetal outcomes in patients with increasing carbohydrate intolerance not meeting the current criteria for the diagnosis of gestational diabetes. STUDY DESIGN: We conducted a prospective analytic cohort study in which nondiabetic women aged > or = 24 years, receiving prenatal care in three Toronto teaching hospitals, were eligible for enrollment. A glucose challenge test and an oral glucose tolerance test were administered at 26 and 28 weeks' gestation, respectively; risk factors for unfavorable maternal-fetal outcomes were recorded. Caregivers and patients were blinded to glucose values except when test results met the current criteria for gestational diabetes. RESULTS: Of 4274 patients screened, 3836 (90%) continued to the diagnostic oral glucose tolerance test. The study cohort was formed by the 3637 (95%) patients without gestational diabetes, carrying singleton fetuses. Increasing carbohydrate intolerance in women without overt gestational diabetes was associated with a significantly increased incidence of cesarean sections, preeclampsia, macrosomia, and need for phototherapy, as well as an increased length of maternal and neonatal hospital stay. Multivariate analysis showed that increasing carbohydrate intolerance is an independent predictor for various unfavorable outcomes. CONCLUSION: Increasing maternal carbohydrate intolerance in pregnant women without gestational diabetes is associated with a graded increase in adverse maternal-fetal outcomes.

Impact of time since last meal on the gestational glucose challenge test. The Toronto Tri-Hospital Gestational Diabetes Project.

OBJECTIVE: The purpose of the study was to evaluate the impact of time since the last meal on the glucose challenge test and to find cut points that are most likely to predict the outcome of the oral glucose tolerance test in patients screened for gestational diabetes. STUDY DESIGN: This prospective analytic cohort study was carried out at the University of Toronto Perinatal Complex. A 50 gm glucose load was given at 26 weeks' gestation and the time since previous meal ingestion was recorded. At 28 weeks' gestation a 100 gm oral glucose tolerance test was administered. A total of 4274 eligible patients were screened. RESULTS: Time since the last meal had a marked effect on mean plasma glucose. Receiver-operator characteristic curve analysis with National Diabetes Data Group criteria to interpret the oral glucose tolerance allowed the selection of the most efficient cut points for the glucose challenge test on the basis of time since the last meal. These cut points were 8.2, 7.9, and 8.3 mmol/L for elapsed postprandial times of < 2, 2 to 3, and > 3 hours, respectively. With this change from the current threshold of 7.8 mmol/L the number of patients with a positive screening test dropped from 18.5% to 13.7%. There was an increase in positive predictive value from 14.4% to 18.7%. The rate of patient misclassification fell from 18.0% to 13.1%. CONCLUSION: We suggest that screening strategies for detection of gestational diabetes be reconsidered, to account for the impact of variable postprandial status on the test results.

Detection and reactions of the globin radical in haemoglobin.

The reaction of methaemoglobin with hydrogen peroxide and other oxidants has been studied using both electron paramagnetic resonance (EPR) and optical spectroscopy. The results obtained are consistent with the formation of an iron(IV)-oxo species (which is one oxidising equivalent above the initial level) and rapid transfer of the second oxidising equivalent into the surrounding globin generating a protein radical; this species has been observed by stopped-flow EPR. The partially resolved hyperfine splittings of the EPR signal (a2H 0.66, a2H 0.17, aH 1.157, aH 0.203 mT), together with its g value (2.0044) suggest that this species is a sterically-constrained tyrosine phenoxyl radical. Experiments with inhibitors and chemically-modified haemoglobins are in agreement with this assignment. This radical is not observed with the apoprotein or oxyhaemoglobin, confirming that the reaction requires the presence of an iron(III) haem. The concentration of the phenoxyl radical is not affected by hydroxyl-radical scavengers but is affected by certain reducing agents and antioxidants, demonstrating that the protein radical is accessible to reagents in bulk solution. Analysis of the protein structure suggests that this radical may be centered on the tyrosine at alpha-42 as this residue is in close proximity to the haem groups and partially exposed on the surface. Addition of the spin trap DMPO to the reaction system results in the observation of a broad, anisotropic, spectrum from a protein-derived spin adduct; this signal is assigned to a peroxyl radical adduct on the basis of the hyperfine coupling constants (aN 2.03, aH 1.4 mT), its short life-time, the detection of oxygen uptake, and the decrease in the intensity of this signal under anoxic conditions. Experiments with modified haemoproteins and inhibitors suggest that this species arises via the tyrosine phenoxyl radical. These observations suggest that the tyrosine residues act as a 'sink' for oxidising equivalents generated by electron-transfer within the protein after initial oxidation at the haem centre.

Prostaglandin E2 desensitizes cAMP-mediated pepsinogen secretion in chief cells.

To evaluate whether pretreatment with prostaglandin E2 (PGE2) could desensitize pepsinogen secretion in chief cells from guinea pig, chief cells were pretreated with 10 microM PGE2 for up to 30 min. Desensitization of subsequent PGE2-stimulated secretion was maximal after 15 min, averaging only 29 +/- 9% (SE) of pepsinogen secretion in control cells stimulated with 10 microM PGE2. Desensitization was half-maximal with 30 nM PGE2. PGE2 pretreatment at 4 degrees C did not cause desensitization. In cells pretreated with 10 microM PGE2 for 15 min and then given 60 min to recover, responsiveness increased to 79 +/- 7% of that for control cells stimulated with PGE2. Thus the desensitization was reversible. Pretreatment with PGD2 and PGF2a did not alter subsequent PGE2-mediated secretion. PGE2-induced desensitization was heterologous but mediator specific because pepsinogen secretion was reduced in response to adenosine 3',5'-cyclic monophosphate (cAMP)-mediated agents (secretin and vasoactive intestinal peptide) but not Ca(2+)-mediated agents (CCK-8, gastrin, or carbachol). Pretreating chief cells with 10 microM PGE2 did not significantly alter cAMP generation in response to PGE2, secretin, or 3-isobutyl-1-methylxanthine, suggesting that desensitization was not mediated by an alteration in the receptor-coupled adenylate cyclase system. Because PGE2 pretreatment also desensitized pepsinogen secretion induced by the synthetic cAMP analogues 8-BrcAMP and 2'-O-monobutyryl-8-BrcAMP, it is likely that the ability of PGE2 to desensitize pepsinogen secretion in chief cells isolated from guinea pig is due to a mechanism distal to generation of cAMP.