I don’t normally blog about animal studies, but on reading a review of recent(-ish) shock research I was interested in the following piece that describes the effect of diffrent induction agents on rat heart muscle: Sedation is frequently necessary in patients with septic shock, and therefore Zausig and colleagues investigated the effects of dose-dependent effects of various induction agents (propofol, midazolam, s(+)-ketamine, methohexitone, etomidate) in a Langendorff heart preparation from rats rendered septic by CLP. Propofol exerted the most pronounced depressant effects on both the maximal systolic contraction and the minimal diastolic relaxation, and cardiac work. Furthermore, propofol only adversely deleteriously affected the myocardial oxygen supply- demand ratio. In contrast, s(+)-ketamine was associated with the best maintenance of cardiac function. Within the limits of the study – that is, the use of an ex vivo isolated organ model – the authors concluded that s(+)-ketamine may be an alternative to the comparably inert etomidate, the use of which is, however, limited due to its endocrine side effects.
Of course we should be cautious about extrapolating animal lab work to clinical practice, but this supports my position of vehement opposition to the injudicious use of propofol for RSI in critically ill patients!
Year in review 2009: Critical Care – shock Critical Care 2010, 14:239 Full text
Suxamethonium and rocuronium were compared in a database of prospectively recorded cases of RSI in the emergency department.
A total of 327 RSI were included in the final analyses. All patients received etomidate as the induction sedative and were successfully intubated. Of these, 113 and 214 intubations were performed using succinylcholine and rocuronium, respectively.
The rate of first-attempt intubation success was similar between the succinylcholine and rocuronium groups (72.6% vs. 72.9%, p = 0.95).
Median doses used for succinylcholine and rocuronium were 1.65 mg/kg (interquartile range [IQR] = 1.26–1.95 mg/kg) and 1.19 mg/kg (IQR = 1–1.45 mg/kg), respectively.
The median dose of etomidate was 0.25 mg/kg in both groups.
In this study succinylcholine and rocuronium were equivalent with regard to first-attempt intubation success in the ED. This finding is consistent with previous investigations that used doses between 0.9 and 1.2 mg/kg and found similar intubating conditions to succinylcholine at these higher doses; subgroup analyses of studies using a lower rocuronium dose of 0.6 to 0.7 mg/kg had a relative risk favoring succinylcholine for excellent intubating conditions.
The low (in my view) rate of first-attempt intubation success in both groups was (72.6% vs. 72.9%), does make one wonder whether the intubating clinicians optimised their strategy for first-pass success. Comparison of Succinylcholine and Rocuronium for First-attempt Intubation Success in the Emergency Department Acad Emerg Med. 2011;18:11-14
Anaesthetist Dr Jan Persson from Stockholm has published an updated review of recent ketamine literature. The following interesting facts about our favourite drug are extracted from Dr Persson’s paper:
Action on multiple receptors earns it the nickname: ‘the nightmare of the pharmacologist’
Recently ketamine has also been shown to inhibit tumor necrosis factor-alpha (TNF- alpha) and interleukin 6 (IL-6) gene expressions in lipopolysaccharide (LPS)-activated macrophages. It has been speculated that these antiproinflammatory effects may be responsible for antihyperalgesic effects of ketamine
Ketamine can exist in two forms, or enantiomers; S-ketamine and R-ketamine. The physical properties of the enantiomers are identical, but their interactions with complex molecules, underlying PK/PD parameters, might differ. It has been well established that the elimination clearance of S-ketamine is larger than that of R-ketamine. The S-form has been commercially available for several years, probably based on the perception that it would have a better effect to side-effect ratio. The recent literature calls into question the proposed advantages of the S-enantiomer.
Ketamine has been shown to induce neuroapoptosis, or neuronal cell death, in newborn animals. This is obviously a concern in paediatrics, where ketamine plays an important role, both in anaesthesia and for sedation/analgesia during painful procedures. The relevance in humans of these effects, however, is unclear, and as pointed out by Green and Cote it does seem unlikely, for various reasons, that such an effect would be of major importance. It does not seem likely, though possible, that a clinically relevant effect would have passed unnoticed.
Another, somewhat unexpected, side effect that has emerged in recent years is bladder dysfunction. In some cases the bladder effects progress to ulcerative cystitis. Although the reported cases have mainly concerned recreational drug users, they are relevant for long-term analgesic use as well. The mechanisms involved are unknown. This side effect might turn out to be the most serious limitation to long-term analgesic treatment with ketamine.
Dr WFS Sellers and colleagues describe several cases that demonstrate convincingly a protective effect of intravenous magnesium sulphate against the tachycardia produced by intravenous salbutamol in patients with asthma. This effect was observed both when magnesium was given before and when given after the salbutamol. It was seen in critically ill asthmatic patients and in a volunteer with well-controlled asthma.
Intravenous magnesium sulphate increases atrial contraction time and refractory times. It is used to treat atrial tachyarrhythmias and has a negative chronotropic and dromotropic effect. Intravenous magnesium sulphate prevents intravenous salbutamol tachycardia in asthma Br J Anaesth. 2010 Dec;105(6):869-70
The ACURASYS study of atracurium vs placebo in ARDS: three ml rapid intravenous infusion of 15 mg of cis-atracurium besylate or placebo was administered, followed by a continuous infusion of 37.5 mg per hour for 48 hours. There appeared to be benefits in the intervention group, although the mechanisms are not clear. Further studies are needed.
BACKGROUND: In patients undergoing mechanical ventilation for the acute respiratory distress syndrome (ARDS), neuromuscular blocking agents may improve oxygenation and decrease ventilator-induced lung injury but may also cause muscle weakness. We evaluated clinical outcomes after 2 days of therapy with neuromuscular blocking agents in patients with early, severe ARDS. METHODS: In this multicenter, double-blind trial, 340 patients presenting to the intensive care unit (ICU) with an onset of severe ARDS within the previous 48 hours were randomly assigned to receive, for 48 hours, either cisatracurium besylate (178 patients) or placebo (162 patients). Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FIO2) of less than 150, with a positive end-expiratory pressure of 5 cm or more of water and a tidal volume of 6 to 8 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e., the 90-day in-hospital mortality rate), adjusted for predefined covariates and baseline differences between groups with the use of a Cox model. RESULTS: The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P=0.04), after adjustment for both the baseline PaO2:FIO2 and plateau pressure and the Simplified Acute Physiology II score. The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (P=0.08). Mortality at 28 days was 23.7% (95% CI, 18.1 to 30.5) with cisatracurium and 33.3% (95% CI, 26.5 to 40.9) with placebo (P=0.05). The rate of ICU-acquired paresis did not differ significantly between the two groups. CONCLUSIONS: In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. (Funded by Assistance Publique-Hôpitaux de Marseille and the Programme Hospitalier de Recherche Clinique Régional 2004-26 of the French Ministry of Health; ClinicalTrials.gov number, NCT00299650.)
A paper of great interest for those of us who spend a lot of time teaching the use of ketamine describes its history from initial synthesis in the early 1960s. Ketamine pioneer Edward F. Domino, M.D describes how it was first given to humans in 1964: ‘Our findings were remarkable! The overall incidence of side effects was about one out of three volunteers. Frank emergence delirium was minimal. Most of our subjects described strange experiences like a feeling of floating in outer space and having no feeling in their arms or legs.‘
Domino goes on to list interesting anecdotes in ketamine’s history, like how his wife came up with the term ‘dissociative anaesthetic’ and how physicians and their partners experimenting with ketamine in the 1970s tried communicating with dolphins, fell in love, and froze to death in a forest. The pharmacology of ketamine is described along with its effects on pain and even depression. Taming the ketamine tiger. Anesthesiology. 2010 Sep;113(3):678-84 Free Full Text
Interesting…a randomised trial compared rocuronium mixed with saline against rocuronium mixed 1:1 with 8.4% sodium bicarbonate.
The principal finding was that rocuronium mixed with sodium bicarbonate 8.4% is more potent than that of rocuronium alone; it resulted in a more rapid onset time, and a prolonged recovery from the neuromuscular blockade.
It is likely that this effect is because the drug is weakly basic, and the change in pH from 4.01 to 7.78 seen after the addition of sodium bicarbonate 8.4% to rocuronium increases the amount of unionised rocuronium in the solution.
I suppose we could just give a bigger dose if we need to though. Potency and recovery characteristics of rocuronium mixed with sodium bicarbonate Anaesthesia. 2010;65(9):899–903
The pathophysiology of angiotensin-converting enzyme inhibitor (ACEi)–induced angioedema most likely resembles that of hereditary angioedema, ie, it is mainly mediated by bradykinin-induced activation of vascular bradykinin B2 receptors. It was hypothesised that the bradykinin B2 receptor antagonist icatibant might therefore be an effective therapy for ACEi-induced angioedema. This month’s Annals of Emergency Medicine reports research assessing its effciacy in a small series of patients, with a retrospective comparison against steroid and antihistamine therapy.
The eight patients with acute ACEi-induced angioedema were treated with a single subcutaneous injection of icatibant. First symptom improvement after icatibant injection occurred at a mean time of 50.6 minutes and complete relief of symptoms at 4.4 hours. In the historical comparison group treated with methylprednisolone and clemastine (an antihistamine / anticholinergic), the mean time to complete relief of symptoms was 33 hours. Some of these patients received a tracheotomy (3/47), were intubated (2/47), or received a second dose of methylprednisolone (12/47). Therapeutic Efficacy of Icatibant in Angioedema Induced by Angiotensin-Converting Enzyme Inhibitors: A Case Series Ann Emerg Med. 2010;56(3):278-82
Results from 24 studies on dexmedetomidine were assessed in a meta-analysis to determine the effect on ICU length of stay. The authors concluded that the limited evidence suggests that dexmedetomidine might reduce length of ICU stay in some critically ill patients, but the risk of bradycardia was significantly higher when both a loading dose and high maintenance doses (>0.7 μg/kg/h) were used. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: a meta-analysis. Intensive Care Med. 2010 Jun;36(6):926-39
Okay so it’s a small case series – but the results warrant further investigation: 10-20 mcg/kg terlipressin was given to five infants and children who arrested in the paediatric intensive care unit and who had not responded to several doses of adrenaline (epinephrine)1. Sustained return of spontaneous circulation (ROSC) was achieved in four, and two survived to be discharged home without sequelae and with good neurologic status at 6 and 12 month follow up. Interestingly, the four patients who had ROSC all had septic shock as the cause of their arrest. The two survivors had severe bradycardia and severe bradycarda-asystole as the arrest rhythms, and both received 20 mcg/kg terlipressin.
Terlipressin is a synthetic arginine vasopressin analog with a significantly longer duration of effect, which previously showed positive effects when administered to a small group of children unresponsive to prolonged resuscitative efforts2. 1. Pediatric cardiac arrest refractory to advanced life support: Is there a role for terlipressin? Pediatr Crit Care Med. 2010 Jan;11(1):139-41 2. Beneficial effects of terlipressin in prolonged pediatric cardiopulmonary resuscitation: A case series. Crit Care Med. 2007 Apr;35(4):1161-4
