Comparing pain intensity rating scales in acute postoperative pain: boundary values and category disagreements.

Pain intensity assessment scales are important in evaluating postoperative pain and guiding management. Different scales can be used for patients to self-report their pain, but research determining cut points between mild, moderate and severe pain has been limited to studies with < 1500 patients. We examined 13,017 simultaneous acute postoperative pain ratings from 913 patients taken at rest and on activity, between 4 h and 48 h following surgery using both a verbal rating scale (no, mild, moderate or severe pain) and 0-100 mm visual analogue scale. We determined the best cut points on the visual analogue scale between mild and moderate pain as 35 mm, and moderate and severe pain as 80 mm. These remained consistent for pain at rest and on activity, and over time. We also explored the presence of category disagreements, defined as patients verbally describing no or mild pain scored above the mild/moderate cut point on the visual analogue scale, and patients verbally describing moderate or severe pain scored below the mild/moderate cut point on the visual analogue scale. Using 30 and 60 mm cut points, 1533 observations (12%) showed a category disagreement and using 35 and 80 mm cut points, 1632 (13%) showed a category disagreement. Around 1 in 8 simultaneous pain scores implausibly disagreed, possibly resulting in incorrect pain reporting. The reasons are not known but low rates of literacy and numeracy may be contributing factors. Understanding these disagreements between pain scales is important for pain research and medical practice.

Factors predicting persistence of biologic drugs in psoriasis: a systematic review and meta-analysis.

BACKGROUND: Long-term therapy for psoriasis is impaired by gradual loss of effectiveness and treatment discontinuation. Identifying factors that affect biologic drug survival may help in treatment optimization. OBJECTIVES: To identify factors that predicted biologic drug persistence or discontinuation in a real-life setting. METHODS: We identified studies of biologic persistence in psoriasis through a comprehensive, systematic literature search using predefined search criteria. Studies were screened by title and abstract then further by full-text review. Hazard ratio (HR) data were extracted for all available predictive factors (HRs > 1 denoted biologic discontinuation, and HRs < 1 denoted biologic persistence). A meta-analysis of HRs (random-effects model) was used to assess any predictive factor included in at least two studies. RESULTS: Sixteen cohort studies were included in the review, with a total of 32 194 patients. A meta-analysis was performed on 13 studies (n = 29 802): nine for female sex (n = 28 090), six for obesity (n = 9311) and six for psoriatic arthritis (n = 24 444). Obesity and female sex predicted treatment discontinuation, with HRs of 1.21 [95% confidence interval (CI) 1.10-1.32, I2 = 0%] and 1.22 (95% CI 1.07-1.38, I2 = 84%), respectively. Concomitant psoriatic arthritis predicted biologic persistence (HR 0.83, 95% CI 0.80-0.86, I2 = 0%). Female sex predicted biologic discontinuation due to side-effects, with a pooled HR of 2.16 (95% CI 1.39-3.35, I2 = 67%). Other reported predictive factors (smoking, metabolic syndrome, biologic naivety, age, Dermatology Life Quality Index, dyslipidaemia, high socioeconomic status and concomitant methotrexate) were insufficiently reported for meta-analysis. CONCLUSIONS: Our meta-analysis demonstrates that female sex and obesity predict biologic discontinuation, and concomitant psoriatic arthritis predicts biologic survival. What's already known about this topic? Ineffectiveness is the main factor that causes drug discontinuation during long-term treatment of psoriasis. It is unclear which factors and comorbidities impact drug persistence. What does this study add? Female sex and obesity predict biologic discontinuation due to ineffectiveness and adverse events. Concomitant psoriatic arthritis is associated with improved drug persistence.

Co-administration of dexamethasone with peripheral nerve block: intravenous vs perineural application: systematic review, meta-analysis, meta-regression and trial-sequential analysis.

BACKGROUND: I.V. and perineural dexamethasone have both been found to prolong loco-regional analgesia compared with controls without dexamethasone. It is unclear whether perineural administration offers advantages when compared with i.v. dexamethasone. METHODS: A systematic literature search was performed to identify randomized controlled double-blind trials that compared i.v. with perineural dexamethasone in patients undergoing surgery. Using the random effects model, risk ratio (for binary variables), weighted mean difference (for continuous variables) and 95% confidence intervals were calculated. We applied trial sequential analysis to assess the risks of type I and II error, meta-regression for the study of the doseresponsive relationship, and the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: We identified 10 randomized controlled double-blind trials (783 patients). When using conventional meta-analysis of nine low risk of bias trials, we found a statistically significantly longer duration of analgesia, our primary outcome with perineural dexamethasone (241 min, 95%CI, 87, 394 min). When trial sequential analysis was applied, this result was confirmed. Meta-regression did not show a dose-response relationship. Despite the precision in the results, using the Grading of Recommendations Assessment, Development, and Evaluation system (GRADE), we assessed the quality of the evidence for our primary outcome as low. CONCLUSIONS: There is evidence that perineural dexamethasone prolongs the duration of analgesia compared with i.v. dexamethasone. Using GRADE, this evidence is low quality.

Paravertebral block and persistent postoperative pain after breast surgery: meta-analysis and trial sequential analysis.

We examined whether paravertebral block has an effect on the prevalence of persistent postsurgical pain after breast surgery. Seven randomised, controlled trials (559 patients) which had the outcome assessor blinded were included, comparing patients who received paravertebral blocks after breast surgery with patients who did not. The risk ratio (95% CI) was 0.75 (0.48-1.15) for the incidence of postoperative pain at 3 months (four studies, 317 patients); the risk ratio (95% CI) obtained from three studies including 301 patients reporting on pain after 6 months was 0.57 (0.29-1.72), and the risk ratio (95% CI) for pain after 12 months (three trials, 237 patients) was 0.42 (0.15-1.23). Conventional meta-analysis using the random effects model thus showed no statistically significant risk reduction for persistent postoperative pain at 3 months, 6 months or 12 months. Trial sequential analysis, used to consider the risk of type 1 and type 2 random error, showed that at 3 months, 6 months and 12 months, the number of subjects in the analyses were only 18.3%, 6.8% and 4.2% of the required information sizes at those time points, respectively. Our study is the first to evaluate data on pain 12 months postoperatively. Trial sequential analysis revealed that the current evidence is not sufficient to reach a conclusion. These findings stand in contrast to previous meta-analyses with fewer studies that had concluded that paravertebral block effectively reduces chronic pain.

Intravenous ketamine during spinal and general anaesthesia for caesarean section: systematic review and meta-analysis.

BACKGROUND: Intravenous ketamine has been used during general and regional anaesthesia for caesarean section. No systematic review and meta-analysis on the desired effects and adverse effects of ketamine administration during caesarean section have yet been performed. METHODS: After a systematic literature search a meta-analysis was conducted with the random effects model. Weighted mean difference (WMD) or risk ratio and 95% confidence intervals (CIs) were computed. RESULTS: Twelve randomised controlled double-blind trials comprising 953 patients were included: seven studies reported on spinal anaesthesia and five on general anaesthesia. Significant differences in the aforementioned outcome variables were found only in the spinal anaesthesia studies. In the spinal anaesthesia studies the time to the first analgesic request was significantly longer in ketamine-treated women, the WMD was 49.36 min (95% CI 43.31-55.41); visual analogue scale pain scores at rest 2 h after surgery were significantly lower. No differences were observed for maternal nausea, vomiting, pruritus, and psychomimetic effects. Only few data were found for neonatal outcomes. CONCLUSIONS: We conclude that ketamine enhances post-operative analgesia after caesarean section under spinal anaesthesia. There is a paucity of data for several maternal adverse effects as well as for neonatal well-being. Further studies are needed for general anaesthesia.

Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions.

BACKGROUND: Ibuprofen and paracetamol have long been used as analgesics in a range of acute, intermittent and chronic pain conditions. Paracetamol is often the first line analgesic recommended, without consensus about which is the better analgesic. METHODS: An overview review of systematic reviews and meta-analyses directly compares ibuprofen and paracetamol at standard doses in particular painful conditions, or uses indirect comparisons against placebo. Electronic searches for systematic reviews were sought published since 1995 using outcomes approximating to ≥50% pain intensity reduction. Painful conditions were acute post-operative pain, dysmenorrhoea, tension-type headache (TTH), migraine, osteoarthritis and rheumatoid arthritis, back pain, cancer and paediatric pain. There was no systematic assessment of harm. RESULTS: Sixteen systematic reviews and four individual patient data meta-analyses were included. Ibuprofen was consistently superior to paracetamol at conventional doses in a range of painful conditions. Two direct comparisons favoured ibuprofen (acute pain, osteoarthritis). Three of four indirect comparisons favoured ibuprofen (acute pain, migraine, osteoarthritis); one showed no difference (TTH), although there were methodological problems. In five pain conditions (dysmenorrhoea, paediatric pain, cancer pain, back pain and rheumatoid arthritis), there were limited data on paracetamol and ibuprofen. CONCLUSIONS: At standard doses in different painful conditions, ibuprofen was usually superior producing more patients with the degree of pain relief that patients feel worthwhile. Neither of the drugs will be effective for everyone, and both are needed. This overview questions the practice of routinely using paracetamol as a first line analgesic because there is no good evidence for efficacy of paracetamol in many pain conditions.

Prophylactic tranexamic acid in parturients at low risk for post-partum haemorrhage: systematic review and meta-analysis.

Tranexamic acid is effective in reducing blood loss during various types of surgery and after trauma. No compelling evidence has yet been presented for post-partum haemorrhage. A systematic literature search of relevant databases was performed to identify trials that assessed blood loss and transfusion incidence after tranexamic acid administration for post-partum haemorrhage. The random effects model was used for meta-analysis. Risk ratios (RRs) and weighted mean differences (WMDs) were calculated with 95% confidence intervals (CIs). Seven trials with a low risk of bias comparing tranexamic acid vs. placebo with a total of 1760 parturients were included in our systematic review and meta-analysis. Blood loss was significantly lower after tranexamic acid use (WMD -140.29 ml, 95% CI -189.64 to -90.93 ml; P<0.00001). Tranexamic acid reduced the risk for blood transfusions (RR 0.34, 95% CI 0.20-0.60, P=0.0001). The incidence of transfusions in the placebo group varied between 1.4% and 33%. When omitting the two trials with the highest incidence of transfusions, the RR was no longer significant. Additional uterotonics were necessary in the placebo groups; gastrointestinal adverse events were more common after tranexamic acid use. Only four cases of thrombosis were found, two each in the tranexamic acid and control groups. Tranexamic acid effectively reduced post-partum blood loss; the effect on the incidence of blood transfusions requires further studies. Only few trials observed adverse events including thromboembolic complications and seizures.

Effects of smoking specified as cigarettes per day and maternal body mass index on hypertensive disorders of pregnancy.

BACKGROUND: We have previously described the prevalence in pregnancy of hypertension, proteinuria, oedema and preeclampsia/eclampsia according to maternal body mass index (BMI) and smoking status. We found that these disorders were less frequent among smoking women. To investigate whether this relationship is causal or a chance finding, we here present an analysis according to BMI and smoking specified according to the number of cigarettes consumed per day. MATERIALS AND METHODS: Data were from the German Perinatal Survey of 1998-2000. We classified women by BMI as underweight (BMI<18.5 kg/m2), normal weight (BMI 18.5-24.99 kg/m2), overweight (25.0-29.99 kg/m2), or obese (BMI≥30 kg/m2). Smoking was categorised as being a non-smoker or smoking 1-7, 8-14 or ≥ 15 cigarettes per day. Datasets from 433 669 singleton pregnancies with information on maternal BMI and smoking were included in the analysis. RESULTS: In all BMI categories hypertension, moderate to severe oedema, and preeclampsia/eclampsia became less prevalent with increasing maternal cigarette consumption. CONCLUSIONS: Dose-dependence was not convincing for proteinuria.Dose-dependence in the relationship between smoking and hypertensive disorders of pregnancy argues against a chance finding and for a causal relationship.

Maternal and foetal effects of remifentanil for general anaesthesia in parturients undergoing caesarean section: a systematic review and meta-analysis.

BACKGROUND: Remifentanil has been suggested for the induction of general anaesthesia for caesarean section. We aimed to define remifentanil effects on maternal stress response as well as neonatal effects. METHODS: Relevant articles were retrieved by a systematic literature search. Randomized, controlled trials comparing remifentanil use before delivery with placebo were selected. Maternal outcome parameters were blood pressure and heart rate; neonatal effects included the need for mask ventilation and intubation, base excess, pH values, Apgar < 7 at 1 and 5 min. The random effects model was used for meta-analysis; risk ratio or weighted mean difference (WMD) and 95% confidence interval (95% CI) were calculated. RESULTS: Five articles including 186 patients were identified. Highest and lowest systolic blood pressure were significantly lower in the remifentanil group (WMD: -29.98, -50.90 to -9.07 mmHg, 95% CI; P = 0.005; and WMD: -12.46, -18.21 to -6.71 mmHg, 95% CI; P < 0.0001), the lowest heart rate was significantly lower after remifentanil treatment (WMD: -8.22, -11.67 to -4.78, 95% CI; P < 0.00001). Base excess was significantly higher in infants of remifentanil-treated mothers (WMD: 1.15, -0.27 to 2.03, 95% CI; P = 0.01); pH was also higher in the remifentanil group, but significance was missed (P = 0.07). No differences were observed for Apgar values or the need of airway assist. CONCLUSION: Remifentanil was found to attenuate the maternal circulatory response to intubation and surgery. Higher base excess and pH suggest a beneficial effect on the neonatal acid-base status. A trial with adequate power is warranted that addresses neonatal side-effects of remifentanil.

Insertion of an intrathecal catheter following accidental dural puncture: a meta-analysis.

BACKGROUND: Inserting an intrathecal catheter after accidental dural puncture in parturients to prevent postdural puncture headache is becoming increasingly popular. We aimed to identify relevant published articles investigating this intervention and subject data to a meta-analysis. METHODS: A systematic literature search was performed, paralleled by a hand search of abstract publications. Studies that reported the dichotomous outcome parameters postdural puncture headache or need for an epidural blood patch were considered eligible. Risk ratios with 95% confidence intervals were calculated. RESULTS: We identified nine reports investigating placement of intrathecal catheters after accidental dural puncture. The risk ratio for an epidural blood patch after intrathecal catheter insertion was 0.64 (95% CI 0.49-0.84, P=0.001). The risk ratio for postdural puncture headache was 0.82 (95% CI 0.67-1.01, P=0.06). DISCUSSION: Inserting an intrathecal catheter significantly reduced the risk for an epidural blood patch; the incidence of postdural puncture headache was reduced but not significantly. Accidental dural puncture is a rare complication and therefore trials on intervention need to include a large number of patients which is time-consuming and costly. Intrathecal catheterisation is a promising approach for the prevention of postdural puncture headache and should be evaluated further. This intervention has additional benefits including a reduced risk of repeat dural puncture, rapid onset of action and use for anaesthesia.

Analysis of the German Perinatal Survey of the Years 2007-2011 and Comparison with Data From 1995-1997: Maternal Characteristics.

Background and Aim: We have previously presented analyses of data obtained from the German Perinatal Survey for the years 1995-1997. Here we present an analysis of data from the years 2007-2011 and compare the data to the previous data from the 1990s. Material and Methods: For the years 1995-1997, the data on 1 815 318 singleton pregnancies were provided by the Chambers of Physicians of all the states of Germany except Baden-Württemberg. For the years 2007-2011, the data on 3 187 920 singleton pregnancies from the German Perinatal Survey (all states of Germany) were obtained from the AQUA Institute in Göttingen, Germany. SPSS was used for data analysis. Plausibility checks were performed on the data. Results: Mean maternal age has increased over the years, from 28.7 years in 1995 to 30.2 years in 2011. We observed a decrease in smoking. While not all cases included data on maternal smoking after the pregnancy was known, when the cases with data on smoking were analysed, in 1995-1997 23.5 % of pregnant women were smokers compared to 11.2 % smokers in 2007-2011. Maternal body mass index (BMI) also changed; 8.2 % of women were obese (BMI: 30-40 kg/m2), while 13.0 % were obese in 2011. In 1995, 0.6 % of women were morbidly obese (BMI ≥ 40 kg/m2) compared to 1.8 % of women in 2011. The mean maternal body weight at the time of the first obstetric consultation also increased from 65.9 kg in 1995 to 68.7 kg in 2011. Conclusions: While the decrease in the number of women smoking over time is clearly a positive development, increasing maternal age and obesity present challenges in clinical practice.

The combined effect of maternal body mass index and smoking status on perinatal outcomes - an analysis of the german perinatal survey.

BACKGROUND: Maternal body mass index (BMI) outside the normal range and smoking are both associated with adverse perinatal outcomes, but their interaction needs further investigation. AIM: The aim of this study was to analyse the combined effects of smoking and BMI on birth weight, preterm birth rate, the somatic development of neonates, and complications of pregnancy. MATERIAL AND METHODS: Data from 508 926 singleton pregnancies from the German Perinatal Survey of 1998-2000 were analysed according to maternal BMI and smoking. RESULTS: Preterm birth rates were higher for non-smoking underweight (8.3%) and obese women (6.7%) than for normal weight (6.0%) or overweight women (5.6%); rates were higher in smokers than in non-smokers for every BMI category. The mean birth weight increased with increasing BMI and was decreased by smoking; it was 2,964 g in underweight smokers and 3,556 g in obese non-smokers. Small for gestational age (SGA) rates were least in obese women and highest in underweight women; large for gestational age (LGA) rates varied in the opposite direction. In smokers SGA rates were higher than in non-smokers for every BMI category and LGA rates were always lower. Hypertension, proteinuria, oedema, and pre-eclampsia/eclampsia were more common as BMI increased but were always lower in smokers. Pre-eclampsia/eclampsia occurred in 0.7% of underweight smokers but in 9.6% of obese non-smokers. CONCLUSIONS: Smoking and low maternal BMI in combination can cause high rates of preterm birth and SGA neonates as well as low mean birth weight. Although smoking offers some apparent benefit regarding LGA rates and pre-eclampsia this should not distract from its overall adverse influence.

The influence of smoking during pregnancy on fetal growth. Considering daily cigarette consumption and the SGA rate according to length of gestation.

BACKGROUND: Smoking is the most important risk factor for adverse pregnancy outcomes in industrialized nations and is associated with, amongst other adverse effects, a higher rate of small-for-gestational-age (SGA) neonates. The rate of SGA neonates born before 32 weeks and its association with smoking have so far not been the focus of attention. MATERIAL AND METHODS: Using data of 643,288 primiparous women from the German perinatal statistics of 1995-2000, we aimed to investigate this relationship. We also analyzed our data according to daily cigarette consumption. RESULTS: We found that smoking during pregnancy was strongly associated with lower birth weight and higher SGA rates. This effect was especially pronounced in women >or=31 years. There was clear dose dependence with regard to daily cigarette consumption. An increase in SGA rates in smokers versus non-smokers can already be seen for very early preterm deliveries (31 weeks of gestation or less). CONCLUSIONS: Our results allow the definition of groups of women who are at higher risk of SGA births. We show that especially older primiparous women (aged >or=31 years) who smoke >10 cigarettes a day are at increased risk of experiencing fetal growth restriction.

[Evaluation of maternal parameters as risk factors for premature birth (individual and combined effects)]. / Evaluierung von mütterlichen Merkmalen als Risikofaktoren für Frühgeburtlichkeit (Einzel- und Kombinationswirkung).

OBJECTIVE: We aimed to examine the individual and combined effects of nine maternal parameters (biological, medical, and social) on rates of prematurity. Our objective was to provide obstetricians with a way of screening women for likely premature deliveries. METHODS: We conducted a retrospective analysis on the data of about 2.3 million pregnancies taken from the German perinatal statistics of 1995-2000. Rates of prematurity were calculated with single and multi-dimensional analyses on the basis of nine maternal parameters (age, weight, height, number of previous live births, stillbirths, miscarriages and terminations of pregnancy, smoking status, previous premature delivery). The following combinations of parameters were investigated in particular: rates of prematurity according to the number of previous stillbirths, miscarriages, and terminations; rates of prematurity according to the number of previous live births and maternal age, height and weight. We also included daily cigarette consumption and previous premature deliveries in our analyses. RESULTS: The rate of prematurity (< or =36 weeks of gestation) in our population was 7.0%; the rate of moderately early premature deliveries (32-36 weeks) was 5.9%, and the rate of very early premature deliveries (< or =31 weeks) was 1.1%. Our multi-dimensional analyses revealed rates of prematurity (< or =36 weeks) between 5.1% and 27.5% depending on the combination of parameters. We found the highest rate of prematurity of 27.5% in women with the following combination of parameters: > or =1 stillbirth, > or =2 terminations of pregnancy and > or =2 miscarriages. A rather high risk of premature delivery (>11%) was also found for elderly (> or =40 years) grand multiparous women as well as small (< or =155 cm) and slim women (< or =45 kg). CONCLUSIONS: We have shown that certain combinations of maternal parameters are associated with a high risk of premature deliveries (>10%). The risk table that we present here may assist in predicting premature delivery.

[The shortening of the duration of pregnancy due to smoking and associated costs for perinatal health care in Germany]. / Erhöhung der Frühgeborenenrate durch Rauchen in der Schwangerschaft und daraus resultierende Kosten für die Perinatalmedizin in Deutschland.

BACKGROUND: As about 20 % of pregnant women smoke, 137,000 of the 685,795 neonates delivered in Germany in 2005 have been affected by smoking during pregnancy. Caring for neonates born prematurely because of smoking results in additional costs. We have attempted to estimate these costs. MATERIAL AND METHODS: Data of 1,815,318 pregnancies were collected from the German perinatal statistics of 1995-1997. In 876,645 cases there was information regarding smoking. Of these, 699,134 pregnant women were non-smokers and 177,511 were smokers. To determine the number of preterm births due to smoking, we compared the distribution of the duration of pregnancy of the non-smoking cohort to that of the smoking cohort. From the difference between this and the actual distribution of the duration of pregnancy among smokers we determined the number of additional preterm births caused by smoking. For the analysis of the associated costs we used the actual costs of care and daily rates used in neonatology. RESULTS: For 2002 we estimate 43 million Euros of additional costs due to neonates born prematurely because of smoking. CONCLUSIONS: We present a rough estimate of the additional health care costs for neonates because of smoking. Costs were estimated only with regard to premature deliveries. Other effects of smoking during pregnancy on neonatal health were not considered. More detailed cost analyses will likely reveal even higher costs.

Effect of preoperative Cox-II-selective NSAIDs (coxibs) on postoperative outcomes: a systematic review of randomized studies.

BACKGROUND: Preoperative use of coxibs has been claimed to reduce postoperative pain and analgesic consumption, and to affect other postoperative outcomes. METHODS: Systematic review of randomized trials comparing preoperative coxib with preoperative placebo, or active comparator. Searching of PubMed and Cochrane Library to August 2004. A qualitative and a quantitative analysis. RESULTS: Twenty-two included trials with 2246 patients had high reporting quality and validity scores, though treatment group sizes were small, with a median size of 30 patients. Most trials used oral preoperative rofecoxib (mainly 50 mg) or celecoxib (mainly 200 mg). Preoperative coxibs significantly reduced both postoperative pain and analgesic consumption compared with preoperative placebo in 15/20 trials. In one further trial postoperative pain was reduced and in one analgesic consumption. There was no significant difference in the incidence of postoperative nausea and vomiting in 13/17 studies or when data were pooled. Postoperative antiemetic use was significantly reduced in all five trials reporting it; the NNT to prevent one patient using postoperative antiemetic was 10 (5.5 to 66). No trial reported any significant difference in intraoperative blood loss or recovery from anaesthesia. Patient satisfaction was significantly increased with preoperative coxib use. No conclusions could be drawn from the three trials comparing preoperative coxib with preoperative NSAID. One study reported significantly improved cost-efficacy with rofecoxib. CONCLUSIONS: Preoperative coxibs had clear benefits in terms of reduced postoperative pain, analgesic consumption and patient satisfaction compared with placebo. Effects on postoperative nausea and vomiting remain uncertain, as do those on recovery from surgery or economic benefit. Future trials should be larger and more pragmatic in nature.

Effects of phosphatidylinositol kinase inhibitors on the activation of the store-operated calcium current ICRAC in RBL-1 cells.

In electrically non-excitable cells, Ca2+ entry is mediated predominantly through the store-operated Ca2+ influx pathway, which is activated by emptying the intracellular Ca2+ stores following an increase in the levels of the second messenger inositol 1,4,5-trisphophate (InsP3). InsP3 is generated from the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). Recently, roles for other phosphoinositides (PIs) in store-operated Ca2+ influx have been suggested because inhibitors of PI kinases reduce Ca2+ influx when the latter is triggered independent of PIP2 hydrolysis. Using the whole-cell patch-clamp technique to record the store-operated Ca2+ current ICRAC in RBL-1 cells, we examined whether PIs are involved in linking store depletion to activation of CRAC channels. Of several structurally distinct PI kinase inhibitors, only one (LY294002) was able to reduce partially the extent of activation of ICRAC although this could not be reversed by exogenous phosphatidylinositol 3,4,5-trisphosphate (PIP3). Our findings suggest that, if a PI kinase is involved in activation of ICRAC in RBL-1 cells, it has a unique pharmacological profile. Alternative explanations for the results are discussed.