Markus Steinfath

Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil : An update

SummaryAlfentanil, fentanyl and sufentanil are synthetic opioid analgesics acting at specific opioid receptors. These opioids are widely used as analgesics to supplement general anaesthesia for various surgical procedures or as primary anaesthetic agents in very high doses during cardiac surgery. Fentanyl and sufentanil especially are administered via infusion for long term analgesia and sedation in intensive care patients.Opioid analgesics are mainly administered using the intravenous route. However, other techniques of administration, including epidural, intrathecal, transdermal and intranasal applications, have been demonstrated.Important pharmacokinetic differences between alfentanil, fentanyl and sufentanil have been shown in many reports. Alfentanil has the most rapid analgesic onset and time to peak effect as well as the shortest distribution and elimination half-lives. The volume of distribution and total body clearance of this agent are smaller when compared with those of fentanyl and sufentanil.The pharmacokinetics of the opioid analgesics can be affected by several factors including patient age, plasma protein content, acid-base status and cardiopulmonary bypass, but not significantly by renal insufficiency or compensated hepatic dysfuntion. In addition, pharmacokinetic properties can be influenced by changes in hepatic blood flow and administration of drug combinations which compete for the same plasma protein carrier or metabolising pathway.Although comparing specific pharmacokinetic parameters such as half-lives is deeply entrenched in the literature and clinical practice, simply comparing half-lives is not a rational way to select an opioid for specific requirements. Using pharmacokinetic-pharmacodynamic models, computer simulations based on changes in the effect site opioid concentration or context-sensitive half-times seem to be extremely useful for selecting an opioid on a more rational basis.

Evidence for Susceptibility to Malignant Hyperthermia in Patients with Exercise-induced Rhabdomyolysis

BackgroundMalignant hyperthermia (MH), heat stroke, and exercise-induced rhabdomyolysis (ER) were suspected to be related syndromes. However, it is not known whether individuals with history of ER have an increased incidence of susceptibility to MH. To establish an association between ER and susceptibility to MH, the authors determined the MH status in patients with a history of MH-like episodes induced by physical stress. MethodsTwelve unrelated patients with ER, 18 patients with anesthesia-induced MH, and 28 controls were investigated with the in vitro contracture test (IVCT) according to the European MH Group protocol and the ryanodine contracture test. In addition, all patients were screened for genetic mutations, and histology was performed on muscle specimens. ResultsTen ER patients had positive IVCT results, one patient had a negative test result, and one patient showed equivocal responses. Samples from patients with positive IVCT results showed pronounced contractures after exposition to ryanodine, as opposed to specimens from patients with negative IVCT results, which developed contractures slowly. Three ER patients had mutations at the ryanodine receptor gene. All anesthesia-induced MH patients had positive IVCT results, two of them presented the C1840T mutation. The control patients had normal contracture test results and no typical MH mutations. Histologic examination determined no specific myopathies in any patient. ConclusionsRegarding these results, the authors recommend performing muscle biopsies for histologic examination and IVCT in patients with ER. In addition, the patient should be seen by a neurologist and screened for genetic abnormalities to shed light on the genetics of MH.

Overlapping induction of anesthesia: an analysis of benefits and costs.

Background:Overlapping induction (OI), i.e., induction of anesthesia with an additional team while the previous patient is still in the operating room (OR), was investigated. Methods:The study period was 60 days in two followed by three ORs during surgical Block Time (7:30 am until 3:00 pm). Patients were admitted the day before surgery and were thus available and did not have surgery that day unless there was a time reduction. Facilities were already constructed. Number of cases, Nonsurgical Time (Skin Suture Finish until next Procedure Start Time), Turnover Time, and Anesthesia Control Time plus Turnover Time were studied. In addition, economic benefit was calculated. Results:Three hundred thirty-five cases were studied. Using OI, the time of care of regularly scheduled cases was shortened, and the number of cases performed within OR Block Time increased (151 to 184 cases; P < 0.05). Nonsurgical Time (in h:min) decreased (1:08 ± 0:26 to 0:57 ± 0:18; P < 0.001), Turnover Time decreased (0:38 ± 0:24 to 0:25 ± 0:15; P < 0.05), and Anesthesia Control Time plus Turnover Time decreased (0:43 ± 0:23 to 0:28 ± 0:18; P < 0.001). Subgroup analysis showed a significant benefit of OI only in three ORs. In three ORs, economic benefit can be gained at a case mix index greater than 0.3 besides additional costs. Conclusions:Overlapping induction increased productivity and profit despite the expense of additional staff. Subgroup analysis emphasizes the importance of the number of ORs involved in OI.

Heart Rate Variability Predicts Severe Hypotension after Spinal Anesthesia for Elective Cesarean Delivery

Background:Hypotension due to vasodilation during subarachnoid block (SAB) for elective cesarean delivery may be harmful. Heart rate variability (HRV), reflecting autonomic control, may identify patients at risk of hypotension. Methods:Retrospectively, HRV was analyzed in 41 patients who were classified into one of three groups depending on the decrease in systolic blood pressure (SBP): mild (SBP > 100 mmHg), moderate (100 > SBP > 80 mmHg), or severe (SBP < 80 mmHg). Prospectively, HRV and hemodynamic data of 19 patients were studied. Relative low frequency (LF), relative high frequency (HF), and LF/HF ratio were analyzed. Results:Retrospective analysis of HRV showed a significantly higher sympathetic and lower parasympathetic drive in the groups with moderate and severe compared with mild hypotension before SAB (median, 25th/75th percentiles): LF/HF: mild: 1.2 (0.9/1.8), moderate: 2.8 (1.8/4.6), P < 0.05 versus mild; severe: 2.7 (2.0/3.5), P < 0.05 versus mild. Results were confirmed by findings of LF and HF. Prospectively, patients were grouped according to LF/HF before SAB: low-LF/HF: 1.5 (1.1/2.0) versus high-LF/HF: 4.0 (2.8/4.7), P < 0.05; low-LF: 58 ± 9% versus high-LF: 75 ± 10%, P < 0.05; low-HF: 41 ± 10% versus high-HF: 25 ± 10%, P < 0.05. High-risk patients had a significantly lower SBP after SAB (76 ± 21 vs. 111 ± 12 mmHg; P < 0.05). Conclusions:Retrospectively analyzed HRV of patients scheduled to undergo elective cesarean delivery during SAB showed significant differences depending on the severity of hypotension after SAB. Preliminary findings were prospectively confirmed. High LF/HF before SAB predicted severe hypotension. Preoperative HRV analysis may detect patients at risk of hypotension after SAB.

A comparison of the Nexfin® and transcardiopulmonary thermodilution to estimate cardiac output during coronary artery surgery

The newly introduced Nexfin® device allows analysis of the blood pressure trace produced by a non‐invasive finger cuff. We compared the cardiac output derived from the Nexfin and PiCCO, using transcardiopulmonary thermodilution, during cardiac surgery. Forty patients with preserved left ventricular function undergoing elective coronary artery bypass graft surgery were studied after induction of general anaesthesia and until discharge to the intensive care unit. There was a significant correlation between Nexfin and PiCCO before (r2 = 0.81, p < 0.001) and after (r2 = 0.56, p < 0.001) cardiopulmonary bypass. Bland–Altman analysis demonstrated the mean bias of Nexfin to be −0.1 (95% limits of agreement −0.6 to +0.5, percentage error 23%) and −0.1 (−0.8 to +0.6, 26%) l.min−1.m−2, before and after cardiopulmonary bypass, respectively. After a passive leg‐raise was performed, there was also good correlation between the two methods, both before (r2 = 0.72, p < 0.001) and after (r2 = 0.76, p < 0.001) cardiopulmonary bypass. We conclude that the Nexfin is a reliable method of measuring cardiac output during and after cardiac surgery.

Influence of increased intra-abdominal pressure on fluid responsiveness predicted by pulse pressure variation and stroke volume variation in a porcine model.

Objective:Dynamic variables of fluid responsiveness such as pulse pressure variation (PPV) and stroke volume variation (SVV) have been shown to reliably predict the response to fluid administration in different patient populations. The influence of increased intra-abdominal pressure (IAP) on the predictive ability of these variables is currently under debate. Therefore, the present study was designed to evaluate whether PPV and SVV are suitable for predicting fluid responsiveness during elevated IAP. Design:Prospective controlled experimental study. Setting:Animal research laboratory. Subjects:14 anesthetized and mechanically ventilated pigs. Interventions:Pigs were studied at different experimental stages: normovolemia at baseline conditions, after induction of pneumoperitoneum (PP) by increasing IAP up to 25 mm Hg, followed by releasing PP and performing a fluid load with 1000 cc hydroxyl-ethyl starch 6%, and finally after inducing PP again. Cardiac output, stroke volume, central venous pressure, and pulmonary artery occlusion pressure were obtained by pulmonary artery thermodilution. Additionally, global end-diastolic volume (GEDV) was measured by transpulmonary thermodilution. PPV and SVV were monitored continuously by pulse contour analysis. Measurements and Main Results:PP induced significant changes in peak airway pressure, esophageal pressure, chest wall compliance, SVV, PPV, central venous pressure, and pulmonary artery occlusion pressure independent of loading conditions. As assessed by receiver operating characteristic curve analysis, PPV, SVV, and GEDV accurately predicted fluid responsiveness before IAP was increased (area under the curve: 0.90, 0.91 and 0.91). A PPV value of ≥11.5%, a SVV value of ≥9.5%, and a GEDV value of ≤963 mL accurately predicted an increase in stroke volume ≥15%. After increasing IAP, the ability of SVV to predict fluid responsiveness was abolished, whereas it was preserved with both PPV and GEDV, although the threshold value for PPV dramatically increased up to ≥20.5%. Conclusions:In this animal model PPV and GEDV proved to be sensitive and specific predictors of fluid responsiveness even during increased IAP.

A Comparison of the Laryngeal Tube with the Laryngeal Mask Airway During Routine Surgical Procedures

The laryngeal mask airway (LMA; Laryngeal Mask Company, Henley-on-Thames, UK) is an established airway device, whereas the laryngeal tube (LT) is relatively new and therefore not as well investigated. Therefore, the purpose of the present prospective, randomized, controlled trial was to compare the LT with the LMA in routine clinical practice. In 50 patients undergoing general anesthesia for minor routine surgery, standardized anesthesia was induced and maintained with alfentanil and propofol. Patients were randomized to controlled ventilation (fraction of inspired oxygen = 0.4; fraction of inspired nitrous oxide = 0.6; tidal volume = 7 mL/kg; respiratory rate = 10 breaths/min) with the LT (n = 25) or the LMA (n = 25). Oxygen saturation was recorded before the induction of anesthesia and after the administration of oxygen. After 2 and 10 min of ventilation with the LT or LMA, oxygen saturation, end-expiratory carbon dioxide, expiratory tidal volume, and peak airway pressure were recorded. Capillary blood gas samples were taken before the induction of anesthesia and after 10 min of ventilation. Time of insertion and airway leak pressure of each device were measured. The time of insertion was comparable with both devices (LT versus LMA, median 21 s versus 19 s;P = not significant). Blood gas samples and ventilation variables revealed sufficient ventilation and oxygenation with either device (P = not significant). Peak airway pressure (LT, 17 ± 3 cm H2O; LMA, 15 ± 3 cm H2O) and airway leak pressure (LT, 36 ± 3 cm H2O; LMA, 22 ± 3 cm H2O) were significantly (P < 0.05) higher when using the LT compared with the LMA. In conclusion, using the LT and LMA resulted in comparable ventilation and oxygenation variables in this model of ASA physical status I and II patients undergoing routine surgical procedures. The newly developed LT may be a simple alternative device to secure the airway.

A comparison of the intubating laryngeal mask airway and the Bonfils intubation fibrescope in patients with predicted difficult airways

Tracheal intubation with the intubating laryngeal mask airway or the Bonfils intubation fibrescope was performed in 80 patients with predicted difficult airways. Mallampati score, thyromental distance, mouth opening and mobility of the atlanto‐occipital joint were used to predict difficult airways. The overall success rate, time to the first adequate lung ventilation and time taken for the successful placement of the tracheal tube were recorded, as well as a subjective assessment of the handling of the device and the incidence of postoperative sore throat and hoarseness. The median [range] time to the first adequate ventilation was significantly shorter with the intubating laryngeal mask airway than with the Bonfils intubation fibrescope (28 [6–85] s vs. 40 [23–77] s, p < 0.005). Tracheal intubation was significantly slower with the intubating laryngeal mask airway than with the Bonfils intubation fibrescope (76 [45–155] s vs. 40 [23–77] s, p < 0.0001. Patients in the Bonfils group suffered less sore throat and hoarseness than those in the other group.

Reduced α1- and β2-adrenoceptor-mediated positive inotropic effects in human end-stage heart failure

1 α1‐Adrenoceptor (phenylephrine in the presence of propranolol) and β2‐adrenoceptor (fenoterol)‐mediated positive inotropic effects were investigated in human ventricular preparations isolated from five nonfailing (prospective organ donors) and from eight explanted failing hearts with end‐stage idiopathic dilative cardiomyopathy (NYHA IV). 2 For comparison, the nonselective β‐adrenoceptor agonist isoprenaline, the phosphodiesterase (PDE) inhibitor 3‐isobutyl‐1‐methylxanthine (IBMX), the cardiac glycoside dihydroouabain, and calcium were studied. 3 Furthermore, the influence of IBMX on adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) PDE activity as well as total β‐adrenoceptor density, β1‐ and β2‐adrenoceptor subtype distribution, and α1‐adrenoceptor density were compared in nonfailing and failing human heart preparations. The radioligands (−)‐[125I]‐iodocyanopindolol for β‐adrenoceptor binding and [3H]‐prazosin for α1‐adrenoceptor binding were used. 4 The inotropic responses to calcium and dihydroouabain in failing human hearts were unchanged, whereas the maximal α1‐ and β2‐adrenoceptor‐mediated positive inotropic effects were greatly reduced. The inotropic effects of the other cyclic AMP increasing compounds, i.e. isoprenaline and IBMX, were also reduced to about 60% of the effects observed in nonfailing controls. The potency of these compounds was decreased by factors 4–10. 5 The basal PDE activity and the PDE inhibition by IBMX were similar in nonfailing and failing preparations. 6 The total β‐adrenoceptor density in nonfailing hearts was about 70 fmol mg−1 protein. In failing hearts the total number of β‐adrenoceptors was markedly reduced by about 60%. The β1/β2‐adrenoceptor ratio was shifted from about 80/20% in nonfailing to approximately 60/40% in failing hearts which was due to a selective reduction of β1‐adrenoceptors. The β2‐adrenoceptor population remaining unchanged. α1‐Adrenoceptor density was increased from about 4 fmol mg−1 protein in nonfailing to 10 fmol mg−1 protein in failing hearts. 7 Changes in PDE activity and adrenoceptor downregulation cannot completely explain the reduced positive inotropic effects of α1‐ and β2‐adrenoceptor agonists in failing human hearts. This supports the hypothesis that impairment of other processes such as the coupling between receptor and effector system, i.e. the respective G‐proteins, are equally important in end‐stage heart failure.

Heart Rate Variability–guided Prophylactic Treatment of Severe Hypotension after Subarachnoid Block for Elective Cesarean Delivery

Background: Baseline low-to-high frequency ratio (LF/HF) of heart rate variability predicted hypotension after subarachnoid block (SAB). LF/HF-guided treatment of hypotension with vasopressors or colloids was investigated. Methods: In 80 women scheduled to undergo cesarean delivery during SAB, LF/HF and systolic blood pressure (SBP) were analyzed. Patients were randomly assigned to a control group (n = 40) or a treatment group (n = 40). Control patients were assigned by their baseline LF/HF to one of two subgroups: LF/HF less than 2.5 or LF/HF greater than 2.5. Treatment patients with baseline LF/HF greater than 2.5 were treated with vasopressor infusion right after SAB (n = 20) or colloid prehydration until LF/HF decreased below 2.5 (n = 20). The incidences of hypotension (SBP < 80 mmHg) and hypertension (SBP > 140 mmHg) were investigated. LF/HF is presented as median and range, and SBP is presented as mean ± SD. Results: Three of 17 control patients with low baseline LF/HF (1.7 [1.3/1.8]) demonstrated hypotension, and mean SBP remained stable (lowest SBP = 105 ± 14 mmHg). In contrast, 20 of 23 control patients with high baseline LF/HF (3.8 [3.3/4.8]; P < 0.0001 vs. low baseline LF/HF) demonstrated hypotension after SAB: lowest SBP = 78 ± 15 mmHg (P < 0.0001 vs. lowest SBP of control group with low baseline LF/HF). LF/HF-guided vasopressor therapy prevented hypotension in 19 of 20 patients: baseline SBP = 123 ± 15 mmHg, lowest SBP = 116 ± 17 mmHg. Mean prophylactic colloid infusion of 1,275 ± 250 ml reduced elevated baseline LF/HF from 5.4 (4.1/7.5) to 1.3 (0.8/1.59) (P < 0.0001). Hypotension was prevented in 17 of 20 patients: baseline SBP = 115 ± 13 mmHg, lowest SBP = 104 ± 19 mmHg. No hypertensive episode was recognized. Conclusions: LF/HF may be a tool to guide prophylactic therapy of patients at high risk for hypotension after SAB. Vasopressor therapy tended to be more effective compared with colloid prehydration.