Continuous Infusion Of Midazolam Research Articles

Seric Concentration of Troponin I and Electrocardiographic Tracing in Dogs Submitted to Long-Term Sedation during 24 Hours

Background: General anesthetics and sedatives are commonly used for long-term sedation in veterinary medicine; however, they can lead to cardiac suppression. Cardiac troponin I is a biomarker used to detect myocardial pathology, monitor treatment, and assess outcomes in veterinary patients. The aim of this study was to evaluate the serum concentration of troponin I (cTnI), the electrocardiographic (ECG) tracing, and the ventricular stroke work index in dogs undergoing two long-term sedation protocols over 24 h.Materials, Methods & Results: Twelve healthy mongrel dogs with an average weight of 13.2 ± 2.3 Kg were admitted for this study. Twenty-four h before the experiment began (M-24), venous blood samples were collected for chemiluminescent cTnI evaluation and ECG data were obtained, specifically heart rate (HR); P, PR, QRS and T wave duration; P, R, T wave amplitude; and ST segment depression. On the day of the experiment, the animals were anaesthetized with propofol and isoflurane, and instrumented. After instrumentation, right and left ventricular stroke work index (RVSWI and LVSWI respectively) and intrapulmonary shunt (Qs/Qt) were performed as baseline parameters. The isoflurane was then discontinued and the animals randomly allocated to two groups (n = 6 each): Midazolam and fentanyl group (GMF), in which the animals received a bolus and continuous rate infusion (CRI) of midazolam (0.5 mg/kg and 0.5 mg/kg/h) and fentanyl (5 µg/kg and 10 µg/kg/h) or ketamine and morphine group (GKM), in which the animals received a bolus and CRI of ketamine (1 mg/kg and 0.6 mg/kg/h) and morphine (0.5 mg/kg and 0.26 mg/kg/h). Both groups also received propofol as a bolus and CRI (3 mg/kg and 0.3 mg/ kg/min) over 24 h. The ECG and cTnI parameters were evaluated at 6, 12, and 24 h during CRI (M6, M12, and M24) and 12 and 24 h after the end of infusion (T12 and T24). The hemodynamic parameters RVSWI, LVSWI, and Qs/Qt were evaluated every 2 h until the end of CRI. There was a non-significant increase in cTnI from M6 in both groups; however, a significant increase was only observed in GMF between M-24 and T12. During sedation, HR decreased an average of 46% in GKM and 51% in GMF compared to M-24. The QT interval (milliseconds) increased in both groups after CRI started, returning to baseline values at T24. There were no differences in P, QRS, and T wave amplitude or ST segment depression in either group.Discussion: The serum concentration of cTnI increased in GMF at T12, more probably due to hemodynamic changes during sedation rather than myocardial lesions, since the increase was relatively mild. A greater hemodynamic change was observed in GMF, with a greater increase in RVSWI compared to baseline than GKM, which may reflect an increase in cardiac effort and possibly cTnI release; however, in both groups, the cTnI values remained within the acceptable values for the species. Bradycardia was reported during long-term sedation, which may be due to the synergism between opioids as a result of vagal stimulation, central sympathetic inhibition, and a possible action on cardiac receptors, and propofol due to the inhibitory effect on the sympathetic nervous system. Increases in QT interval did not lead to marked changes in this study. T wave amplitude and ST segment depression remained unchanged and within acceptable values for the species, and thus agreed with cTnI data, implying that no myocardial lesions were produced by these protocols. It has been established that for both protocols, cTnI remained within physiological ranges for healthy dogs, and therefore, these methods could be used safely for long-term sedation without producing hypoxia/ischemia of the myocardium or ST-segment depression.

Efficacy of two types of palliative sedation therapy defined using intervention protocols: proportional vs. deep sedation.

This study investigated the effect of two types of palliative sedation defined using intervention protocols: proportional and deep sedation. We retrospectively analyzed prospectively recorded data of consecutive cancer patients who received the continuous infusion of midazolam in a palliative care unit. Attending physicians chose the sedation protocol based on each patient's wish, symptom severity, prognosis, and refractoriness of suffering. The primary endpoint was a treatment goal achievement at 4h: in proportional sedation, the achievement of symptom relief (Support Team Assessment Schedule (STAS) ≤ 1) and absence of agitation (modified Richmond Agitation-Sedation Scale (RASS) ≤ 0) and in deep sedation, the achievement of deep sedation (RASS ≤ - 4). Secondary endpoints included mean scores of STAS and RASS, deep sedation as a result, and adverse events. Among 398 patients who died during the period, 32 received proportional and 18 received deep sedation. The treatment goal achievement rate was 68.8% (22/32, 95% confidence interval 52.7-84.9) in the proportional sedation group vs. 83.3% (15/18, 66.1-100) in the deep sedation group. STAS decreased from 3.8 to 0.8 with proportional sedation at 4h vs. 3.7 to 0.3 with deep sedation; RASS decreased from + 1.2 to - 1.7 vs. + 1.4 to - 3.7, respectively. Deep sedation was needed as a result in 31.3% (10/32) of the proportional sedation group. No fatal events that were considered as probably or definitely related to the intervention occurred. The two types of intervention protocol well reflected the treatment intention and expected outcomes. Further, large-scale cohort studies are promising.

Influenza-associated encephalopathy – case report

Objective: Influenza is associated with various neurologic complications with seizures being most common. Influenza-related encephalopathy is severe complication with high mortality rate and frequent neurological sequelae. Methods: We present a case of a patient with severe influenza- associated encephalopathy. Results: A 6-year-old boy without pre-existing medical conditions and a 5-day history of pyrexia, vomiting and diarrhea was admitted to hospital because he became increasingly lethargic and developed right-sided hemiparesis. During examination patient was somnolent and had right-sided hemiconvulsions that were controlled after a continuous midazolam infusion. CT brain scan did not indicate any abnormalities, blood and cerebrospinal fluid examination were within normal limits. However, patient’s consciousness deteriorated progressively to a deep coma in a few hours. He was intubated, mechanically ventilated and empirical therapy with acyclovir and ceftriaxone was started along with mannitol and dexamethasone. Upon initial evaluation, EEG was done and showed burst suppression. MRI within 24 h of admission revealed diffuse cerebral oedema with ischemic lesions in irrigation areas of middle and anterior cerebral artery and lesions in splenium of the corpus callosum. Following influenza A (H1N1) detection in a nasopharyngeal swab oseltamivir, methylprednisolone and intravenous immunoglobulins in high doses were started under the diagnosis of influenza-associated encephalopathy. Despite the therapy, there was no improvement in the patient’s condition. Follow up MRI showed further progression of cerebral oedema hence the plasma exchange therapy was initiated. Patient subsequently regained consciousness and recovered with mild neurological sequelae. Conclusion: This case emphasizes the importance of awareness of this severe complication during the influenza season. If suspected early, appropriate diagnosis and treatment may prevent rapid progression.

Experience with palliative sedation (PS) in an inpatient oncology setting.

63 Background: Palliative sedation (PS) is an intervention to treat refractory symptoms and to relieve suffering at the end of life. Its prevalence and practice patterns vary widely. Methods: This is a retrospective study of the use of PS in cancer patients who died at our comprehensive cancer center between March 1, 2012 and December 31, 2014. PS was defined as the use of continuous infusion of midazolam or neuroleptics for refractory symptoms as stated in the progress notes. Patients who died in the ICU were excluded. The aim of our study was to evaluate PS practice patterns, describing its frequency, clinical indications and outcomes. Results: During the study period, 556 cancer patients died at the institution and 203 (36.5%) received PS. Main reasons for exclusion were death in the ICU (168 patients) and no use of midazolam or neuroleptics (77 patients). Patients who received PS as compared to those not sedated were younger (67.8 vs. 71.5 years-old, p = 0.007) and more likely to have a primary diagnosis of lung cancer (23% vs. 15% p < 0.001). Patients receiving PS were more likely to be seen by oncology/hematology rather than other specialties (70% vs 45% p < 0.001) and more likely to have a longer hospital stay from admission to death (47.9 days vs 26.2 days p < 0.001). Only 25 patients (12%) were seen by a dedicated palliative care team. The most common indications for sedation were dyspnea (51.5%) and delirium (19.5%) and the most common dugs used were midazolam (52.9%) or midazolam and a neuroleptic (39.2%). Median initial midazolam infusion rate was 0.75 mg/h (interquartile range – IQR - 0.6-1.5) and final rate was 1.5 mg/h (IQR 0.9-3.0). Median time from sedation to death was 27 hours (IQR 12-58). Conclusions: Palliative sedation is a common practice at our hospital and it is not associated with shortening of hospital stay. Further research is needed to identify factors that may affect the frequency and outcomes associated with palliative sedation.

Refractory Status Epilepticus in Children: Intention to Treat With Continuous Infusions of Midazolam and Pentobarbital.

To describe pediatric patients with convulsive refractory status epilepticus in whom there is intention to use an IV anesthetic for seizure control. Two-year prospective observational study evaluating patients (age range, 1 mo to 21 yr) with refractory status epilepticus not responding to two antiepileptic drug classes and treated with continuous infusion of anesthetic agent. Nine pediatric hospitals in the United States. In a cohort of 111 patients with refractory status epilepticus (median age, 3.7 yr; 50% male), 54 (49%) underwent continuous infusion of anesthetic treatment. The median (interquartile range) ICU length of stay was 10 (3-20) days. Up to four "cycles" of serial anesthetic therapy were used, and seizure termination was achieved in 94% by the second cycle. Seizure duration in controlled patients was 5.9 (1.9-34) hours for the first cycle and longer when a second cycle was required (30 [4-120] hr; p = 0.048). Midazolam was the most frequent first-line anesthetic agent (78%); pentobarbital was the most frequently used second-line agent after midazolam failure (82%). An electroencephalographic endpoint was used in over half of the patients; higher midazolam dosing was used with a burst suppression endpoint. In midazolam nonresponders, transition to a second agent occurred after a median of 1 day. Most patients (94%) experienced seizure termination with these two therapies. Midazolam and pentobarbital remain the mainstay of continuous infusion therapy for refractory status epilepticus in the pediatric patient. The majority of patients experience seizure termination within a median of 30 hours. These data have implications for the design and feasibility of future intervention trials. That is, testing a new anesthetic anticonvulsant after failure of both midazolam and pentobarbital is unlikely to be feasible in a pediatric study, whereas a decision to test an alternative to pentobarbital, after midazolam failure, may be possible in a multicenter multinational study.

Midazolam Promotes the Mobilization of Endothelial Progenitor Cells and Increases the Plasma Concentration of VEGF in Rats with Myocardial Ischemia Treated with G-CSF

Background: Midazolam is commonly used during the perioperative period in patients with cardiac operations, especially in the patients with myocardial ischemia (MI). Some studies have demonstrated that midazolam stimulates vascular endothelial growth factor (VEGF) release in aortic smooth muscle cells. As we all know, VEGF is a hypoxia-inducible factor, which enhances vascular permeability, promotes angiogenesis, and appears to play an important role in the mobilization of endothelial progenitor cells (EPCs). The aim of this study was to evaluate the effects of midazolam on both VEGF release and the mobilization of EPCs in rats with myocardial ischemia treated with granulocyte colony-stimulating factor (G-CSF).Methods: Thirty-six rats with myocardial ischemia were randomly divided into three groups (n=12): control group, G-CSF alone-group and G-CSF plus midazolam group (control group, G-CSF group and midazolam group), pretreated with G-CSF for five days, and followed by continuous infusion of saline and midazolam into the veins for six hours on the sixth day. The number of CD34+ mononuclear cells (MNCs) and EPCs, and the plasma concentrations of VEGF and C-reactive protein (CRP) were measured at the end of the six-hour infusion. Left ventricular end-diastolic pressure (LVEDP), and maximal and minimal rates of rise of pressure in the left ventricle (dp/dtmax and dp/dtmin, respectively) were measured with a modified non-circulating Langendorff apparatus.Results: Compared to the control group, rats in the G-CSF group had a higher concentration of VEGF and increased levels of CD34+ MNCs and EPCs (P<0.05). Whereas compared to the G-CSF group, the concentrations of VEGF and the number of CD34+ MNCs and EPCs in the midazolam group were significantly higher (P<0.05). The LVEDP of the rats in both the midazolam and G-SF groups were significantly lower than that of the control group (P<0.05); while the dp/dtmin of the rats in both the midazolam and G-CSF groups were significantly higher than that of the control group, and the dp/dtmin in the midazolam group was higher than that of the G-CSF group (P<0.05).Conclusions: G-CSF can increase VEGF concentration and promote EPC mobilization in rats with myocardial ischemia. Midazolam reinforces the above effects and increases vascular dilation. Citation: Ting-Ting Chen, Wei-Dong Mi, Gang Wang, Li-Bing Li. Midazolam promotes the mobilization of endothelial progenitor cells and increases the plasma concentration of VEGF in rats with myocardial ischemia treated with G-CSF. J Anesth Perioper Med 2016; 3: 119-124. doi: 10.24015/JAPM.2016.0016This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Opioid and Benzodiazepine Withdrawal Syndrome in PICU Patients: Which Risk Factors Matter?

Although iatrogenic withdrawal syndrome (IWS) has been recognized in patients exposed to opioids and benzodiazepines, very few studies have used a validated tool for diagnosis and assessment of IWS in critically ill children. We sought to determine IWS rate, risk factors, and outcomes of IWS patients. Prospective observational study conducted in a pediatric intensive care unit. A total of 137 patients (31 with IWS and 106 with no IWS) received a continuous infusion of fentanyl and midazolam for 3 or more days. The Sophia Observation withdrawal Symptoms scale was repeatedly applied when children were weaned off sedation/analgesia. The overall incidence of IWS was 22.6%. Of the 31 IWS patients, 6 showed IWS with less than 5 days sedation or analgesia. Logistic regression showed that the median peak dose of midazolam was associated with IWS development (odds ratio 1.4). Receiver-operating curve showed a cut-off value of 0.35 mg/kg/h for midazolam peak dose (sensitivity 96.7%, specificity 51%, positive predictive value 36.6%, and negative predictive value 98.2%), with area under the curve of 0.80. IWS patients had a longer time on mechanical ventilation, prolonged pediatric intensive care unit, and hospital stays, and required prolonged period to have drugs discontinued. Although length of sedation/analgesia for at least5 days has been widely proposed for monitoring IWS, our data suggest that initiating monitoring after 3 sedation days is highly recommended. In addition, patients requiring infusion rates of midazolam above 0.35 mg/kg/h should be considered at high risk for IWS.

Immune-mediated thrombocytopaenia secondary to pulmonary tuberculosis: Diagnostic and therapeutic dilemma.

A myriad of haematological manifestations are reported with tuberculosis (TB) such as anaemia, leucocytosis and pancytopenia. Thrombocytopenia occurring in association with TB can be immune mediated, often induced by anti-tubercular drugs. Immune-mediated thrombocytopenia due to TB itself is extremely rare. Isolated thrombocytopenia has been reported in 23–43% of patients with disseminated TB.[1] Newly diagnosed immune thrombocytopenia in TB is rare; only 27 cases have been reported so far.[2] When a patient with TB presents with haemoptysis to the Intensive Care Unit (ICU), one should rule out coexisting thrombocytopenia. Untreated thrombocytopenia may result in dreaded complications such as retro-orbital, retro-peritoneal and intracranial haemorrhage.

Effect of continuous infusion of midazolam on immune function in pediatric patients after surgery.

The current study was performed to investigate the effects of midazolam on immune function in pediatric patients after surgery and possible mechanism involved. Patients who needed sedation for more than 2 consecutive days after undergoing surgery in the Pediatric Surgery Department of our hospital were enrolled for the study. Fifty-six patients (5-14 years old) were randomly divided into midazolam and propofol treatment groups (N = 28 each in each group). Pediatric patients received midazolam or profolol via continuous intravenous administration, and their plasma cytokine levels were compared after 48 h. Cultured rat C6 brain glioma cells were pretreated with a range of concentrations of midazolam or propofol for 60 minutes prior to incubation with 10 ng/mL IL-1β in serum-free medium or vehicle for 36 h. IL-6 concentration was subsequently measured using ELISA. In comparison with levels measured before the infusion of midazolam for 48 h, concentrations of all cytokines decreased, with the differences in IL-1β, IL-8, and TNF-α concentrations reaching significance (all P < 0.05). Midazolam significantly suppressed the IL-1β-induced release of IL-6 in rat C6 glioma cells. This inhibition was concentration-dependent between 0.3 and 3 μM, with 3 μM concentration of midazolam decreasing the IL-1β-induced release of IL-6 by 43.58%. Midazolam can significantly inhibit the release of cytokines in pediatric patients after surgery. One of the mechanisms may be the inhibition of IL-1β- induced release of IL-6 in the central nervous system.

Complications during the management of pediatric refractory status epilepticus with benzodiazepine and pentobarbital infusions.

The objective of this retrospective study was to evaluate complications in the management of refractory status epilepticus (RSE) treated with benzodiazepine and pentobarbital infusions. Of 28 children with RSE, eleven (39%) were treated with a pentobarbital infusion after failure to control RSE with a benzodiazepine infusion; while17 children (61%) required only a benzodiazepine infusion. The mean maximum pentobarbital infusion dosage was 5.2 ± 1.8 mg/kg/h. Twenty-five patients received a continuous midazolam infusion with an average dosage of 0.41 ± 0.43 mg/kg/h. The median length of stay was longer for the pentobarbital group. Children requiring pentobarbital therapy were more likely to develop hypotension, require inotropic support, need intubation, mechanical ventilation, peripheral nutrition, and blood products; furthermore, they were more likely to develop hypertension and movement disorder after or during weaning. In conclusion, children with RSE who required pentobarbital therapy had a longer hospital stay with more complications.

Intensive care treatment of uncontrolled status epilepticus in children: systematic literature search of midazolam and anesthetic therapies*.

A systematic literature search and review of the best evidence for intensive care treatment of refractory status epilepticus in children using continuous infusion of midazolam or anesthetic agents. MEDLINE and EMBASE search before December 2013 using key words and/or Medical Subject Headings identified English-language citations that were screened for eligibility and used if 1) the study was about high-dose benzodiazepine or anesthetic agent for children; 2) the treatment protocol was described and used for refractory status epilepticus; 3) the outcomes included seizure control; and 4) the series included at least five children. Sixteen studies (645 patients) were identified, including midazolam (nine studies), barbiturate (four studies), and other anesthetic approaches (three studies). When midazolam was used as the initial agent for refractory status epilepticus, the rate of clinical seizure control was 76%, which was achieved on average 41 minutes after starting the infusion. When midazolam was used in conjunction with continuous electroencephalography, the time to seizure control was much longer and the mean dose required for seizure control was 10.7 μg/kg/min compared with a lower dose (2.8 μg/kg/min) in the studies not using this form of monitoring, suggesting that continuous electroencephalography provided additional targets for treatment. Barbiturates were usually used after midazolam failed and treatment was started, on average, 66 hours after refractory status epilepticus onset with the goal of electroencephalography burst suppression, which was achieved, on average, 22.6 hours later. Among patients failing midazolam, barbiturate infusion was effective in 65%. Inhaled anesthetics, ketamine, and hypothermia were generally used after prior therapy with midazolam and barbiturates had failed, usually several days after seizure onset. The data on intensive care treatment of pediatric refractory status epilepticus are of poor quality, yet they show a hierarchy in strategies: early midazolam, then barbiturates, and then trial of other anesthetic strategies. In addition, using a solely clinical endpoint for seizure control may be missing significant seizure burden in pediatric refractory status epilepticus.

Optimal Control of Midazolam Infusion for Post Operative Patients in Intensive Care Units

AbstractThe critical task of anesthesia administration demands optimal drug titration by considering patient‐specific features and sedation requirements. Though there exist several sedation assessment monitors, physicians still largely rely on subjective sedation scoring systems. This paper presents an optimal infusion controller for the continuous infusion of midazolam along with the analgesic fentanyl. Specifically, we extend the convex optimization‐based optimal drug dosing regimen for propofol to midazolam. We additionally propose an alternative optimization approach using the Kullback‐Leibler divergence measure of two probability distributions. It is shown that by using the new proposed approach one can achieve the desired sedation level by using less drug infusion in comparison with previous methods. A nonlinear two‐compartment model is used to describe the pharmacokinetics of midazolam and a stochastic pharmacodynamic model is used that utilizes the modified Ramsay sedation scoring method to link the plasma drug concentration with the effective probabilistic sedation level.

Practice and documentation of palliative sedation: a quality improvement initiative.

Palliative sedation (ps), the continuous use of sedating doses of medication to intentionally reduce consciousness and relieve refractory symptoms at end of life, is ethically acceptable if administered according to standards of best practice. Procedural guidelines outlining the appropriate use of ps and the need for rigorous documentation have been developed. As a quality improvement strategy, we audited the practice and documentation of ps on our palliative care unit (pcu). A pharmacy database search of admissions in 2008 identified, for a subsequent chart review, patients who had received either a continuous infusion of midazolam (≥10 mg/24 h), regular parenteral dosing of methotrimeprazine (≥75 mg daily), or regular phenobarbital. Documentation of the decision-making process, consent, and medication use was collected using a data extraction form based on current international ps standards. Interpretation and comparison of data were difficult because of an apparent lack of a consistent operational definition of ps. Patient records had no specific documentation in relation to ps initiation, to clearly identified refractory symptoms, and to informed consent in 60 (64.5%), 43 (46.2%), and 38 (40.9%) charts respectively. Variation in the medications used was marked: 54 patients (58%) were started on a single agent and 39 (42%), on multiple agents. The 40 patients (43%) started on midazolam alone received a mean daily dose of 21.4 mg (standard deviation: 24.6 mg). The lack of documentation and standardized practice of ps on our pcu has resulted in a quality improvement program to address those gaps. They also highlight the importance of conducting research and developing clinical guidelines in this area.

Continuous infusions of midazolam and interrupted hydration - like insulin infusions without glucose?

The Liverpool Care Pathway (LCP) for the dying patient is a UK care pathway covering palliative care options for patients in the final days or hours of life; it has recently been recommended for decommission in the UK following an independent review. The pathway was widely implemented in UK hospitals in part because of governmental financial incentives. One of the criticisms of the LCP included reports of the rapid escalation to continuous infusions of sedatives in patients who then became quickly unconscious and unable to communicate.

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Introduction: Continuous infusion sedation is associated with adverse outcomes such as prolonged mechanical ventilation, extubation failure, increased risk for development of ventilator-associated pneumonia, and increased intensive care unit and hospital lengths of stay in critically ill adults. The purpose of this study was to examine excess sedation and incidence of extubation failure in pediatric patients. Methods: Data were retrospectively collected on consecutive patients who received mechanical ventilation longer than 48 hours with a continuous infusion benzodiazepine and/or opioid infusion longer than 24 hours between January 1, 2009 through October 31, 2012. The primary outcome was incidence of extubation failure in patients who were oversedated (defined by State Behavioral Scale (SBS) score of -3 or -2) within 72 hours of extubation compared to patients who were not oversedated. Secondary outcomes included evaluation of risk factors associated with oversedation and extubation failure. The primary endpoint was evaluated using a one-sided chi-square test at a significance level of p = 0.05. The risk factor analysis utilized univariate and multivariate logistic regression. Covariance-adjusted odds ratios and their corresponding 95% confidence intervals were estimated for the final set of risk factors in the models. Results: One hundred eight patients were included in the analysis, representing 62 oversedated patients and 46 non-oversedated patients. Groups were well matched with regards to baseline characteristics. Most patients received fentanyl and midazolam continuous infusions. There was no difference in extubation failure in oversedated patients versus non-oversedated patients [14 patients (22.58%) versus 7 patients (15.22%), respectively; p = 0.33]. After adjusting for potential risk factors, patients with lower Glasgow Coma Scale (GCS) scores prior to intubation (OR 1.15; 95% CI 0.74-0.97) and higher maximum benzodiazepine dose per day (OR 1.93; 95% CI 1.01-3.71) were associated with an increased risk of oversedation. Longer durations of mechanical ventilation (OR 1.10; 95% CI 0.97-1.25) and higher maximum benzodiazepine dose per day (OR 1.47; 95% CI 0.71-3.05) were associated with an increased risk of extubation failure. Conclusions: Rates of extubation failure were similar among oversedated versus non-oversedated patients. Higher maximum benzodiazepine dose per day was associated with increased risk for oversedation and extubation failure. Benzodiazepine dosing should potentially be re-evaluated in this population.

Disposition of Midazolam in Asphyxiated Neonates Receiving Therapeutic Hypothermia – A Pilot Study

Moderate hypothermia has become an established therapy for asphyxiated neonates. Midazolam is a frequently used sedative for this indication, although it has never been investigated how therapeutic hypothermia and asphyxia influence midazolam metabolism in neonates.9 asphyxiated newborns were treated with whole body hypothermia of 32-34°C for 72 h and all of them received continuous midazolam infusion for sedation. Serum concentrations of midazolam and its metabolites 1-hydroxy-midazolam and 4-hydroxy-midazolam were measured during hypothermia and the rewarming period. Renal and hepatic parameters were assessed to take into account the influence of asphyxia related renal or hepatic impairment.We found a high interindividual variability of serum midazolam concentrations in asphyxiated neonates with therapeutic hypothermia; median midazolam concentration was 369.3 ng/ml (minimum 36.6; maximum 3 218.6 ng/ml). The population pharmacokinetic model revealed a midazolam clearance of 2.57 ml/kg/min, comparable to midazolam clearances observed in normothermic critically ill neonates. However, midazolam clearance was significantly decreased in patients with asphyxia related renal and hepatic impairment.It seems that isolated hypothermia does not significantly influence midazolam metabolism. However, neonates with asphyxia related hepatic and renal impairment are at risk of generating unexpectedly high serum midazolam concentrations. In addition pronounced interindividual variability of midazolam metabolism may contribute to dangerously high midazolam concentrations.

Ketamine Continuous Infusion for Refractory Status Epilepticus in a Patient With Anticonvulsant Hypersensitivity Syndrome

Refractory status epilepticus (RSE) requires aggressive management with multiple antiepileptic drugs (AEDs) often requiring the initiation of continuous infusions of propofol, midazolam, or pentobarbital to achieve adequate control in addition to intermittent agents. Ketamine has been implicated in several case reports as a successful agent for treating RSE given that it blocks the N-methyl-D-aspartate receptor, which is overexpressed in prolonged status epilepticus. We describe a previously healthy 27-year-old woman who presented with prolonged RSE requiring the initiation of multiple AEDs, including high-dose propofol and midazolam continuous infusions. As a result of hypotension from propofol and inadequate seizure control with midazolam, the patient was successfully transitioned to a pentobarbital infusion in combination with multiple AEDs. Although the patient achieved control of her RSE, her course was complicated by the development of an anticonvulsant hypersensitivity syndrome (AHS) with transaminitis. Limited with the options of AED that could have been used, it was decided to initiate the patient on a continuous ketamine infusion plus midazolam and slowly wean the patient off pentobarbital as well as to avoid further use of phenytoin and phenobarbital. The patient was successfully transitioned off pentobarbital to a ketamine infusion plus midazolam with complete seizure control after several dose escalations. Her AHS and transaminitis resolved on a ketamine infusion for a total of 12 days, and she was successfully discharged from the hospital after 60 days in the ICU. This is the first case report to describe a successful transition to a ketamine infusion in a patient with AHS and transaminitis.

Withdrawal syndrome in the pediatric intensive care unit. Incidence and risk factors

ObjectiveTo determine the incidence of withdrawal syndrome after prolonged infusion of fentanyl and midazolam in children, and the associated risk factors. DesignHistoric or retrospective cohort study. SettingPediatric Intensive Care Unit in an academic center. PatientsForty-eight pediatric patients who received sedation and analgesia only with fentanyl and midazolam through continuous infusion for at least 48h. InterventionsNone. Main variables of interestCollected data included demographic and clinical parameters, dose and duration of sedation received, and incidence, severity and treatment of withdrawal syndrome. ResultsFifty percent of the patients developed withdrawal syndrome. There were significant differences between the patients who developed withdrawal syndrome and those who did not, in terms of the duration of infusion and the cumulative doses of both drugs. A cumulative fentanyl dose of 0.48mg/kg, a cumulative midazolam dose of 40mg/kg, and a duration of infusion of both drugs of 5.75days were risk factors for the development of withdrawal syndrome. Most children developed mild or moderate disease, beginning about 12–36h after weaning from infusion. Methadone was used in most cases for treating withdrawal. ConclusionsThere is a high incidence of withdrawal syndrome in children following the continuous infusion of midazolam and fentanyl. The duration of infusion of both drugs and higher cumulative doses are associated with the development of withdrawal syndrome.

Fluctuations in sedation levels may contribute to delirium in ICU patients

Delirium in patients admitted to the intensive care unit (ICU) is a serious complication potentially increasing morbidity and mortality. The aim of this study was to investigate the impact of fluctuating sedation levels on the incidence of delirium in ICU. A prospective cohort study of adult patients at three multidisciplinary ICUs. The Richmond Agitation and Sedation Scale (RASS) and the Confusion Assessment Method for the ICU were used at least twice a day. Delirium was detected at least once in 65% of the patients (n = 640). Delirious patients were significantly older, more critically ill, more often intubated, had longer ICU stays, and had higher ICU mortality than non-delirious patients. The median duration of delirium was 3 days (interquartile range: 1;10), and RASS was less than or equal to 0 (alert and calm) 91% of the time. The odds ratio (OR) for development of delirium if RASS changed more than two levels was 5.19 when adjusted for gender, age, severity of illness, and ICU site and setting. Continuous infusion of midazolam was associated with a decrease in delirium incidence (OR: 0.38; P = 0.002). Fluctuations in sedation levels may contribute to development of delirium in ICU patients. The risk of developing delirium might be reduced by maintaining a stable sedation level or by non-sedation.

Psychogenic Cough

Cough is the most common respiratory symptom and a common reason for consultation in both primary care and emergency departments, as a result of family concerns. We report an 11-year-old girl who complains of constant cough episode for 4 hours without any rest. After sequential treatment with nebulized salbutamol and budesonide, dexamethasone, codeine, and midazolam, the patient showed transient improvement, with cough disappearing altogether, but 10 minutes later, it started over with the same intensity from the beginning. When she got distracted and talked, the access decreased, starting again when the word "cough" or similar terms were mentioned in front of her. She remained asymptomatic for 2 hours, after which her symptoms began similarly to the initial, coinciding with taking 1 tablet of clarithromycin, so it was decided to start a continuous infusion of midazolam, with the cough disappearing completely after 15 minutes of starting the infusion. One hour after starting the infusion, the child fell asleep. At waking, the cough had disappeared. She continued treatment with oral codeine for 3 days, showing no relapse. It is important to include psychogenic cough in the differential diagnosis of persistent or recurrent chronic cough and asthma that is difficult to control and communicate that diagnostic criteria are based on indicative symptoms (cough access only when awake), with normal radiology, spirometry, and bronchoscopy, to avoid misdiagnosis and inadequate pharmacological actions. Successful treatment is based on recognizing the underlying cause and use of different forms of cognitive-behavioral therapies that aim to break the habit.