4-Chloro-m-cresol is a Trigger of Malignant Hyperthermia in Susceptible Swine

1999 ◽  
Vol 90 (6) ◽  
pp. 1733-1740. ◽  
Author(s):  
Frank Wappler ◽  
Jens Scholz ◽  
Marko Fiege ◽  
Kerstin Kolodzie ◽  
Christiana Kudlik ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Malignant Hyperthermia ◽  
Carbon Dioxide Concentration ◽  
Central Venous ◽  
Mechanically Ventilated ◽  
Oxygen Fraction ◽  
Animal Care ◽  
Inspired Oxygen

Background 4-Chloro-m-cresol (4-CmC) induces marked contractures in skeletal muscle specimens from individuals susceptible to malignant hyperthermia (MHS). In contrast, 4-CmC induces only small contractures in specimens from normal (MHN) patients. 4-CmC is a preservative within a large number of commercially available drug-preparations (e.g., insulin, heparin, succinylcholine), and it has been suggested that 4-CmC might trigger malignant hyperthermia. This study was designed to investigate the effects of 4-CmC in vivo and in vitro in the same animals. Methods After approval of the animal care committee, six Pietrain MHS and six control (MHN) swine were anesthetized with azaperone 4 mg/kg intramuscularly and metomidate 10 mg/kg intraperitoneally. After endotracheal intubation, lungs were mechanically ventilated (inspired oxygen fraction 0.3) and anesthesia was maintained with etomidate 2.5 mg x kg(-1) x h(-1) and fentanyl 50 microg x kg(-1) x h(-1). Animals were surgically prepared with arterial and central venous catheters for measurement of hemodynamic parameters and to obtain blood samples. Before exposure to 4-CmC in vivo, muscle specimens were excised for in vitro contracture tests with 4-CmC in concentrations of 75 and 200 microM. Subsequently, pigs were exposed to cumulative administration of 3, 6, 12, 24, and 48 mg/kg 4-CmC intravenously. If an unequivocal episode of malignant hyperthermia occurred, as indicated by venous carbon dioxide concentration > or = 70 mmHg, pH < or = 7.25, and an increase of temperature > or = 2 degrees C, the animals were treated with dantrolene, 3.5 mg/kg. Results All MHS swine developed malignant hyperthermia after administration of 4-CmC in doses of 12 or 24 mg/kg. Venous carbon dioxide concentration significantly increased and pH significantly decreased. Temperature increased in all MHS animals more than 2 degrees C. Blood lactate concentrations and creatine kinase levels were significantly elevated. All MHS swine were treated successfully with dantrolene. In contrast, no MHN swine developed signs of malignant hyperthermia. After receiving 4-CmC in a concentration of 48 mg/kg, however, all MHN animals died by ventricular fibrillation. The in vitro experiments showed that both concentrations of 4-CmC produced significantly greater contractures in MHS than in MHN specimens. Conclusions 4-CmC is in vivo a trigger of malignant hyperthermia in swine. However, the 4-CmC doses required for induction of malignant hyperthermia were between 12 and 24 mg/kg, which is about 150-fold higher than the 4-CmC concentrations within clinically used preparations.

scholarly journals Effects of Theophylline on Anesthetized Malignant Hyperthermia-Susceptible Pigs

2011 ◽  
Vol 2011 ◽  
pp. 1-4
Author(s):  
Marko Fiege ◽  
Ralf Weisshorn ◽  
Kerstin Kolodzie ◽  
Frank Wappler ◽  
Mark U. Gerbershagen
Keyword(s):  
Malignant Hyperthermia ◽  
Body Core Temperature ◽  
Central Venous ◽  
Blood Concentrations ◽  
Malignant Hyperthermia Susceptible ◽  
Body Core ◽  
Genetically Determined ◽  
In Vivo Effects

Background. Theophylline was shown to induce contracture development in porcine malignant hyperthermia (MH) susceptible (MHS) skeletal muscles in vitro. The purpose of the current study was to investigate the in vivo effects of theophylline in MHS and MH normal (MHN) swine.Methods. MH-trigger-free general anesthesia was performed in MHS and MHN swine. Theophylline was administered intravenously in cumulative doses up to 93.5 mg⋅kg-1. The clinical occurrence of MH was defined by changes of central-venous pCO2, central-venous pH, and body core temperature.Results. Theophylline induced comparable clinical alterations in the anesthetized MHS and MHN swine, especially in regard to hemodynamic data. No pig developed hypermetabolism and/or MH according to defined criteria. All animals died with tachycardia followed by ventricular fibrillation.Conclusions. The cumulative theophylline doses used in this study were much higher than doses used therapeutically in humans, as demonstrated by measured blood concentrations. Theophylline is thus not a trigger of MH in genetically determined swine.

4-Chloro-m-cresol Triggers Malignant Hyperthermia in Susceptible Swine at Doses Greatly Exceeding Those Found in Drug Preparations

1999 ◽  
Vol 90 (6) ◽  
pp. 1723-1732. ◽  
Author(s):  
Paul A. Iaizzo ◽  
Brooks A. Johnson ◽  
Kaoru Nagao ◽  
William J. Gallagher
Keyword(s):  
Malignant Hyperthermia ◽  
Blood Chemistry ◽  
Response Curves ◽  
End Tidal ◽  
In Vivo Effects ◽  
Higher Doses ◽  
End Tidal Co2 ◽  
Cardiovascular Reactions

Background Chlorocresols are used as preservatives in numerous commercial drugs that have been shown to induce myoplasmic Ca2+ release; the most potent isoform is 4-chloro-m-cresol. The aims of this study were to (1) examine the in vivo effects of 4-chloro-m-cresol on swine susceptible to malignant hyperthermia and (2) contrast in vivo versus in vitro dose-response curves. Methods Susceptible swine (weight: 38.5 kg+/-3.55 kg) were anesthetized and monitored for variations in physiological responses, including end-tidal CO2, heart rate, blood pressure, blood chemistry, and temperatures. In the first animals studied, 4-chloro-m-cresol, at equivalent cumulative doses of 0.14, 0.28, 0.57, 1.14, 2.27, 4.54, and 9.08 mg/kg (n = 3; 12.5, 25, 50, 100, 200, 400, and 800 micromol) were administered, and in a second group, larger doses were used: 1.14, 3.41, 7.95, 17.04 (n = 4), and/or 35.22 (n = 1) mg/kg (100, 300, 700, 1,500, and/or 3,100 micromol). For comparison, in vitro rectus abdominis muscle preparations obtained from normal and susceptible swine were exposed to 4-chloro-m-cresol, at cumulative concentrations of 6.25, 12.5, 25, 50, 100, 200, 400, 800, and 1,600 micromol; standard caffeine and halothane contracture testing was also performed. Results Episodes of malignant hyperthermia were not triggered in response to administration of low doses of 4-chloro-m-cresol, but transient cardiovascular reactions (e.g., tachycardia, arrhythmias, and hypotension) were observed. Subsequently, episodes in these animals were triggered when halothane (0.87; 1 MAC) and succinylcholine (2 mg/kg) were given. Animals administered the higher doses of 4-chloro-m-cresol all had fulminant episodes of malignant hyperthermia that were fatal, when equivalent cumulative concentrations were greater than 1,500 micromol. The levels of 4-chloro-m-cresol in the plasma rapidly decreased: e.g., 5 min postadministration of the 1,500-micromol dose, the mean plasma level was only 52+/-18 micromol (n = 4). Hemolysis was detected following 4-chloro-m-cresol administration at concentrations > 200 micromol. In vitro, muscle from susceptible animals elicited contractures > 200 mg at 50-micromol bath concentrations of 4-chloro-m-cresol (n = 29), whereas normal muscle did not elicit such contractures until bath concentrations were > 800 micromol (n = 10). Conclusions 4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine, but only when serum concentrations are far above those likely to be encountered in humans. A relatively low concentration of 4-chloro-m-cresol, 50 micromol, is sufficient to activate sarcoplasmic [Ca+2] release in vitro (e.g., contractures); this same bolus dose administered in vivo (0.57 mg/kg) has minimal effects due to the rapid decrease in its plasma levels.

Differential Effects of Halothane and Thiopental on Surfactant Protein C Messenger RNA  In Vivo and  In Vitro in Rats 

2000 ◽  
Vol 93 (3) ◽  
pp. 805-810 ◽  
Author(s):  
Catherine Paugam-Burtz ◽  
Serge Molliex ◽  
Bernard Lardeux ◽  
Corinne Rolland ◽  
Michel Aubier ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Protein C ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Type Ii Cells ◽  
Mechanically Ventilated ◽  
Mrna Content

Background Pulmonary surfactant is a complex mixture of proteins and phospholipids synthetized by alveolar type II cells. Volatile anesthetics have been shown to reduce surfactant phospholipid biosynthesis by rat alveolar type II cells. Surfactant-associated protein C (SP-C) is critical for the alveolar surfactant functions. Our goal was to evaluate the effects of halothane and thiopental on SP-C messenger RNA (mRNA) expression in vitro in rat alveolar type II cells and in vivo in mechanically ventilated rats. Methods In vitro, freshly isolated alveolar type II cells were exposed to halothane during 4 h (1, 2, 4%) and 8 h (1%), and to thiopental during 4 h (10, 100 micrometer) and 8 h (100 micrometer). In vivo, rats were anesthetized with intraperitoneal thiopental or inhaled 1% halothane and mechanically ventilated for 4 or 8 h. SP-C mRNA expression was evaluated by ribonuclease protection assay. Results In vitro, 4-h exposure of alveolar type II cells to thiopental 10 and 100 micrometer increased their SP-C mRNA content to 145 and 197%, respectively, of the control values. In alveolar type II cells exposed for 4 h to halothane 1, 2, and 4%, the SP-C mRNA content increased dose-dependently to 160, 235, and 275%, respectively, of the control values. In vivo, in mechanically ventilated rats, 4 h of halothane anesthesia decreased the lung SP-C mRNA content to 53% of the value obtained in control (nonanesthetized, nonventilated) animals; thiopental anesthesia increased to 150% the lung SP-C mRNA content. Conclusions These findings indicate that halothane and thiopental used at clinically relevant concentrations modulate the pulmonary SP-C mRNA content in rats. In vivo, the additive role of mechanical ventilation is suggested.

scholarly journals Oxygen and Carbon Dioxide Transport Characteristics of the Blood of the Nile Monitor Lizard (Varanus Niloticus)

1987 ◽  
Vol 130 (1) ◽  
pp. 27-38
Author(s):  
JAMES W. HICKS ◽  
ATSUSHI ISHIMATSU ◽  
NORBERT HEISLER
Keyword(s):  
Carbon Dioxide ◽  
Haemoglobin Concentration ◽  
Oxygen Affinity ◽  
Total Blood ◽  
Carbon Dioxide Transport ◽  
Monitor Lizard ◽  
The Right ◽  
Dissociation Curves

Oxygen and carbon dioxide dissociation curves were constructed for the blood of the Nile monitor lizard, Varanus niloticus, acclimated for 12h at 25 and 35°C. The oxygen affinity of Varanus blood was low when Pco2 w a s in the range of in vivo values (25°C: P50 = 34.3 at PCOCO2 = 21 mmHg; 35°C: P50 = 46.2 mmHg at PCOCO2 = 35 mmHg; 1 mmHg = 133.3 Pa), and the oxygen dissociation curves were highly sigmoidal (Hill's n = 2.97 at 25°C and 3.40 at 35°C). The position of the O2 curves was relatively insensitive to temperature change with an apparent enthalpy of oxygenation (ΔH) of −9.2kJ mol−1. The carbon dioxide dissociation curves were shifted to the right with increasing temperature by decreasing total CCOCO2 at fixed PCOCO2, whereas the state of oxygenation had little effect on total blood CO2 content. The in vitro buffer value of true plasma (Δ[HCO3−]pl/-ΔpHpl) rose from 12.0 mequiv pH−1−1 at 25°C to 17.5 mequiv pH−11−1 at 35°C, reflecting a reversible increase of about 30% in haemoglobin concentration and haematocrit levels during resting conditions in vivo.

Carbon dioxide inhalation causes pulmonary inflammation

2009 ◽  
Vol 296 (4) ◽  
pp. L657-L665 ◽  
Author(s):  
Mohammad Abolhassani ◽  
Adeline Guais ◽  
Philippe Chaumet-Riffaud ◽  
Annie J. Sasco ◽  
Laurent Schwartz
Keyword(s):  
Carbon Dioxide ◽  
Nuclear Translocation ◽  
Rnase Protection Assay ◽  
Airway Hyperreactivity ◽  
Cellular Respiration ◽  
Rnase Protection ◽  
Monocyte Chemoattractant Protein 1 ◽  
Enhanced Production

The aim of this study was to assess whether one of the most common poisons of cellular respiration, i.e., carbon dioxide, is proinflammatory. CO2 is naturally present in the atmosphere at the level of 0.038% and involved in numerous cellular biochemical reactions. We analyzed in vitro the inflammation response induced by exposure to CO2 for 48 h (0–20% with a constant O2 concentration of 21%). In vivo mice were submitted to increasing concentrations of CO2 (0, 5, 10, and 15% with a constant O2 concentration of 21%) for 1 h. The exposure to concentrations above 5% of CO2 resulted in the increased transcription (RNase protection assay) and secretion (ELISA) of proinflammatory cytokines [macrophage inflammatory protein-1α (MIP-1α), MIP-1β, MIP-2, IL-8, IL-6, monocyte chemoattractant protein-1, and regulated upon activation, normal T cell expressed, and, presumably, secreted (RANTES)] by epithelial cell lines HT-29 or A549 and primary pulmonary cells retrieved from the exposed mice. Lung inflammation was also demonstrated in vivo by mucin 5AC-enhanced production and airway hyperreactivity induction. This response was mostly mediated by the nuclear translocation of p65 NF-κB, itself a consequence of protein phosphatase 2A (PP2A) activation. Short inhibiting RNAs (siRNAs) targeted toward PP2Ac reversed the effect of carbon dioxide, i.e., disrupted the NF-κB activation and the proinflammatory cytokine secretion. In conclusion, this study strongly suggests that exposure to carbon dioxide may be more toxic than previously thought. This may be relevant for carcinogenic effects of combustion products.

scholarly journals Hematologic changes in propofol-anesthetized dogs with or without tramadol administration

2013 ◽  
Vol 65 (5) ◽  
pp. 1306-1312 ◽  
Author(s):  
P.F. Costa ◽  
N. Nunes ◽  
E.A. Belmonte ◽  
J.V. Moro ◽  
P.C.F. Lopes
Keyword(s):  
Blood Cells ◽  
Early Postoperative Period ◽  
Control Group ◽  
Anesthesia Induction ◽  
Monocyte Count ◽  
Mechanically Ventilated ◽  
Oxygen Fraction ◽  
Anesthetized Dogs ◽  
Inspired Oxygen ◽  
Rate Infusion

Drugs commonly used in anesthesia practice may significantly alter the oxidative state of blood cells. This mechanism could contribute to the immune suppression that occurs transiently in the early postoperative period. Thus, we assessed the effects of continuous rate infusion (CRI) of propofol associated or not with tramadol on hematologic parameters in dogs. Eight adult mongrel dogs were anesthetized on 2 occasions, 15 d apart. Two groups were formed: control group (CG) and tramadol group (GT). Propofol was used for induction (10mg kg-1) followed by a CRI (0.7mg kg-1minute-1). The animals were positioned in lateral recumbency and mechanically ventilated with inspired oxygen fraction of 0.6. In TG, tramadol (2mg kg-1) followed by a CRI (0.5mg kg-1minute-1) was administered in dogs. In the CG the sodium chloride (NaCl) solution at 0.9% was administered followed by its CRI, in the same volume that was used in TG. The measurement was taken before anesthesia induction (Tbasal), 30 minutes after induction (T0) and then at 30-minute intervals (T30 to T60). Red blood cells, hematocrit, hemoblogin concentration and total leukocytes count decreased from T0 in both groups. In TG, lymphocytes count at Tbasal [1.86 (0.82) x103µl-1] was greater than at T0, T30 and T60 [0.96(0.50), 0.92(0.48) and 0.95(0.48) x103µl-1, respectively]. No significant differences were observed for platelets neutrophil, eosinophil, basophil and monocyte count. In dogs, propofol-anesthesia associated or not with tramadol promoted decrease in blood cell count and should be used with caution in immunossupressed patients.

scholarly journals Impact of statin intake on malignant hyperthermia: an in vitro and in vivo swine study

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Asensio Gonzalez ◽  
Tinen L. Iles ◽  
Paul A. Iaizzo ◽  
Oliver Bandschapp
Keyword(s):  
Malignant Hyperthermia ◽  
Clinical Presentation ◽  
Sevoflurane Anesthesia ◽  
Short Term ◽  
Simvastatin Treatment ◽  
Simvastatin Therapy ◽  
Diagnostic Sensitivity And Specificity ◽  
Masseter Spasm

Abstract Background Statin intake is associated with muscular side effects, among which the unmasking of latent myopathies and of malignant hyperthermia (MH) susceptibility have been reported. These findings, together with experimental data in small animals, prompt speculation that statin therapy may compromise the performance of skeletal muscle during diagnostic in vitro contracture tests (IVCT). In addition, statins might reduce triggering thresholds in susceptible individuals (MHS), or exacerbate MH progression. We sought to obtain empirical data to address these questions. Methods We compared the responses of 3 different muscles from untreated or simvastatin treated MHS and non-susceptible (MHN) pigs. MHS animals were also invasively monitored for signs of impending MH during sevoflurane anesthesia. Results Muscles from statin treated MHS pigs responded with enhanced in vitro contractures to halothane, while responses to caffeine were unaltered by the treatment. Neither agent elicited contractures in muscles from statin treated MHN pigs. In vivo, end- tide pCO2, hemodynamic evolution, plasma pH, potassium and lactate concentrations consistently pointed to mild acceleration of MH development in statin-treated pigs, whereas masseter spasm and rigor faded compared to untreated MHS animals. Conclusions The diagnostic sensitivity and specificity of the IVCT remains unchanged by a short-term simvastatin treatment in MHS swine. Evidence of modest enhancement in cardiovascular and metabolic signs of MH, as well as masked pathognomonic muscle rigor observed under simvastatin therapy suggest a potentially misleading influence on the clinical presentation of MH. The findings deserve further study to include other statins and therapeutic regimes.

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