Johan F. Coetzee

Effect of various propofol plasma concentrations on regional myocardial contractility and left ventricular afterload

The cardiovascular effects of propofol infusions, designed to maintain constant plasma concentrations, were examined in an open-chested pig model. Regional myocardial contractility was measured with the end-systolic pressure-length relationship (Ees) and left ventricular afterload quantified by the effective arterial elastance (Ea). The propofol plasma concentrations in this study varied between 0 and 7.73 (SEM 0.96) μg/mL. A significant correlation for the increasing propofol plasma concentration and a decrease in myocardial contractility (P = 0.0056) was demonstrated, and the Ea remained constant. This gave rise to a reduction in stroke volume (P = 0.002) and, combined with a decrease in the heart rate (P = 0.000l), led to a reduction in the cardiac output (P = 0.0001). When the propofol infusion was stopped, myocardial contractility did not recover in parallel with the decrease in plasma propofol concentration.

The performance of compartmental and physiologically based recirculatory pharmacokinetic models for propofol: a comparison using bolus, continuous, and target-controlled infusion data.

BACKGROUND: With the growing use of pharmacokinetic (PK)-driven drug delivery and/or drug advisory displays, identifying the PK model that best characterizes propofol plasma concentration (Cp) across a variety of dosing conditions would be useful. We tested the accuracy of 3 compartmental models and 1 physiologically based recirculatory PK model for propofol to predict the time course of propofol Cp using concentration-time data originated from studies that used different infusion schemes. METHODS: Three compartmental PK models for propofol, called the “Marsh,” the “Schnider,” and the “Schüttler” models, and 1 physiologically based recirculatory model called the “Upton” model, were used to simulate the time course of propofol Cp. To test the accuracy of the models, we used published measured plasma concentration data that originated from studies of manual (bolus and short infusion) and computer-controlled (target-controlled infusion [TCI] and long infusion) propofol dosing schemes. Measured/predicted (M/P) propofol Cp plots were constructed for each dataset. Bias and inaccuracy of each model were assessed by median prediction error (MDPE) and median absolute prediction error (MDAPE), respectively. RESULTS: The M/P propofol Cp in the 4 PK models revealed bias in all 3 compartmental models during the bolus and short infusion regimens. In the long infusion, a worse M/P propofol Cp at higher concentration was seen for the Marsh and the Schüttler models than for the 2 other models. Less biased M/P propofol Cp was found for all models during TCI. In the bolus group, after 1 min, a clear overprediction was seen for all 3 compartmental models for the entire 5 min; however, this initial error resolved after 4 min in the Schnider model. The Upton model did not predict propofol Cp accurately (major overprediction) during the first minute. During the bolus and short infusion, the Marsh model demonstrated worse MDPE and MDAPE compared with the 3 other models. During short infusion, MDAPE for the Schnider and Schüttler models was better than the Upton and the Marsh models. All models showed similar MDPE and MDAPE during TCI simulations. During long infusion, the Marsh and the Schüttler models underestimated the higher plasma concentrations. CONCLUSION: When combining the performance during various infusion regimens, it seems that the Schnider model, although still not perfect, is the recommended model to be used for TCI and advisory displays.

Arterial oxygenation and one-lung anesthesia.

Purpose of review In the presence of the obligatory shunt during one-lung ventilation, arterial oxygenation is determined by the magnitude of the shunt in addition to the oxygen content of the mixed venous blood coursing through that shunt. The present discussion aims to heighten awareness of factors determining arterial oxygenation during one-lung anesthesia, other than the magnitude of the shunt and dependent lung low-ventilation perfusion units. Recent findings A convenient way to increase mixed venous and thereby arterial oxygenation is to raise cardiac output. While this approach has achieved some success when increasing cardiac output from low levels, other studies have highlighted limitations of this approach when cardiac output attains very high levels. The effect of anesthesia techniques on the relationship between oxygen consumption and cardiac output could also explain unanswered questions regarding the pathophysiology of arterial oxygenation during one-lung anesthesia. Summary The effects of anesthesia techniques on oxygen consumption, cardiac output and therefore mixed venous oxygenation can significantly affect arterial oxygenation during one-lung anesthesia. While pursuing increases in cardiac output may, under limited circumstances, benefit arterial oxygenation during one-lung ventilation, this approach is not a panacea and does not obviate the necessity to optimize dependent lung volume.

Allometric or lean body mass scaling of propofol pharmacokinetics: towards simplifying parameter sets for target-controlled infusions.

Uncertainty exists as to the most suitable pharmacokinetic parameter sets for propofol target-controlled infusions (TCI). The pharmacokinetic parameter sets currently employed are clearly not universally applicable, particularly when patient attributes differ from those of the subjects who participated in the original research from which the models were derived. Increasing evidence indicates that the pharmacokinetic parameters of propofol can be scaled allometrically as well as in direct proportion to lean body mass (LBM). Appraisal of hitherto published studies suggests that an allometrically scaled pharmacokinetic parameter set may be applicable to a wide range of patients ranging from children to obese adults. On the other hand, there is evidence that propofol pharmacokinetic parameters, scaled linearly to LBM, provide improved dosing in normal and obese adults. The ‘Schnider’ pharmacokinetic parameter set that has been programmed into commercially available TCI pumps cannot be employed at present for morbidly obese patients (body mass index >40 kg/m2), because of anomalous behaviour of the equation used to calculate LBM, resulting in administration of excessive amounts of propofol. Simulations of TCI using improved equations to calculate LBM indicate that the Schnider model delivers similar amounts of propofol to morbidly obese patients as do the allometrically scaled pharmacokinetic parameter sets. These hypotheses deserve further investigation. To facilitate further investigation, researchers are encouraged to make their data freely available to the WorldSIVA Open TCI Initiative (http://opentci.org).

Anesthetic modulation of myocardial ischemia and reperfusion injury in pigs: comparison between halothane and sevoflurane

PurposeHalothane offers protection against the reperfusion injury of the myocardium. This study compared sevoflurane with halothane in its potential to modulate the effects of acute severe ischemia and reperfusion on the myocardium.MethodsExperiments were conducted on 25 pigs. Anesthesia consisted of thiopental, vecuronium and fentanyl. The lungs were mechanically ventilated with oxygen and nitrogen. Animals were randomly allocated to receive either I MAC halothane or sevoflurane. A control group received fentanyl and pentobarbital. Regional myocardial function was measured with sonomicrometers. The left anterior descending coronary artery was occluded for 15 min followed by 60 min reperfusion.ResultsNeither halothane nor sevoflurane protected the heart against the effects of acute and severe regional myocardial ischemia. During reperfusion, 89% of the animals receiving sevoflurane suffered from ventricular fibrillation compared with 30% in the halothane group (P < 0.005). Five minutes into the reperfusion period the animals subjected to halothane anesthesia demonstrated an 88% recovery in regional myocardial systolic function while in the sevoflurane group the recovery was 40% of pre-ischemic control (P < 0.05).ConclusionHalothane is associated with less reperfusion arrhythmias and, in addition, recovery of regional myocardial function during reperfusion was more rapid in the presence of halothane than with sevoflurane.RésuméObjectifL’halothane offre une protection contre les lésions reliées à la reperfusion du myocarde. La présente étude a comparé le sévoflurane et l’halothane quant au pouvoir de moduler les effets de l’ischémie aiguë sévère et de la reperfusion du myocarde.MéthodeLes expériences ont été menées avec 25 porcs. On a utilisé du thiopental, du vécuronium et du fentanyl pour l’anesthésie. La ventilation mécanique des poumons s’est faite avec de l’oxygène et de l’azote. Les animaux, répartis de façon aléatoire, ont reçu I CAM d’halothane ou de sévoflurane. Un groupe témoin a reçu du fentanyl et du pentobarbital. La fonction régionale du myocarde a été mesurée à l’aide de sonomicromètres. Locclusion de 15 min de l’artère interventriculaire antérieure a été suivie de 60 min de reperfusion.RésultatsNi l’halothane ni le sévoflurane n’ont réussi à protéger le coeur des effets d’une ischémie régionale aiguë et sévère du myocarde. Pendant la reperfusion, 89 % des animaux qui avaient reçu du sévoflurane et 30 % de ceux qui avaient reçu de l’halothane ont souffert de fibrillation ventriculaire (P < 0,005). En cinq minutes de reperfusion, les animaux soumis à l’anesthésie à base d’halothane ont présenté un taux de récupération de la fonction systolique régionale du myocarde de 88% tandis que ceux qui avaient reçu du sévoflurane n’ont recouvré qu’à 40 % l’état préischémique enregistré (P < 0,05).ConclusionComparé au sévoflurane, l’halothane est associé à moins d’arythmie de reperfusion et à une récupération plus rapide de la fonction régionale du myocarde pendant la reperfusion.

Arterial oxygenation during one-lung anesthesia.

S zegedi et al. (1) studied the effects of normovolemic acute hemodilution on arterial oxygenation in supine subjects during one-lung anesthesia (OLA). After hemodilution, patients who had chronic obstructive airways disease (COAD) exhibited decreases in Pao2, whereas there were no changes in subjects with normal lungs, nor in a control group with COAD who did not undergo hemodilution. The effects of hemodilution during OLA have not been previously described, and the reasons for their findings are not obvious. Intuitively, one may suspect that hemodilution increased pulmonary shunting in the COAD group. There are however, a number of factors influencing arterial oxygenation during OLA that need to be considered (2). These factors may be introduced by considering the shunt equation:

Heparinase Thromboelastography Compared With Activated Coagulation Time for Protamine Titration After Cardiopulmonary Bypass

OBJECTIVE The present study is a comparison of two point-of-care (POC) tests as endpoints of protamine titration after CPB. The authors hypothesized that using the heparinase-kaolin thromboelastography (TEG-HK) R-time difference would more readily identify residual heparin necessitating additional protamine than when using activated coagulation time (ACT). The primary endpoint was the between-group difference in protamine dose. Whether this approach would lessen postoperative bleeding and sequelae also was investigated. DESIGN Single center, blinded, prospective, randomized study. SETTING University teaching hospital. PARTICIPANTS Eighty-two adult patients for on-pump coronary artery bypass and/or valve surgery. INTERVENTIONS Patients were randomized. In the ACT group, protamine was titrated until ACT did not exceed baseline by more than 10%. In the TEG group, a TEG-HK R-time difference less than 20% was targeted. Protamine was repeated to achieve the endpoints. Clinicians in the ACT group were blinded to TEG data and vice versa. MEASUREMENTS AND MAIN RESULTS There was no between-group difference in total protamine dose (3.9 ± 0.6 and 4.2 ± 0.7; 95% CI of the difference between means: -0.544 to 0.008 mg/kg; p = 0.057) or protamine:heparin ratios (1.3:1 and 1.4:1; 95% CI of the difference between means: -0.05 to 0.03 mg/mg; p = 0.653). In the ACT group, 17% of patients required a second protamine dose, and in the TEG group, 24% of patients required a second protamine dose. No between-group differences in the postoperative transfusion requirements or intensive care unit length of stay were demonstrated. CONCLUSION No difference was identified in protamine dosing using either ACT or TEG-HK R-time difference as endpoints. Heparinase TEG may be useful for monitoring heparin reversal.

What keeps health professionals working in rural district hospitals in South Africa

Background The theme of the 2014 Southern African Rural Health Conference was ‘Building resilience in facing rural realities’. Retaining health professionals in South Africa is critical for sustainable health services. Only 12% of doctors and 19% of nurses have been retained in the rural areas. The aim of the workshop was to understand from health practitioners why they continued working in their rural settings. Conference workshop The workshop consisted of 29 doctors, managers, academic family physicians, nurses and clinical associates from Southern Africa, with work experience from three weeks to 13 years, often in deep rural districts. Using the nominal group technique, the following question was explored, ‘What is it that keeps you going to work every day?’ Participants reflected on their work situation and listed and rated the important reasons for continuing to work. Results Five main themes emerged. A shared purpose, emanating from a deep sense of meaning, was the strongest reason for staying and working in a rural setting. Working in a team was second most important, with teamwork being related to attitudes and relationships, support from visiting specialists and opportunities to implement individual clinical skills. A culture of support was third, followed by opportunities for growth and continuing professional development, including teaching by outreaching specialists. The fifth theme was a healthy work-life balance. Conclusion Health practitioners continue to work in rural settings for often deeper reasons relating to a sense of meaning, being part of a team that closely relate to each other and feeling supported.

Comparative MIC evaluation of a generic ceftriaxone by broth microdilution on clinically relevant isolates from an academic hospital complex in South Africa

We evaluated the in vitro microbiological efficacy of a generic ceftriaxone product against several clinically significant organisms collected from sterile sites. The minimum inhibitory concentration (MIC) of each was determined simultaneously with the reference and the generic ceftriaxone product. Comparative analysis of MICs between the two products for each isolate was performed using both categorical (interpretive) agreement and essential (actual MIC value) agreement. A total of 260 isolates were tested. Overall, there was categorical agreement of 98.9% and essential agreement of 95.8%. The categorical agreement for all isolates (96.7 - 100%) accorded with international standards, as no very major errors were seen and the major error rate was less than 3%. Of the 90 isolates of E. coli (40), Klebsiella spp. (40) and Salmonella spp. (10), 87.6% had an MIC less than or equal to 0.12mg/l. The generic ceftriaxone product showed equivalent efficacy by MIC determination to the reference formulation. Ceftriaxone remains a viable and useful antimicrobial agent against a variety of clinically relevant organisms in our setting.

Entropy of the electroencephalogram as applied in the M-Entropy S/5™ Module (GE Healthcare) during increases in nitrous oxide and constant sevoflurane concentrations

Abstract Background: It has been suggested that spectral entropy of the electroencephalogram as applied in the M-Entropy S/5TM Module (GE Healthcare) does not detect the effects of nitrous oxide (N2O). The aim of this study was to investigate the effect on entropy by graded increases in N2O concentrations in the presence of a constant concentration of sevoflurane, in the absence of surgical stimulation. Method: This single-blind, randomised study was conducted at an altitude of approximately 1 400 m. Patients received sevoflurane 2% (1.7% at sea level) and N2O, at end-tidal concentrations of 0%, 10%, 20%, 30%, 40%, 50%, 60% or 70% (equivalent to 8.5%, 17%, 25.5%, 34%, 42.6%, 51.1% and 59.6% at sea level). Entropy was measured before, during and after N2O administration. The absolute changes and ratios of entropy relative to the baseline were calculated. Between- and within-group comparisons were made using analysis of variance and covariance. Results: None of the entropy variables differed significantly within and between groups before and after N2O administration. Within-group analysis revealed that entropy during N2O administration was significantly lower than before or after N2O administration (P < 0.007). While a minor clinical but statistically significant linear relationship was observed between increasing N2O concentration and decreasing entropy from N2O 0% to 60%, a steeper and clinically important decrease (relative change > 20%) was noted at N2O > 60% (> 51% at sea level). Conclusions: The M-Entropy Module S/5TM responds to increasing concentrations of N2O in the presence of 2% (1.7% at sea level) sevoflurane, in the absence of surgical stimulation. There is a linear relationship between increasing N2O concentrations and decreasing entropy with a steep and clinically important decrease at N2O > 60% (> 51% at sea level). The influence of ambient pressure on the partial pressures, which determine the effects of anaesthetic agents, must be taken into account.