Early prediction of mortality at sepsis diagnosis time in critically ill patients by using interpretable machine learning.

This study applied machine learning for the early prediction of 30-day mortality at sepsis diagnosis time in critically ill patients. Retrospective study using data collected from the Medical Information Mart for Intensive Care IV database. The data of the patient cohort was divided on the basis of the year of hospitalization, into training (2008-2013), validation (2014-2016), and testing (2017-2019) datasets. 24,377 patients with the sepsis diagnosis time < 24 h after intensive care unit (ICU) admission were included. A gradient boosting tree-based algorithm (XGBoost) was used for training the machine learning model to predict 30-day mortality at sepsis diagnosis time in critically ill patients. Model performance was measured in both discrimination and calibration aspects. The model was interpreted using the SHapley Additive exPlanations (SHAP) module. The 30-day mortality rate of the testing dataset was 17.9%, and 39 features were selected for the machine learning model. Model performance on the testing dataset achieved an area under the receiver operating characteristic curve (AUROC) of 0.853 (95% CI 0.837-0.868) and an area under the precision-recall curves of 0.581 (95% CI 0.541-0.619). The calibration plot for the model revealed a slope of 1.03 (95% CI 0.94-1.12) and intercept of 0.14 (95% CI 0.04-0.25). The SHAP revealed the top three most significant features, namely age, increased red blood cell distribution width, and respiratory rate. Our study demonstrated the feasibility of using the interpretable machine learning model to predict mortality at sepsis diagnosis time.

Effects of Dexmedetomidine on Intestinal Microcirculation and Intestinal Epithelial Barrier in Endotoxemic Rats.

BACKGROUND: Dexmedetomidine reduces cytokine production in septic patients and reduces inflammation and mortality in experimental models of endotoxemia and sepsis. This study investigated whether dexmedetomidine attenuates endothelial dysfunction, intestinal microcirculatory dysfunction, and intestinal epithelial barrier disruption in endotoxemic rats. METHODS: Ninety-two male Wistar rats were randomly assigned to the following four groups: (1) Sham; (2) lipopolysaccharide, received IV lipopolysaccharide 15 and 10 mg/kg at 0 and 120 min; (3) dexmedetomidine, received IV dexmedetomidine for 240 min; and (4) lipopolysaccharide + dexmedetomidine, received both lipopolysaccharide and dexmedetomidine. Sidestream dark-field videomicroscope, tissue oxygen monitor, and full-field laser perfusion image were used to investigate the microcirculation of the terminal ileum. Serum endocan level was measured. The Ussing chamber permeability assay, lumen-to-blood gadodiamide passage by magnetic resonance imaging, and bacterial translocation were conducted to determine epithelial barrier function. Mucosal apoptotic levels and tight junctional integrity were also examined. RESULTS: The density of perfused small vessels in mucosa, serosal muscular layer, and Peyer patch in the lipopolysaccharide + dexmedetomidine group was higher than that of the lipopolysaccharide group. Serum endocan level was lower in the lipopolysaccharide + dexmedetomidine group than in the lipopolysaccharide group. Mucosal ratio of cleaved to full-length occludin and spleen bacterial counts were significantly lower in the lipopolysaccharide + dexmedetomidine group than in the lipopolysaccharide group. CONCLUSION: The study finding suggests that dexmedetomidine protects against intestinal epithelial barrier disruption in endotoxemic rats by attenuating intestinal microcirculatory dysfunction and reducing mucosal cell death and tight junctional damage. (Anesthesiology 2016; 125:355-67).

Comparison of dexmedetomidine versus propofol sedation on microcirculation and organ injuries in critically ill surgical patients: A randomized controlled pilot study.

BACKGROUND: Recent studies have shown that dexmedetomidine may improve microcirculation and prevent organ failure. However, most evidence was obtained from experimental animals and patients receiving cardiac surgery with cardiopulmonary bypass. This study aimed to investigate the effect of dexmedetomidine on microcirculation and organ injuries in critically ill general surgical patients. METHODS: In this prospective randomized trial, patients admitted to the surgical intensive care unit after general surgery were enrolled and randomly allocated to the dexmedetomidine or propofol groups. Patients received continuous dexmedetomidine or propofol infusions to meet their requirement of sedation according to their grouping. At each time point, sublingual microcirculation images were obtained using the incident dark field video microscope. RESULTS: Overall, 60 patients finished the trial and were analyzed. Microcirculation parameters did not differ significantly between two groups. Heart rate at 4 h after ICU admission and mean arterial pressures at 12 h and 24 h after ICU admission were lower in the dexmedetomidine group than in the propofol group. At 24 h, serum aspartate aminotransferase (41 (25-118) vs 86 (34-129) U/L, p = 0.035) and alanine aminotransferase (50 (26-160) vs 68 (35-172) U/L, p = 0.019) levels were significantly lower in the dexmedetomidine group than in the propofol group. CONCLUSION: Microcirculation parameters did not differ significantly between the dexmedetomidine and propofol groups. At 24 h after ICU admission, serum liver enzyme levels were lower in patients receiving dexmedetomidine as compared to propofol.

Correlation between early sublingual small vessel density and late blood lactate level in critically ill surgical patients.

BACKGROUND: Surgical stress may cause excessive inflammation and lead to microcirculatory dysfunction. The hypothesis of this study was that early microcirculatory dysfunction may result in anaerobic glycolysis and lead to elevated blood lactate levels in patients admitted to surgical intensive care units. METHODS: This prospective observational study enrolled adult patients admitted to surgical intensive care units after general surgery or thoracic surgery. We measured blood lactate levels before the operation and at 1 h and 24 h after the operation. We obtained images of sublingual microcirculation using a sidestream dark field video microscope and analyzed them employing automated analysis software. RESULTS: A total of 31 patients completed the study. Perioperative total and perfused small vessel densities were lower in patients with a blood lactate level ≥3 mmol/L. We observed a significant correlation between the total small vessel density at 1 h and the blood lactate level at 24 h (r = -0.573; P = 0.001). In addition, we saw a significant correlation between the perfused small vessel density at 1 h and the blood lactate level at 24 h (r = -0.476; P = 0.008). CONCLUSIONS: Early total and perfused small vessel density may be used as an early predictor or therapeutic goal for critically ill surgical patients in further studies.

An observational study of microcirculation among healthy individuals by age and sex.

OBJECTIVE: This study measured normal ranges of microcirculatory parameters in healthy individuals and investigated differences in parameters by age and sex. METHODS: Participants were enrolled into three groups with equal numbers of male and female: young (20-39 years), middle-aged (40-59 years), and elderly (60-79 years). Sublingual microcirculation images were obtained using the incident dark field (IDF). RESULTS: A total of 75 female and 75 male healthy individuals were enrolled. The elderly group had a higher TVD (26.5 [2] vs. 25.2 [1.8]; p = 0.019) and a lower PPV (97 [2] vs. 98 [3]; p = 0.03) than did the young group. In the elderly group, systolic blood pressure (SBP) and mean arterial pressure (MAP) were moderately and positively correlated with MFI score (r = 0.407, p <  0.05, and r = 0.403, p <  0.05, respectively). The female participants had a lower MFI score than did the male participants (2.9 [2.8-3] vs. 3.0 [2.9-3]; p = 0.015). CONCLUSIONS: This study revealed the range of microcirculatory parameters between different ages and sexes in healthy individuals. We found that blood pressure levels were correlated with microcirculatory parameters, especially in elders and female.

Early prediction of delirium upon intensive care unit admission: Model development, validation, and deployment.

STUDY OBJECTIVE: To develop, validate, and deploy models for predicting delirium in critically ill adult patients as early as upon intensive care unit (ICU) admission. DESIGN: Retrospective cohort study. SETTING: Single university teaching hospital in Taipei, Taiwan. PATIENTS: 6238 critically ill patients from August 2020 to August 2021. MEASUREMENTS: Data were extracted, pre-processed, and split into training and testing datasets based on the time period. Eligible variables included demographic characteristics, Glasgow Coma Scale, vital signs parameters, treatments, and laboratory data. The predicted outcome was delirium, defined as any positive result (a score ≥ 4) of the Intensive Care Delirium Screening Checklist that was assessed by primary care nurses in each 8-h shift within 48 h after ICU admission. We trained models to predict delirium upon ICU admission (ADM) and at 24 h (24H) after ICU admission by using logistic regression (LR), gradient boosted trees (GBT), and deep learning (DL) algorithms and compared the models' performance. MAIN RESULTS: Eight features were extracted from the eligible features to train the ADM models, including age, body mass index, medical history of dementia, postoperative intensive monitoring, elective surgery, pre-ICU hospital stays, and GCS score and initial respiratory rate upon ICU admission. In the ADM testing dataset, the incidence of ICU delirium occurred within 24 h and 48 h was 32.9% and 36.2%, respectively. The area under the receiver operating characteristic curve (AUROC) (0.858, 95% CI 0.835-0.879) and area under the precision-recall curve (AUPRC) (0.814, 95% CI 0.780-0.844) for the ADM GBT model were the highest. The Brier scores of the ADM LR, GBT, and DL models were 0.149, 0.140, and 0.145, respectively. The AUROC (0.931, 95% CI 0.911-0.949) was the highest for the 24H DL model and the AUPRC (0.842, 95% CI 0.792-0.886) was the highest for the 24H LR model. CONCLUSION: Our early prediction models based on data obtained upon ICU admission could achieve good performance in predicting delirium occurred within 48 h after ICU admission. Our 24-h models can improve delirium prediction for patients discharged >1 day after ICU admission.

Dexmedetomidine prevents alterations of intestinal microcirculation that are induced by surgical stress and pain in a novel rat model.

BACKGROUND: Anesthesia can become inadequate inadvertently or by misjudgment during surgery or emergence, and the surgical stress and pain stimulation will increase without adequate treatment. Overt stimulation may activate the sympathetic nervous system, increase the blood level of catecholamines, and lead to splanchnic arterial vasoconstriction. METHODS: We divided 30 male Wistar rats into the following 3 groups: control, surgical stress and pain (SSP), and surgical stress and pain + dexmedetomidine (SSP + Dex). The rats received midline laparotomy to exteriorize a segment of terminal ileum for microcirculation examination by a full-field laser perfusion imager and sidestream dark-field video microscope on mucosa, muscle, and Peyer patch. The inspired concentration of isoflurane was decreased from 1.2% to 0.7% in SSP and SSP + Dex groups. In the SSP + Dex group, the rats received an initial loading dose of dexmedetomidine (0.5 µg/kg) and a maintenance infusion (0.5 µg · kg(-1) · h(-1)). RESULTS: Dexmedetomidine prevented surgical stress and pain-related tachycardia and hypertension, and it attenuated the reduction of the microcirculatory blood flow intensity in intestinal mucosa (1100 ± 185 perfusion units [PU] vs 800 ± 105 PU, P = 0.001) and muscle (993 ± 208 PU vs 713 ± 92 PU, P < 0.001). Dexmedetomidine restored perfused small vessel density in intestinal mucosa and muscle. CONCLUSIONS: We established a promising rat model to investigate the effect of surgical stress and pain stimulation on the intestinal microcirculation during light anesthesia. Using this rat model, we found that dexmedetomidine can normalize global hemodynamics and prevent the alteration of intestinal microcirculation.

Effects of perioperative dexmedetomidine infusion on renal function and microcirculation in kidney transplant recipients: a randomised controlled trial.

OBJECTIVE: Ischemia-reperfusion injury affects postoperative transplanted kidney function in kidney transplant recipients. Dexmedetomidine was reported to attenuate ischemia-reperfusion injury and improve microcirculation, but its propensity to cause bradycardia and hypotension may adversely affect microcirculation. This study investigated the effect of dexmedetomidine on postoperative renal function and sublingual microcirculation in kidney recipients. METHODS: The enrolled kidney transplant recipients were randomly allocated to the control group or dexmedetomidine group. After anaesthesia induction, patients in the dexmedetomidine group received dexmedetomidine infusion until 2 h after surgery. Sublingual microcirculation was recorded using an incident dark-field video microscope and analysed. The primary outcomes were the creatinine level on a postoperative day 2 and total vessel density at 2 h after surgery. RESULTS: A total of 60 kidney recipients were analysed, and the creatinine levels on postoperative day 2 were significantly lower in the dexmedetomidine group than in the control group (1.5 (1.1-2.4) vs. 2.2 (1.7-3.0) mg/dL, median difference -0.6 (95% CI, -0.7 to -0.5) mg/dL, p = .018). On a postoperative day 7, the creatinine levels did not differ significantly between the two groups. Total vessel density at 2 h after surgery did not differ significantly between the two groups. CONCLUSION: We found that early postoperative renal function was better in kidney transplant recipients receiving dexmedetomidine infusion, but total vessel density was not significantly different between the intervention and control groups. Key messagesIschemia-reperfusion injury affects postoperative transplanted kidney function, and dexmedetomidine was reported to attenuate ischemia-reperfusion injury and improve microcirculation in other clinical conditions.This study showed that early postoperative renal function was better in kidney transplant recipients receiving dexmedetomidine.Dexmedetomidine's side effect of bradycardia and hypotension may affect microcirculation, our results revealed that the perioperative sublingual microcirculation did not differ significantly in kidney transplant recipients receiving dexmedetomidine.

Effects of dexmedetomidine on renal microcirculation in ischemia/reperfusion-induced acute kidney injury in rats.

Microcirculatory dysfunction plays a crucial role in renal ischemia/reperfusion (IR)-induced injury. Dexmedetomidine was reported to ameliorate IR-induced acute kidney injury. This study investigated the effects of dexmedetomidine on renal microcirculation after IR-induced acute kidney injury in rats. In total, 50 rats were randomly allocated to the following five groups (10 in each group): Sham, Control‒IR, Dex (dexmedetomidine) ‒Sham, Dex‒IR, and IR‒Dex group. The microcirculation parameters included total small vessel density, perfused small vessel density (PSVD), proportion of perfused small vessels, microvascular flow index, and tissue oxygen saturation (StO2) were recorded. The repeated measures analysis showed that PSVD on renal surface was higher in the Dex‒IR group than in the Control‒IR group (3.5 mm/mm2, 95% confidence interval [CI] 0.6 to 6.4 mm/mm2, P = 0.01). At 240 min, StO2 on renal surface was lower in the Control‒IR group than in the Sham group (- 7%, 95% CI - 13 to - 1%, P = 0.021), but StO2 did not differ significantly among the Sham, Dex‒IR, and IR‒Dex groups. Our results showed that pretreatment with dexmedetomidine improved renal microcirculation in rats with IR-induced acute kidney injury. However, the adverse effects of low mean arterial pressure and heart rate might offset the protective effect of dexmedetomidine on organ injury.

Endotoxin Activity in Patients With Extracorporeal Membrane Oxygenation Life Support: An Observational Pilot Study.

Background: Extracorporeal membrane oxygenation (ECMO) life support has become an integral part of intensive care. The endotoxin activity assay (EAA) is a useful test to measure endotoxemia severity in whole blood. To date, no information is available regarding the EAA levels and their effect on clinical outcomes in critically ill patients with ECMO support. Methods: This prospective observational pilot study enrolled adult critically ill patients with ECMO support from August 2019 to December 2020. The EAA levels were measured within 24 h (T1), and at 25-48 (T2), 49-72 (T3), and 73-96 h (T4) after ECMO initiation. This study primarily aimed to investigate the incidence of high EAA levels (≥0.6) at each time point. Subsequent exploratory analyses were conducted to compare the EAA levels of venoarterial ECMO (VA-ECMO) patients between 30-day survivors and non-survivors. Post-hoc analysis was performed to compare the clinical outcomes of VA-ECMO patients with elevated EAA levels at T3 (vs. T1) and those without elevated EAA levels. Results: A total of 39 VA-ECMO patients and 15 venovenous ECMO (VV-ECMO) patients were enrolled. At T1, the incidence of high EAA level (≥0.6) was 42% in VV-ECMO patients and 9% in VA-ECMO patients (P = 0.02). At T2, the incidence of high EAA level was 40% in VV-ECMO patients and 5% in VA-ECMO patients (P = 0.005). In VA-ECMO patients, EAA levels at T3 were significantly higher in 30-day non-survivors than in survivors (median [interquartile range]: 0.49 [0.37-0.93] vs. 0.31 [0.19-0.51], median difference 0.16 [95% confidence interval [CI], 0.02-0.31]; P = 0.024). Moreover, VA-ECMO patients with elevated EAA levels at T3 (vs. T1) had lower 30-day survival than patients without elevated EAA levels (39 vs. 83%, P = 0.026) and fewer ECMO free days by day 30 (median: 3 vs. 23 days, median difference 12 days [95% CI, 0-22]; P = 0.028). Conclusions: A certain proportion of patients experienced high EAA levels (≥0.6) after VV-ECMO or VA-ECMO initiation. VA-ECMO patients with an elevated EAA level at 49-72 h were associated with poor clinical outcomes.

Microcirculatory Response to Changes in Venoarterial Extracorporeal Membrane Oxygenation Pump Flow: A Prospective Observational Study.

Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) pump flow is crucial for maintaining organ perfusion in patients with cardiogenic shock, but VA-ECMO pump flow optimization remains as a clinical challenge. This study aimed to investigate the response of sublingual microcirculation to changes in VA-ECMO pump flow. Methods: Sublingual microcirculation was measured before and after changing VA-ECMO pump flow according to the treatment plan of ECMO team within 24 h and at 24-48 h after VA-ECMO placement. In clinical events of increasing VA-ECMO pump flow, those events with increased perfused vessel density (PVD) were grouped into group A, and the others were grouped into group B. In clinical events of decreasing VA-ECMO pump flow, those events with increased PVD were grouped into group C, and the others were grouped into group D. Results: Increased PVD was observed in 60% (95% CI, 38.5-81.5%) of the events with increasing VA-ECMO pump flow. The probability of increasing PVD after increasing VA-ECMO pump flow were higher in the events with a PVD < 15 mm/mm2 at baseline than those with a PVD ≥ 15 mm/mm2 [100% (95% CI, 54.1-100%) vs. 42.9% (95% CI, 17.7-71.1%), P = 0.042]. Other microcirculatory and hemodynamic parameters at baseline did not differ significantly between group A and B or between group C and D. Conclusion: This study revealed contradictory and non-contradictory responses of sublingual microcirculation to changes in VA-ECMO pump flow. Tandem measurements of microcirculation before and after changing VA-ECMO pump flow may help to ensure a good microcirculation.

Effects of endotoxin adsorber hemoperfusion on sublingual microcirculation in patients with septic shock: a randomized controlled trial.

BACKGROUND: Endotoxins can induce an excessive inflammatory response and result in microcirculatory dysfunction. Polymyxin-B hemoperfusion (PMX-HP) has been recognized to effectively remove endotoxins in patients with sepsis and septic shock, and a rat sepsis model revealed that PMX-HP treatment can maintain a better microcirculation. The primary aim of this study was to investigate the effect of PMX-HP on microcirculation in patients with septic shock. METHODS: Patients with septic shock were enrolled and randomized to control and PMX-HP groups. In the PMX-HP group, patients received the first session of PMX-HP in addition to conventional septic shock management within 24 h after the onset of septic shock; the second session of PMX-HP was provided after another 24 h as needed. RESULTS: Overall, 28 patients finished the trial and were analyzed. The mean arterial pressure and norepinephrine infusion dose did not differ significantly between the control and PMX-HP groups after PMX-HP treatment. At 48 h after enrollment, total vessel density (TVD) and perfused vessel density (PVD) were higher in the PMX-HP group than in the control group [TVD 24.2 (22.1-24.9) vs. 21.1 (19.9-22.9) mm/mm2; p = 0.007; PVD 22.9 (20.9-24.9) vs. 20.0 (18.9-21.6) mm/mm2, p = 0.008]. CONCLUSIONS: This preliminary study observed that PMX-HP treatment improved microcirculation but not clinical outcomes in patients with septic shock at a low risk of mortality. Nevertheless, larger multicenter trials are needed to confirm the effect of PMX-HP treatment on microcirculation in patients with septic shock at intermediate- and high-risk of mortality. Trial registration ClinicalTrials.gov protocol registration ID: NCT01756755. Date of registration: December 27, 2012. First enrollment: October 6, 2013. https://clinicaltrials.gov/ct2/show/NCT01756755.

Interpol review of toxicology 2016-2019.

This review paper covers the forensic-relevant literature in toxicology from 2016 to 2019 as a part of the 19th Interpol International Forensic Science Managers Symposium. The review papers are also available at the Interpol website at: https://www.interpol.int/content/download/14458/file/Interpol%20Review%20.Papers%202019.pdf.

Combination of low-dose nalbuphine and morphine in patient-controlled analgesia decreases incidence of opioid-related side effects.

BACKGROUND/PURPOSE: The addition of ultra-low-dose naloxone to patient-controlled analgesia (PCA) with morphine reduces opioid-related side effects. Nalbuphine, a mixed opioid agonist-antagonist, may be able to attenuate opioid-related side effects. The goal of the present study was to investigate the effect of combined low-dose nalbuphine and morphine in PCA for postoperative pain control after gynecological surgery. METHODS: This randomized, double-blind, controlled study enrolled 174 female patients who were undergoing total abdominal hysterectomy, myomectomy, or ovarian tumor excision. In the control group, the PCA formula was 1 mg/mL pure morphine. In the study group, the PCA formula was 1 mg/mL morphine and 10 microg/mL nalbuphine (1:100). Numerical rating score, PCA requirement, nausea, vomiting, use of antiemetics, pruritus, use of antipruritics, and opioid-related adverse events were investigated at 1, 2, 4, and 24 hours postoperatively. RESULTS: One hundred and sixty-nine patients completed the study: 86 in the control group and 83 in the study group. The incidence of nausea was lower in the study group (41%) than in the control group (65%). The incidence of vomiting, use of antiemetics, pruritus, and use of antipruritics did not differ between the two groups. The numerical rating pain score and PCA requirements were not significantly different between the two groups. CONCLUSION: Combination of low-dose nalbuphine and morphine in PCA decreases the incidence of opioid-related nausea, without affecting the analgesia and PCA requirement. This novel combination can improve the quality of PCA used for postoperative pain control after gynecological surgery.

Lingual nerve injury following the use of an oropharyngeal airway under endotracheal general anesthesia.

We report a patient who presented for elective myomectomy. Laryngoscopy and endotracheal intubation were achieved smoothly without unduly force. An oropharyngeal airway was inserted after endotracheal intubation for biting and was left in the oral cavity until the end of surgery. Two days after surgery, the patient complained of numbness on the right side of her tongue. Neurological examination revealed an area of hypesthesia about 1 cm in diameter on the right side of the tongue tip. The motor function, taste perception, and speech articulation were all intact. A right lingual nerve lesion with terminal branch involvement was diagnosed. The patient was then reassured and discharged home. At the 4-week follow-up, spontaneous resolution occurred. After reviewing the history, we speculated that the mechanism of nerve injury in this case was a direct compression of the tongue tip by the oropharyngeal airway. This is the first report of lingual nerve injury caused by improper placement of the oropharyngeal airway. We recommend careful manipulation in the use of the oropharyngeal airway and vigilant surveillance being undertaken when an oropharyngeal airway is left in place for a prolonged period.

Raman spectroscopy of short-lived terthiophene radical cations generated by photochemical and chemical oxidation.

The Raman spectra of various terthiophene radical cations are investigated; namely those of unsubstituted terthiophene and two styryl-substituted terthiophenes. Transient pump-probe resonance Raman spectroscopy is used to measure the short-lived radical cation spectra of non-end-capped 2,2':5',2''-terthiophene (3T) and 3'-[(E)-2-(4-nitrophenyl)ethenyl]-2,2':5',2''-terthiophene (NO2-pe3T). For these two compounds, the radical cations are generated via either direct photogeneration or photochemically using the electron acceptor tetracyanoethylene. The radical cation of 5,5''-dimethyl-3'-[(E)-2-phenylethenyl]-2,2':5',2''-terthiophene (DM-pe3T) is stable for up to five minutes as a result of the two alpha end caps and continuous-wave resonance Raman spectroscopy and chemical oxidation is used to obtain the spectrum of this radical cation. The resonance Raman spectra of all three terthiophene radical cations are dominated by a group of very intense bands in the low-frequency region. These bands have been assigned, by density functional theory methods, to C-S stretching modes coupled to thiophene ring deformations. These modes are significantly less intense in the sigma-dimer of NO2-pe3T [i.e. the corresponding styryl sexithiophene (NO2-pe3T)2]. This observation is attributed to a smaller change in the C--S bond order in the sexithiophene compared to the analogous terthiophene. This bond order difference may be rationalised by consideration of the singly occupied molecular orbital and lowest unoccupied molecular orbital, which are involved in the electronic transition probed by the laser excitation wavelength.

Ultrafast time-resolved transient absorption and resonance raman spectroscopy study of the photodeprotection and rearrangement reactions of p-hydroxyphenacyl caged phosphates.

The kinetics and mechanism of the photodeprotection and rearrangement reactions for the pHP phototrigger compounds p-hydroxyphenacyl diethyl phosphate (HPDP) and diphenyl phosphate (HPPP) were studied using transient absorption (TA) and picosecond time-resolved resonance Raman (ps-TR(3)) spectroscopy. TA spectroscopy was employed to detect the dynamics of the triplet precursor decay as well as to investigate the influence of the solvent and leaving group on the triplet quenching process. Ps-TR(3) spectroscopy was used to directly monitor the formation dynamics for the photosolvolytic rearrangement product and its solvent and leaving group dependence. The TA and TR(3) spectroscopy experiments were also used to characterize the structural and electronic properties of the triplet precursor to the HPDP and HPPP deprotection reactions. The solvent effect observed in conjunction with the leaving group dependence of the triplet decay dynamics are consistent with a concerted solvent assisted triplet cleavage through a heterolytic mechanism for the HPDP and HPPP photodeprotection process. Correlation of the dynamics between the deprotection and rearrangement processes reveals there is a consecutive mechanism and the involvement of an intermediate between the two reaction steps. The reaction rate of the deprotection and rearrangement steps and the influence of the solvent and leaving group were determined and evaluated based on kinetic modeling of the dynamical data obtained experimentally for HPDP and HPPP in H(2)O/MeCN mixed solvents with varying water concentration in the solvent system. A solvation complex with a contact ion pair character was proposed to be the intermediate involved in the deprotection and rearrangement pathway. The results here combined with our previous study on the photophysical events occurring on the early picosecond time scale (Ma; et al. J. Am. Chem. Soc. 2005, 127, 1463-1472) provide a real time overall mechanistic description for the photodeprotection and rearrangement reactions of pHP caged phosphate phototrigger compounds.

Time-resolved resonance Raman and density functional theory study of hydrogen-bonding effects on the triplet state of p-methoxyacetophenone.

Picosecond and nanosecond time-resolved resonance Raman spectroscopy combined with density functional theory calculations have been performed to characterize the structure, dynamics, and hydrogen-bonding effects on the triplet state of the phototrigger model compound p-methoxyacetophenone (MAP) in cyclohexane, MeCN, and 50% H2O/50% MeCN (v:v) mixed solvent. Analogous work has also been done to study the corresponding ground state properties. The ground and triplet states of MAP were both found to be associated strongly with the water solvent molecules in the 50% H2O/50% MeCN solvent system. A hydrogen-bond complex model involving one or two water molecules bonded with the oxygen atoms of the MAP carbonyl and methoxy moieties has been employed to explore the hydrogen-bond interactions and their influence on the geometric and electronic properties for the ground and triplet states of MAP. Among the various hydrogen-bond configurations examined, the carbonyl hydrogen-bond configuration involving one water molecule was calculated to lead to the most stable hydrogen-bond complex for both the ground and the triplet states with the strength of the hydrogen-bond interaction being stronger in the triplet state than the ground state. The increased carbonyl located hydrogen-bond strength in the triplet state results in substantial modification of both the electronic and the structural conformation so that the triplet of the hydrogen-bond complex can be considered as a distinct species from the free MAP triplet state. This provides a framework to interpret the differences observed in the TR3 spectral and triplet lifetime obtained in the neat MeCN solvent (attributed to the free MAP triplet state) and the 50% H2O/50% MeCN solvent (due to the triplet of the hydrogen-bond complex). Temporal evolution at early picosecond times indicates rapid ISC conversion, and subsequent relaxation of the excess energy of the initially formed energetic triplets occurs for both the free MAP and the hydrogen-bond complex. The triplet of the carbonyl hydrogen-bond complex appears to be generated directly from the corresponding ground state complex and it does not dissociate back to the free triplet state within the triplet state lifetime. We briefly discuss the influence of the carbonyl hydrogen-bond effect on the pi pi* triplet reactivity for MAP and closely related compounds.