Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of the low pKa fluorinated fentanyl analogs, FF3 and NFEPP.

RATIONALE: Recent studies report that fentanyl analogs with relatively low pKa values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception. OBJECTIVES: The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats. METHODS: Nociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects. RESULTS: All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects. CONCLUSIONS: Low pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.

Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.

BACKGROUND AND PURPOSE: Opioid-induced respiratory depression limits the use of µ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti-nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy. EXPERIMENTAL APPROACH: Respiration was measured in awake, freely moving male CD-1 mice using whole body plethysmography. Anti-nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR-17018 were administered orally. Receptor activation and arrestin-3 recruitment were measured in HEK293 cells using BRET assays. KEY RESULTS: Across the dose ranges examined, all opioids studied depressed respiration in a dose-dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR-17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti-nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds. CONCLUSION AND IMPLICATIONS: In addition to providing effective anti-nociception, the novel opioids, oliceridine, tianeptine and SR-17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.

Toxicity assessment of gelsenicine and the search for effective antidotes.

BACKGROUND: Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth (G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. OBJECTIVE: This study aimed to analyse the toxicity characteristics of gelsenicine. METHODS: Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. RESULTS: In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood-brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. CONCLUSIONS: Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine-related poisoning and its toxicity mechanisms.

An assessment of opioids on respiratory depression in children with and without obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea is a risk factor for respiratory depression following opioid administration as well as opioid-induced hyperalgesia. Little is known on how obstructive sleep apnea status is associated with central ventilatory depression in pediatric surgical patients given a single dose of fentanyl. METHODS: This was a single-center, prospective trial in children undergoing surgery requiring intubation and opioid administration. Sixty patients between the ages of 2-8 years presenting for surgery at Texas Children's Hospital were recruited. Twenty non-obstructive sleep apnea controls and 30 patients with moderate to severe obstructive sleep apnea met inclusion criteria. Following induction of general anesthesia and establishment of steady-state ventilation, participants received 1 mcg/kg intravenous fentanyl. Ventilatory variables (tidal volume, respiratory rate, end-tidal CO2 , and minute ventilation) were assessed each minute for 10 min. The primary outcome was the extent of opioid-induced central ventilatory depression over time by obstructive sleep apnea status when compared with baseline values. Secondary aims assessed the impact of demographics and SpO2 nadir on ventilatory depression. RESULTS: We found no significant difference in percent decrease in respiratory rate (38.1% and 37.1%; p = .950), tidal volume (6.4% and 5.4%; p = .992), and minute ventilation (35.0 L/min and 35.0 L/min; p = .890) in control and obstructive sleep apnea patients, respectively. Both groups experienced similar percent increases in end-tidal CO2 (4.0% vs. 2.2%; p = .512) in control and obstructive sleep apnea patients, respectively. CONCLUSIONS: In pediatric surgical patients, obstructive sleep apnea status was not associated with significant differences in central respiratory depression following a single dose of fentanyl (1 mcg/kg). These findings can help determine safe opioid doses in future pediatric obstructive sleep apneapatients.

Opioid-induced respiratory depression increases hospital costs and length of stay in patients recovering on the general care floor.

BACKGROUND: Opioid-induced respiratory depression is common on the general care floor. However, the clinical and economic burden of respiratory depression is not well-described. The PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial created a prediction tool to identify patients at risk of respiratory depression. The purpose of this retrospective sub-analysis was to examine healthcare utilization and hospital cost associated with respiratory depression. METHODS: One thousand three hundred thirty-five patients (N = 769 United States patients) enrolled in the PRODIGY trial received parenteral opioids and underwent continuous capnography and pulse oximetry monitoring. Cost data was retrospectively collected for 420 United States patients. Differences in healthcare utilization and costs between patients with and without ≥1 respiratory depression episode were determined. The impact of respiratory depression on hospital cost per patient was evaluated using a propensity weighted generalized linear model. RESULTS: Patients with ≥1 respiratory depression episode had a longer length of stay (6.4 ± 7.8 days vs 5.0 ± 4.3 days, p = 0.009) and higher hospital cost ($21,892 ± $11,540 vs $18,206 ± $10,864, p = 0.002) compared to patients without respiratory depression. Patients at high risk for respiratory depression, determined using the PRODIGY risk prediction tool, who had ≥1 respiratory depression episode had higher hospital costs compared to high risk patients without respiratory depression ($21,948 ± $9128 vs $18,474 ± $9767, p = 0.0495). Propensity weighted analysis identified 17% higher costs for patients with ≥1 respiratory depression episode (p = 0.007). Length of stay significantly increased total cost, with cost increasing exponentially for patients with ≥1 respiratory depression episode as length of stay increased. CONCLUSIONS: Respiratory depression on the general care floor is associated with a significantly longer length of stay and increased hospital costs. Early identification of patients at risk for respiratory depression, along with early proactive intervention, may reduce the incidence of respiratory depression and its associated clinical and economic burden. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02811302 .

Respiratory events associated with concomitant opioid and sedative use among Medicare beneficiaries with chronic obstructive pulmonary disease.

BACKGROUND: Opioids and sedatives are commonly prescribed in chronic obstructive pulmonary disease (COPD) patients for symptoms of dyspnoea, pain, insomnia, depression and anxiety. Older adults are advised to avoid these medications due to increased adverse events, including respiratory events. This study examines respiratory event risks associated with concomitant opioid and sedative use compared with opioid use alone in older adults with COPD. METHODS: A 5% nationally representative sample of Medicare beneficiaries with COPD and opioid use between 2009 and 2013 was used for this retrospective cohort study. Current and past concomitant use were identified using drug dispensed within 7 days from the censored date: at respiratory event, at death, or at 12 months post index. Concomitant opioid and sedative use were categorised into no overlap (opioid only), 1 to 10, 11 to 30, 31 to 60 and >60 days of total overlap. The primary outcome was hospitalisation or emergency department (ED) visits for respiratory events (COPD exacerbations or respiratory depression). Propensity score matching was implemented and semi-competing risk models were used to address competing risk by death. RESULTS: Among 48 120 eligible beneficiaries, 1810 (16.7%) concomitant users were matched with 9050 (83.3%) opioid only users. Current concomitant use of 1 to 10, 11 to 30 and 31 to 60 days was associated with increased respiratory events (HRs (95% CI): 2.8 (1.2 to 7.3), 9.3 (4.9 to 18.2) and 5.7 (2.5 to 12.5), respectively), compared with opioid only use. Current concomitant use of >60 days or past concomitant use of ≤60 days was not significantly associated with respiratory events. Consistent findings were found in sensitivity analyses, including in subgroup analysis of non-benzodiazepine sedatives. Additionally, current concomitant use significantly increased risk of death. CONCLUSION: Short-term and medium-term current concomitant opioid and sedative use significantly increased risk of respiratory events and death in older COPD Medicare beneficiaries. Long-term past concomitant users, however, demonstrated lower risks of these outcomes, possibly reflecting a healthy user effect or developed tolerance to the effects of these agents.

Independent Validation in a Large Privately Insured Population of the Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose.

OBJECTIVE: To assess the generalizability of the overdose or serious opioid-induced respiratory depression risk index (VHA-RIOSORD), created by Zedler et al., using claims data from a large private insurer. DESIGN: A retrospective nested case-control analysis of health care claims data. SUBJECTS: Commercially insured individuals with a claim for an opioid prescription between October 1, 2014, and September 30, 2016 (N = 1,431,737). METHODS: An overdose or serious opioid-induced respiratory depression (OSORD) occurred in 1,097 patients. Ten controls were selected per case (N = 10,970). Items and the assignment of point values to predictors were consistent with those determined by Zedler et al. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution. RESULTS: All 15 items of the VHA-RIOSORD were used to determine a member's risk of OSORD. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 90% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The model's C-statistic was 0.88. CONCLUSIONS: Consistent with the findings of its developers, the VHA-RIOSORD performed well in identifying members of a large private insurance company who were medical users of prescription opioids at elevated risk of overdose or life-threatening respiratory depression, those most likely to benefit from preventive interventions.

Association of Opioid and Benzodiazepine Use with Adverse Respiratory Events in Older Adults with Chronic Obstructive Pulmonary Disease.

Rationale: Older adults with chronic obstructive pulmonary disease (COPD) are at substantially increased risk for medication-related adverse events. Two frequently prescribed classes of drugs that pose a particular risk to this patient group are opioids and benzodiazepines. Research on this topic has yielded conflicting findings.Objectives: The purpose of this study was to examine, among older adults with COPD, whether: 1) independent or concurrent use of opioid and benzodiazepine medications was associated with hospitalizations for respiratory events, and 2) this association was exacerbated by the presence of obstructive sleep apnea (OSA).Methods: We conducted a case-control study of Medicare beneficiaries aged ≥66 years, who were diagnosed with COPD in 2013, using the 5% national Medicare database. Cases (n = 3,232) were defined as patients hospitalized for a primary COPD-related respiratory diagnosis in 2014 and were matched with up to two control subjects (n = 6,247) on index date, age, sex, socioeconomic status, comorbidity, presence of OSA, COPD medication, and COPD complexity.Results: In comparison to the referent (no opioid or benzodiazepine use), opioid use alone (adjusted odds ratio [aOR], 1.73; 95% confidence interval [CI], 1.52-1.97), benzodiazepine use alone (aOR, 1.42; 95% CI, 1.21-1.66), and concurrent opioid/ benzodiazepine use (aOR, 2.32; 95% CI, 1.94-2.77) in the 30 days before the event/index date were all associated with an increased risk of hospitalization for a respiratory condition. Risk of hospitalization was higher with concurrent opioid and benzodiazepine use when compared with use of either medication alone. There was no statistically significant interaction between OSA and either of the drugs, alone or in combination. However, the adverse respiratory effects of concurrent opioid and benzodiazepine use were increased in patients with a high degree of COPD complexity. All of the above findings persisted using exposure windows that extended to 60 and 90 days before the event/index date.Conclusions: Among older adults with COPD, use of opioid and benzodiazepine medications alone or in combination were associated with increased adverse respiratory events. The adverse effects of these medications were not exacerbated in patients with COPD-OSA overlap syndrome. However, the adverse impact of dual opioid and benzodiazepine was greater in patients with high-complexity COPD.

Relative Risk and Clinical Severity Assessment in Patients with Non-Oral Route Organophosphate Poisoning Compared with Oral Route Poisoning.

PURPOSE: Organophosphates, commonly used in agricultural pesticides, pose high risks and incidences of poisoning. In the present study, we investigated the relative risk and clinical severity, including laboratory results, of non-oral route poisoning (NORP) patients, compared to oral route poisoning (ORP) patients. MATERIALS AND METHODS: A single institutional toxicology database registry was utilized to gain information on clinical laboratory results on organophosphate poisoning patients who visited the emergency department (ED) between January 2000 and October 2016. Clinical outcomes, such as mortality and complication rates, were compared using 1:2 propensity score matching in the total cohort. RESULTS: Among a total of 273 patients in our study, 34 experienced NORP. After 1:2 propensity score matching, rates of respiratory complications and mortality were higher in the ORP group than in the NORP group. However, there was no difference in hospitalization time and time spent in the intensive care unit between the two groups. Compared with ORP patients after matching, the relative risk of mortality in NORP patients was 0.34, and the risk of respiratory distress was 0.47. The mean level of pseudocholinesterase was significantly higher in the NORP group than in the ORP group, while recovery rates were similar between the two groups. CONCLUSION: Although the majority of NORP patients were admitted to the ED with unintentional poisoning and the relative risk of NORP was lower than that for ORP, we concluded that NORP is as critical as ORP. Considerable medical observation and intensive therapeutic approaches are also needed for NORP patients.

Validation of a Screening Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in a US Commercial Health Plan Claims Database.

Objective: To validate a risk index that estimates the likelihood of overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids. Subjects and Methods: A case-control analysis of 18,365,497 patients with an opioid prescription from 2009 to 2013 in the IMS PharMetrics Plus commercially insured health plan claims database (CIP). An OIRD event occurred in 7,234 cases. Four controls were selected per case. Validity of the Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (RIOSORD), developed previously using Veterans Health Administration (VHA) patient data, was assessed. Multivariable logistic regression was used within the CIP study population to develop a slightly refined RIOSORD. The composition and performance of the CIP-based RIOSORD was evaluated and compared with VHA-based RIOSORD. Results: VHA-RIOSORD performed well in discriminating OIRD events in CIP (C-statistic = 0.85). Additionally, re-estimation of logistic model coefficients in CIP yielded a 0.90 C-statistic. The resulting comorbidity and pharmacotherapy variables most highly associated with OIRD and retained in the CIP-RIOSORD were largely concordant with VHA-RIOSORD. These variables included neuropsychiatric and cardiopulmonary disorders, impaired drug excretion, opioid characteristics, and concurrent psychoactive medications. The average predicted probability of OIRD ranged from 2% to 83%, with excellent agreement between predicted and observed incidence across risk classes. Conclusions: RIOSORD had excellent predictive accuracy in a large population of US medical users of prescription opioids, similar to its performance in VHA. This practical risk index is designed to support clinical decision-making for safer opioid prescribing, and its clinical utility should be evaluated prospectively.

Risk Factors for Serious Prescription Opioid-Induced Respiratory Depression or Overdose: Comparison of Commercially Insured and Veterans Health Affairs Populations.

Objective: To characterize the risk factors associated with overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids in a commercially insured population (CIP) and to compare risk factor profiles between the CIP and Veterans Health Administration (VHA) population. Subjects and Methods: Analysis of data from 18,365,497 patients in the IMS PharMetrics Plus health plan claims database (CIP) who were dispensed a prescription opioid in 2009 to 2013. Baseline factors associated with an event of serious OIRD among 7,234 cases and 28,932 controls were identified using multivariable logistic regression. The CIP risk factor profile was compared with that from a corresponding logistic regression among 817 VHA cases and 8,170 controls in 2010 to 2012. Results: The strongest associations with serious OIRD in CIP were diagnosed substance use disorder (odds ratio [OR] = 10.20, 95% confidence interval [CI] = 9.06-11.40) and depression (OR = 3.12, 95% CI = 2.84-3.42). Other strongly associated factors included other mental health disorders; impaired liver, renal, vascular, and pulmonary function; prescribed fentanyl, methadone, and morphine; higher daily opioid doses; and concurrent psychoactive medications. These risk factors, except depression, vascular disease, and specific opioids, largely aligned with VHA despite CIP being substantially younger, including more females and less chronic disease, and having greater prescribing prevalence of higher daily opioid doses, specific opioids, and most selected nonopioids. Conclusions: Risk factor profiles for serious OIRD among US medical users of prescription opioids with private or public health insurance were largely concordant despite substantial differences between the populations in demographics, clinical conditions, health care delivery systems, and clinical practices.

Assessment of mechanically ventilated patients intoxicated with organophosphates by a novel surface electromyographic index.

PURPOSE: We present a new electromyographic index, named Engagement of Respiratory Muscle (ERM), for assessing the level of participation of respiratory muscles during spontaneous breathing test in patients poisoned with organophosphorus compound. METHODS: Diaphragm and sternocleidomastoid muscles activity was recorded by surface electromyography during spontaneous breathing test. A population of 23 patients poisoned with organophosphates and mechanically ventilated, and a control group of 28 healthy subjects were analyzed. RESULTS: All patients developed respiratory failure and 48% were diagnosed with intermediate syndrome by medical staff. The ERM index classified the patients in three clusters (p-value<0.005): Cluster I presented more engagement of the sternocleidomastoid compared to diaphragm, Cluster II had low muscle engagement of both muscles and also muscle weakness, Cluster III were characterized for the diaphragm recovery associated with higher engagement. The control group showed a similar muscle engagement to Cluster III. The capacity of ERM index for classifying patients with (sensitivity) and without (specificity) muscle weakness were 90.91% and 100% respectively. CONCLUSIONS: The ERM is a promising index to assess the level of participation of respiratory muscle on spontaneous breathing test in patients poisoned with organophosphorus compounds, which could improve the extubation prognosis for these patients.

Assessment of the appropriateness of naloxone administration to patients receiving long-term opioid therapy.

BACKGROUND: The most dangerous adverse effect of opioids is respiratory depression. Naloxone is used to reverse this, although in patients receiving long-term opioid therapy it can cause acute opioid withdrawal and opioid-refractory pain. OBJECTIVE: To determine if naloxone is appropriately administered to patients receiving long-term opioid therapy. METHODS: This retrospective case series based on chart reviews systematically identified patients over one year in a district general hospital. All patients aged 18 years or older receiving long-term opioid therapy admitted to medicine, surgery or the high dependency unit who were administered naloxone during their admission were included. RESULTS: A total of 1206 patient drug administration records were reviewed. Sixteen patients receiving long-term opioid therapy were administered naloxone. Twelve of these did not have opioid-induced respiratory depression and four did not have respiratory rate and oxygen saturations documented in the medical notes. All naloxone doses administered were higher than those recommended by national guidelines for this patient group. CONCLUSIONS: No patient receiving long-term opioid therapy who was administered naloxone had evidence of respiratory depression. More thorough assessment and documentation are needed. Verbal and physical stimulation as well as oxygenation should be considered prior to naloxone administration; this should be followed by close observation, hydration, renal function tests and opioid dose review.

Avoiding Adverse Events Secondary to Opioid-Induced Respiratory Depression: Implications for Nurse Executives and Patient Safety.

BACKGROUND: Guidelines with recommendations for monitoring type and timing of hospitalized patients for opioid-induced respiratory depression have been published, yet adverse events continue to occur. OBJECTIVE: This study reports on the monitoring practices of 8 hospitals that volunteered to pilot test a Centers for Medicare & Medicaid Services e-quality measure that was under development. Recommendations for nurse executives are provided to support patient safety. METHODS: Data on monitoring practices were collected retrospectively from the electronic medical records at 8 hospitals on all patients receiving intravenous (IV) opioids for more than 2.5 continuous hours via patient-controlled analgesia (PCA). Analysis included the percentage of patients who were monitored according to specific standards developed by a panel of technical experts with comparisons of naloxone use to monitoring practices. RESULTS: Recommended patient assessments occurred in only 8.3% of the patients. No patients who were assessed at least every 2.5 hours received naloxone. CONCLUSIONS: Care for patients receiving IV PCA is lacking in adherence to latest safety standards. Nurse executives must implement structures and processes to promote vigilance with evidence-based monitoring practices.

Quantifying the Risk of Analgesic-Related Adverse Events After Knee Arthroscopy.

Opioids are frequently used as part of multimodal pain management protocols for knee arthroscopy; however, their use may be associated with opioid-related adverse events. The purpose of this study was to evaluate the risk of potential analgesic-related complications after knee arthroscopy using a nationally representative database. Using 2010\endash 2012 Medicare claims data, patients undergoing knee arthroscopy procedures (including ligament repair, meniscectomy, and chondroplasty) were identified. The risk of complications related to typical modalities of analgesia, including opioids, within 90 days following surgery was assessed using multivariate Cox regression. Based on follow-up of 16,567 cases, respiratory complications (bradypnea, pulmonary insufficiency, asphyxia, and hypoxemia) were the most frequently diagnosed complications (n = 418; 2.52%), followed by postoperative nausea and vomiting (n = 174; 1.05%) and urinary retention complications (n = 166; 1.00%). Risk factors including older age, male gender, lower socioeconomic status, and a high number of comorbidities were associated with development of postsurgical complications.

Robustness of arterial blood gas analysis for assessment of respiratory safety pharmacology in rats.

Whole body plethysmography using unrestrained animals is a common technique for assessing the respiratory risk of new drugs in safety pharmacology studies in rats. However, wide variations in experimental technique make cross laboratory comparison of data difficult and raise concerns that non-appropriate conditions may mask the deleterious effects of test compounds - in particular with suspected respiratory depressants. Therefore, the objective of this study was to evaluate the robustness of arterial blood gas analysis as an alternative to plethysmography in rats. We sought to do this by assessing the effect of different vehicles and times post-surgical catheterization on blood gas measurements, in addition to determining sensitivity to multiple opioids. Furthermore, we determined intra-lab variability from multiple datasets utilizing morphine and generated within a single lab and lastly, inter-lab variability was measured by comparing datasets generated in two separate labs. Overall, our data show that arterial blood gas analysis is a measure that is both flexible in terms of experimental conditions and highly sensitive to respiratory depressants, two key limitations when using plethysmography. As such, our data strongly advocate the adoption of arterial blood gas analysis as an investigative approach to reliably examine the respiratory depressant effects of opioids.

A Costly Lesson: Fatal Respiratory Depression Induced by Clindamycin during Postoperative Patient Controlled Analgesia.

Many drugs can cause neuromuscular blockade. Clindamycin-related neuromuscular blockade is commonly reported, but fatal clindamycin-induced neuromuscular blockade is rarely reported. We describe a 47-year-old woman who initially presented with endometrial carcinoma. She underwent a laparoscopic-assisted vaginal hysterectomy (LAVH) and bilateral adnexectomy under general anesthesia, secondary to antibiotic treatment with clindamycin 1.2g in 250 mL for about 30 minutes through the peripheral intravenous route during postoperative patient controlled analgesia (PCA). She became unconscious near the end of the infusion, then, despite resuscitation attempts, she died. Clindamycin appeared to have triggered delayed respiratory depression during PCA. A combination of clindamycin and fentanyl led to her respiratory depression in the fatal case.

Postoperative opioid-induced respiratory depression: a closed claims analysis.

BACKGROUND: Postoperative opioid-induced respiratory depression (RD) is a significant cause of death and brain damage in the perioperative period. The authors examined anesthesia closed malpractice claims associated with RD to determine whether patterns of injuries could guide preventative strategies. METHODS: From the Anesthesia Closed Claims Project database of 9,799 claims, three authors reviewed 357 acute pain claims that occurred between 1990 and 2009 for the likelihood of RD using literature-based criteria. Previously cited patient risk factors for RD, clinical management, nursing assessments, and timing of events were abstracted from claim narratives to identify recurrent patterns. RESULTS: RD was judged as possible, probable, or definite in 92 claims (κ = 0.690) of which 77% resulted in severe brain damage or death. The vast majority of RD events (88%) occurred within 24 h of surgery, and 97% were judged as preventable with better monitoring and response. Contributing and potentially actionable factors included multiple prescribers (33%), concurrent administration of nonopioid sedating medications (34%), and inadequate nursing assessments or response (31%). The time between the last nursing check and the discovery of a patient with RD was within 2 h in 42% and within 15 min in 16% of claims. Somnolence was noted in 62% of patients before the event. CONCLUSIONS: This claims review supports a growing consensus that opioid-related adverse events are multifactorial and potentially preventable with improvements in assessment of sedation level, monitoring of oxygenation and ventilation, and early response and intervention, particularly within the first 24 h postoperatively.

Monitoring for opioid-induced advancing sedation and respiratory depression: ASPMN membership survey of current practice.

Adverse events secondary to opioid-induced advancing sedation and respiratory depression continue to occur during hospitalizations despite efforts to increase awareness and clinical practice guidelines to address prevention strategies. In 2009, ASPMN surveyed membership on current practices surrounding this topic. ASPMN clinical practice guidelines were then published in 2011. In winter of 2013, ASPMN membership was again surveyed to assess progress in preventing adverse events. This is a report of the follow-up membership survey. In general, monitoring practices are slowly improving over time, but there are many facilities that have not instituted best practices for avoiding adverse events.