case scenario - increased end-tidal carbon dioxide

EDUCATION Anesthesiology 2010; 112:440–6

Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins

Bruno Riou, M.D., Ph.D., Editor

Case Scenario: Increased End-tidal Carbon Dioxide

A Diagnostic Dilemma

Timothy J. Tautz, M.D.,* Albert Urwyler, M.D.,† Joseph F. Antognini, M.D.‡

MONITORING of end-tidal carbon dioxide is one ofthe most important means of determining the physi-

ologic well-being of anesthetized patients. Exhaled carbondioxide, both in terms of its quantity and pattern, providesdetailed information on the cardiopulmonary system. Manythings must occur for the exhaled carbon dioxide tracing toappear normal (fig. 1). This hypothetical case acts as a springboard to a discussion of the differential diagnosis of a rapidlyrising exhaled carbon dioxide concentration, with specialemphasis on malignant hyperthermia (MH).

Case ReportA 55-yr-oldmanwas scheduled to have incision and drainageof a large thigh abscess during general anesthesia. He admit-ted to extensive substance abuse, including alcohol, tobacco,methamphetamines, and cocaine. He inhaled an unknownquantity of methamphetamines 12 h before his arrival in theoperating room. He denied family or personal problems withanesthesia. He did not take anymedications. He did not haveany history of cardiac or pulmonary disease. He weighed 77kg and was 189-cm tall. His preoperative blood pressure was145/85 mmHg, and his resting heart rate was 85 beats/min.His tympanic membrane temperature was 37.8°C. Twohundred milligrams of propofol was administered intrave-nously followed by 50 mg of rocuronium. The trachea wasintubated with an 8.0-mm endotracheal tube. Chest auscul-tation revealed equal bilateral breath sounds. Mechanicalventilation was initiated with tidal volume � 600 ml and 12

breaths/min. Sevoflurane was started at 2.5% on the vapor-izer. Thirty minutes after induction of anesthesia, and 10min after the surgery had begun, the end-tidal carbon diox-ide was 35 mmHg; end-tidal sevoflurane was 2.2%. Over thenext 30 min, the end-tidal carbon dioxide increased from 35to 45 mmHg, accompanied by a slight increase in heart ratefrom 95 to 105 beats/min. Nasopharyngeal temperature was38.9°C. The increasing end-tidal carbon dioxide, heart rate,and temperature suggested a physiologic perturbation thatrequired immediate attention and investigation.

A thorough check of the anesthesia machine and circuit re-vealed no leaks. Inspiratory pressures were 15 cm H2O, andchest auscultation demonstrated equal breath sounds with nowheezing; chest excursion with each breath seemed adequateand appropriate for the tidal volume. The ventilation rate wasincreased to15 breaths/min. Despite the change in ventilation,the end-tidal carbondioxide continued to increase to 60mmHgover 5 min. Heart rate was 110 beats/min.

Antibiotics (1 g of cephazolin and 100 mg of gentamicin)were administered in response to surgical manipulation ofthe abscess and possible bacterial seeding into the blood-stream, but end-tidal carbon dioxide continued to increaseand was 65 mmHg despite a further increase in minute ventila-tion (tidal volume, 900 ml; rate, 20 breaths/min). The electro-cardiogram showed sinus tachycardia with normal T waves.There did not seem to be anymuscle rigidity, but after placing aurinary catheter to follow urine output, the urine was observedto be dark. A urine dipstick test was positive for hemoglobin ormyoglobin.Amuscle twitchmonitor (electrodes placedover theulnar nerve) demonstrated only one twitch in a train-of-fourstimulation. An arterial blood gas analysis showed pH � 7.13,PaCO2 � 73 mmHg, PaO2 � 225 mmHg, O2 saturation �99%, HCO3

� � 19 mEq/l, and K� � 5.0 mEq/l. The end-tidal carbon dioxide was 67 mmHg at the time of the blood gassampling. The creatine kinase was 1200 IU/l, and the partialthromboplastin time was normal.

Diagnosis of Increasing End-tidal CarbonDioxideCarbon dioxide is produced in cells, and after diffusing intothe blood, it is transported to the lung for excretion. The

* Associate Professor, ‡ Professor, Department of Anesthesiologyand Pain Medicine, University of California, Davis. † Professor, De-partment of Anesthesiology, University of Basel, Basel, Switzerland.

Received from Department of Anesthesiology, University of Cal-ifornia, Davis, Davis, California. Submitted for publication July 29,2009. Accepted for publication November 10, 2009. Support wasprovided solely from institutional and/or departmental funds.

Address correspondence to Dr. Antognini: Department of Anes-thesiology, TB-170, University of California, Davis, Davis, California95616. [email protected]. Information on purchasing reprintsmay be found at www.anesthesiology.org or on the masthead pageat the beginning of this issue. ANESTHESIOLOGY’s articles are madefreely accessible to all readers, for personal use only, 6 months fromthe cover date of the issue.

Anesthesiology, V 112 • No 2 440 February 2010

differential diagnosis of increased end-tidal carbon dioxide islong but can be separated into two categories: decreased ex-cretion or increased production. The causes of decreased ex-cretion can be further divided into increased inspired carbondioxide, decreased ventilation, and increased dead space. In-creased production can have many causes, as shown in table1, and is discussed later. Furthermore, there are iatrogeniccauses, such as carbon dioxide insufflation during laparos-copy, tourniquet release, and treatment of acidosis with bi-carbonate. In addition, the clinician must always considerthe possibility of a monitor malfunction, a calibration error,or a gas supply switch.2 Whenever there is an unexplainedincrease in end-tidal carbon dioxide (�10–20% above base-line) and it does not respond to appropriate measures (e.g.,increased ventilation and additional anesthesia), the clinician

should consider obtaining an arterial blood gas and electro-lyte analysis.

Problems with the anesthesiamachine can cause increasedexpired carbon dioxide by increasing inspired carbon diox-ide. Exhausted soda lime, channeling through the soda lime,or a faulty inspiratory or expiratory valve might increase theend-tidal carbon dioxide level. Under normal patient condi-tions, carbon dioxide absorbents will last several hours, butthere is substantial variation. Although dye indicators canhelp determine remaining capacity, these can be inaccurate.Channeling is difficult to detect but could be treated in thesame way as in the case of exhausted soda lime, that is, byreplacement. A faulty valve in the circle system can be ob-served and replaced if needed. All these causes would result inincreased inspired carbon dioxide, although careful inspec-

Fig. 1. End-tidal carbon dioxide (CO2) tracings. A normal tracing is shown in the center, whereas examples of increased end-tidal carbondioxide are shown around it. There are several causes for increased expired carbon dioxide, but these can be separated based on whether theinspired carbon dioxide level is increased or whether there is a delayed upstroke (indicating high resistance), as would be seen with mucousplugging or bronchospasm. When only the end-tidal carbon dioxide is increased (no inspired carbon dioxide and no delayed upstroke) thenexternal and patient causes must be explored. However, a low inspired carbon dioxide tracing does not exclude the possibility of rebreathing.The clinician must also consider the possibility of artifact, for example, problems with the sampling or the gas analyzer, such as calibration error.

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Tautz et al. Anesthesiology, V 112 • No 2 • February 2010

tion of the waveform is needed. Increased inspired carbondioxide was not observed on the capnograph of this patient.It is possible that the nadir of the inspired carbon dioxideconcentration could be zero, but that some of the inspired gashas carbon dioxide in it, although this would not likely leadto a markedly increased end-tidal carbon dioxide.

Inadequate ventilation would also lead to increased car-bon dioxide partial pressure. Indeed, high carbon dioxidelevels will result whenever metabolic production exceeds ex-cretion. Thus, despite the fact that no changes were made tothe ventilator parameters, it is possible that something wasamiss with ventilation. There could be a leak in the circlesystem, such that part of the “tidal volume” is leaking out(e.g., a nasogastric tube placed inadvertently into the tra-chea). This leak would be large enough to decrease minuteventilation but small enough to not trigger the low-pressurealarm. Bronchospasm will impede ventilation and is usually

associated with wheezing; bronchodilators are often (but notalways) effective. Partial tube blockage, either with mucousplugging or a kink, could prevent normal ventilation, andthis would lead to increased inspiratory pressures; tubeblockage is particularly problematic during pediatric caseswhere small endotracheal tubes are used. Suctioning the en-dotracheal tube will remove secretions, but replacementmight be needed in extreme cases. Increased dead spacewould also decrease minute ventilation; causes include adultrespiratory distress syndrome.

Because there seemed to be no problem with ventilationin this patient, consideration must be given to increased car-bon dioxide production as the cause of the hypercapnia.There are numerous causes, and common things occur fre-quently. Ventilatory problems have already been ruled out.Awakening from anesthesia can increase metabolic produc-tion of carbon dioxide; however, the delivery of sevofluraneseemed adequate, and the end-tidal sevoflurane was incon-sistent with the scenario of inadequate anesthesia. Further-more, the patient received rocuronium that would minimizethe risk of light anesthesia causing muscle shivering.

Sepsis is a common cause of increased metabolism, as isfever from any cause. This patient had pathology (i.e., anabscess) that could lead to bacteremia, entry of pyrogens intothe blood stream, and fever, resulting in increased metabo-lism and carbon dioxide production. His recent history ofsubstance abuse increases the possibility of toxic drug reac-tion. For example, methamphetamines or cocaine couldcause hypermetabolism (i.e., metabolic rate above normal)and possibly rhabdomyolysis. Blood toxicology would ad-dress this possibility, although results would not be availablequickly enough to permit a fast diagnosis.

Other possible causes of increased metabolism includesurgical stress, seizures, hyperthyroidism, and burns. Al-though this patient was anesthetized, physiologic responsesto surgery (i.e., surgical stress) will result in increased metab-olism. Seizures, especially if there is marked muscle tonic-clonic activity, will markedly increase carbon dioxide pro-duction. This patient did not have tonic-clonic seizures. Thepresence of hyperthyroidism could be investigated withblood tests for thyroid hormone, although this might takeconsiderable time. The diagnosis of burns is self-evident.More rarely, a pheochromocytoma or transfusion reactionmight cause an increased metabolic rate.

Most of the diseases and situations described in the pre-ceding paragraphs would cause a nonprogressive increasedcarbon dioxide. MH is looking more likely as the cause ofthis patient’s clinical presentation, in part, because there wasa progressive increase in carbon dioxide. Although its occur-rence is rare, and there are numerous conditions that mimicit (table 1), the clinician must think of MH, because itstreatment is lifesaving and dependent on time of initiation. Aclinical grading scale has been developed, which assigns qual-itative likelihood to a clinical episode of suspected MH (table2).3,4 In this case, points would be assigned for respiratoryand muscle processes, as well as temperature increase and

Table 1. Conditions That Can Increase End-tidalCarbon Dioxide

External causesAlcohol therapy for limb arteriovenous malformationContrast dyeDrug toxicity or abuseEnvironmental heat gain more than lossExercise hyperthermiaHeat strokeVentilation problems (kinked or blocked endotracheal tube)Equipment malfunction (faulty expiratory valve)Treatment of acidosisTourniquet releaseNeuroleptic malignant syndromeCarbon dioxide insufflation

Disease relatedCystinosisHypokalemic periodic paralysisIntracranial free bloodMuscular dystrophies (Duchenne, Becker)Central core diseaseMyotoniasDiabetic comaFreeman-Sheldon syndromeHyperthyroidismOsteogenesis imperfectaPheochromocytomaPrader-Willi syndromeRhabdomyolysisSepsisKing Denborough diseaseWolf-Hirschhorn syndromeIdiopathic hyperCKemiaMalignant hyperthermia

Each of the nonmalignant hyperthermia conditions can poten-tially increase end-tidal carbon dioxide and, depending on thespecific condition, produce other signs and symptoms (such asmuscle breakdown, hyperkalemia, metabolic acidosis, and hy-perthermia) that will mimic malignant hyperthermia. The condi-tions are separated according to whether the primary cause is anexternal factor (such as drug ingestion or administration) orwhether it is related to a specific patient disease. In some cases,this distinction is not clear. Adapted from Gronert et al.1 withpermission.

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Anesthesiology, V 112 • No 2 • February 2010 Tautz et al.

possible cardiac involvement (unexplained tachycardia). Thedark urine indicates possible muscle breakdown and is an-other sign of MH. If rhabdomyolysis is suspected, aggressivetherapy is warranted to prevent kidney damage and hyperka-lemia. Although increased temperature is part of the syn-drome, it usually occurs late and the clinician must not waitfor this sign before making the diagnosis and initiating ther-apy (dantrolene). Delaying diagnosis and treatment will in-crease mortality.

Intraoperative ManagementThe sevoflurane was discontinued, and anesthesia was main-tained with remifentanil and propofol. Dantrolene (2.5 mg/kg) was administered over more than 15 min (the slow rate ofmixing and solvation prevents faster administration). Cool-ing measures were initiated, including placing iced wet tow-els on the torso. Intravenous fluids were administered at a

rapid rate, both to help cool the patient and to prevent renaldamage from rhabdomyolysis. There was a rapid resolutionof the hypercarbia, and end-tidal carbon dioxide was 25mmHg; ventilation was decreased (tidal volume, 700 ml;rate, 8 breaths/min). Nasopharyngeal temperature was37.4°C. After the surgery was completed, the patient wasawakened and extubated. Serial blood samples showed nohyperkalemia but creatine kinase peaked at 25,000 IU/L 24 hpostoperatively.

Postoperative Management

There are several issues that must be addressed when takingcare of a patient who has had a suspected episode of MH.First, the patient must be watched closely for recrudescence.Risk factors for recrudescence include muscular build, a tem-perature increase, a high score (�35) on the clinical gradingscale, and a delayed period between exposure to triggers andthe initial reaction.5 Frequent monitoring of vital signs,urine, electrolytes, and arterial blood gases should help guidemanagement. Any increases in potassium, worsening acido-sis, or resumption of hypermetabolism should prompt re-peated doses of dantrolene (1 mg/kg every 6–12 h). Becausecoagulation can be impaired as a result of the shock state,baseline clotting values (prothrombin time, partial thrombo-plastin time, and D-dimer) should be obtained. Second, be-cause ofmuscle breakdown, there is a risk of kidney damage.6

This patient should receive alkalinization of his urine anddiuretics (furosemide and mannitol) to help clear myoglobinthat might have been deposited in the renal tubules. Third,creatine kinase in blood must be determined every 6–8 huntil values begin to fall. If markedly increased, the clinicianmust be more aggressive about administering diuretic ther-apy to increase renal clearance of myoglobin. In many casesof suspected MH, creatine kinase does not increase or does soonly mildly.7 Fourth, serum electrolytes need to be moni-tored, especially potassium, because rhabdomyolysis can leadto hyperkalemia. Failure to diagnose and treat hyperkalemiacan lead to cardiac arrhythmias and death. The risk of deathfor patients with an acute MH episode ranges between 1 and17%.8,9 In unusual cases, MH can present in the immediatepostoperative period.10

This patient must be advised regarding the presumptivediagnosis of MH and that, because it is almost always aninherited disorder, family members must be told about theirrisk of having this subclinical disease. Currently, the acceptedstandard for diagnosis is the in vitro contracture test. Patientswith a high likelihood of MH given the clinical events shouldbe actively encouraged to pursue testing as the positive pre-dictive value is increased for them. Genetic testing is alsoavailable, but this has limited sensitivity because it does notdetect all genetic abnormalities that are likely to be associatedwith MH.

A patient who is suspected of having had a MH episodecan be referred to a biopsy center, of which there are 6 inNorth America (2 in Canada and 4 in the United States), 24

Table 2. Criteria Used in the Clinical GradingScale for Malignant Hyperthermia

Process Clinical Criteria Points

Muscle rigidity Generalized rigidity 15Masseter muscle rigidity 15

Musclebreakdown

Creatine kinase �10,000 units/l

Cola-colored urine 15Excess myoglobin in

urine or serum5

K� � 6 mEq/l 3Respiratory

acidosisEnd-tidal CO2 � 55

mmHg; PaCO2 � 60mmHg

15

Inappropriate tachypnea 10Temperature

increaseRapidly increasing

temperature15

Inappropriatetemperature � 38.8°C

10

Cardiacinvolvement

Unexplained sinustachycardia,ventricular

3

Tachycardia orventricular fibrillation

Family history MH history in first-degree relative

15

MH history in family, notfirst-degree relative

5

Only the highest score in any one process should be used whenmore than one event or sign occurs in a process. The morecriteria that a patient fulfills, the more likely that an MH episodehas occurred. If only one criterion is fulfilled then malignanthyperthermia is not likely, whereas malignant hyperthermia isalmost certain if all criteria are fulfilled. Other criteria to considerinclude base excess ��8 mEq/L (10 points), pH � 7.25 (10points), and rapid reversal of malignant hyperthermia signs withdantrolene therapy (5 points). The likelihood according to pointscore: 0, almost never; 3–9, unlikely; 10–19, somewhat less thanlikely; 20–34, somewhat greater than likely; 35–49, very likely; �50,almost certain. Adapted from Larach et al.3 with permission.CO2 � carbon dioxide; MH � malignant hyperthermia; PaCO2 �arterial carbon dioxide tension.

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in Europe, and 4 in Australia andNewZealand (updated listsare available).§ In general, most biopsy centers will need toreview the medical records in addition to speaking with thepatient and the anesthesiologist or anesthetist. Once this in-formation is reviewed, a decision is made regarding the ad-visability of performing the biopsy procedure. Clinical infor-mation, along with the biopsy results, can be entered into theMH registries to facilitate future data analysis.

The caffeine-halothane contracture test requires freshmuscle sample that must be obtained immediately beforetesting and therefore in close proximity to the biopsy center.The muscle sample cannot be mailed or sent by express de-livery service. The test requires a small muscle sample (2cm � 2 cm � 2 cm) obtained from the vastus lateralis. Avideo of the procedure is available for viewing.�

Like all biologic tests, contracture testing has limits on itssensitivity and specificity (the former is the ability to detectthe disorder and the latter relates to whether the test will bepositive when the disorder is not present). Usually, there is atradeoff between the two, such that increased sensitivitycomes at the expense of decreased specificity. The diagnosticthresholds were established to minimize the possibility offalse-negative results. The North American protocol has asensitivity and a specificity of 97–98% and 78–80%, respec-tively (although specific values will vary from laboratory tolaboratory).11 Thus, there is a 2% chance that contracturetesting will incorrectly mislabel a MH-susceptible individualas normal, whereas there is a 20% chance that a person with-out the disease will be labeled as susceptible.

Some clinicians question the value of the contracture testother than for research purposes. They argue that, given theless than 100% sensitivity of contracture test, a patient whotests negative still should not receive triggering agents. Thus,if testing will not change anesthetic practice, then why per-form invasive and expensive biopsy procedures? Generally, itis quite practical to give anesthesia using nontriggering anes-thetics. However, for certain patients (pediatrics, severe asth-matics, and those with difficult airways) and procedures (my-ringotomy tubes), potent inhaled anesthetics are useful.Further, the implications for family members of patients la-beled MH susceptible can become burdensome. If a singlepatient is incorrectly presumed susceptible without biopsy,what about their children and grandchildren? Biopsy centerdirectors routinely evaluate patients whose elective proce-dures were cancelled by anesthesiologists who were uncom-fortable anesthetizing them before their MH status had beenestablished by biopsy. Nevertheless, we cannot fault a clini-cian whowishes to give a nontriggering anesthetic to a personwho has had contracture testing and who is not susceptible toMH. The consensus among experts, however, is that suchpatients can safely receive triggering anesthetics.

Pathophysiologic Basis of MHMH, a pharmacogenetic disturbance of skeletal muscle, oc-curs in susceptible individuals on exposure to potent haloge-nated anesthetic vapors (sevoflurane, desflurane, isoflurane,and halothane) or the depolarizing muscle relaxant succinyl-choline.12 The reaction is characterized by skeletal musclehypermetabolism after exposure to these triggering drugs.Patients susceptible toMHexhibit uncontrolled intracellularcalcium release inmuscle, triggering large increases in aerobicand anaerobic metabolism as the muscle cells attempt tosequester unbound ionized calcium and restore homeostasis.Muscular rigidity occurs when the unbound intracellular cal-cium concentration reaches myofibrillar contractile thresh-olds. Heat production and lactic acid levels increase, initiat-ing respiratory and metabolic acidosis, whereas adenosinetriphosphate stores are depleted, which leads to increased cellpermeability. When left unchecked, rhabdomyolysis will oc-cur, which can lead to acute renal failure. Similarly, otherorgans can fail and result in death.

Therapy should be aimed at stopping the uncontrolledcalcium release by discontinuing triggering agents and ad-ministering dantrolene. Dantrolene is a skeletal muscle relax-ant that slows the release of calcium from the sarcoplasmicreticulum, permitting the cell time to reestablish homeosta-sis; it does not act at the neuromuscular junction. Once thediagnosis of MH is entertained every effort should be exertedto obtain, mix, and administer dantrolene. Hyperventila-tion, external cooling, correction of acidosis with bicarbon-ate and intravenous fluids are important but should be insti-tuted in parallel with dantrolene therapy not in place of it.

Epidemiology of MHMH in humans is a syndrome often inherited as an autoso-mally dominant trait with variable expressivity and incom-plete penetrance. Some individuals might have an episode onthe first exposure to triggering agents whereas another indi-vidual might not trigger on repeated exposures. There is re-cent evidence linking ryanodine receptor variants and quan-titative differences in phenotype, including onset time afterexposure to triggering agents.13 Because the presence of otheranesthetic drugs and exposures to low concentrations of trig-gering agents can affect the onset of a MH episode,14 it isunclear to what extent true phenotypic variation impacts thevariable clinical picture.

A primary genetic defect is in the genes that code for theryanodine receptor. The ryanodine receptor is located inskeletal muscle sacroplasmic reticulum where it functions asa calcium channel to modulate contraction and release. Ge-netic testing for MH in humans focuses on the ryanodinereceptor. There are more than 300 known mutations in theryanodine receptor.15 So far, 29 causative mutations havebeen identified in humans on chromosome 19 in the locicoding for the ryanodine receptor; however, only approxi-mately 50% of susceptible individuals have one of the knowndefects.16 Unfortunately, because of genetic complexity, the

§ www.mhaus.org and www.emhg.org. Accessed September 24,2009.

� http://medical.mhaus.org/index.cfm/fuseaction/video.display/videoId/1.cfm. Accessed September 24, 2009.



absence of mutations does not establish MH negative status.Discordance between contracture testing and genetic muta-tions occurs among families. In such cases, patients mighthave second mutations in unscreened portions of the ryano-dine receptor or a defect in another focus entirely. There maybe polymorphisms or variants that have unclear significance.There are only two certified laboratories in North Americathat perform genetic analysis for MH.# The problems notedearlier have diminished the clinical diagnostic value of ge-netic testing for MH susceptibility, although continued re-search should improve its usefulness.

Although research has focused on the ryanodine receptor,other defects have been described. For example, theCACNL1A3 gene that encodes the �-1 subunit of the skeletalmuscle dihydropyridine receptor has been implicated to playa causative role.17 In addition, calsequestrin-1 is a calcium-binding protein in skeletal muscle that, when absent, leads toMH-like episodes inmice.18 Whether this defect is present inhumans remains to be determined, but such a defect couldexplain susceptibility to MH in patients who do not haveabnormal ryanodine receptors.

In our opinion, genetic testing should be done for patientswithMHdiagnosed through contracture testing to screen fora causative mutation. If found, first-degree relatives may un-dergo screening and establish MH susceptibility if the caus-ative mutation is found, thus avoiding contracture testing. Ifno mutations are found, relatives must still undergo musclebiopsy testing to establish their status.

Plasma concentrations of creatine kinase can be increasedin patients susceptible to MH, although by itself such anelevation is not diagnostic for this disorder (e.g., it lacks spec-ificity). On the other hand, if creatine kinase is increased inan individual who has a first-degree relative who has provenMH susceptibility, then that individual may also be consid-ered to be susceptible.

Contrasts of Evaluation of MH in NorthAmerica and Europe

One of the major goals of MH research has always been thedevelopment of a reliable diagnostic screening test. Afterpublication of the increased sensitivity of skeletal muscle ofMH-susceptible individuals to caffeine or halothane or both,in vitro muscle contracture testing was introduced as a diag-nostic tool using various protocols, drugs, and drug combi-nations.19,20 This development led to the formation of twodifferent groups worldwide, the North American MHGroup and the European MH Group. Both groups createdtheir own protocols using caffeine and halothane in a slightlydifferent way. However, comparisons of both protocolsshowed more or less similar test results.21 These findings andthe aim of the individual laboratories to use their own expe-

rience for the investigation of new patients made it difficultto establish one single protocol for MH screening in theworld.

Although in vitro muscle contracture testing has beenused much more frequently in several European countriesover the past decades, it is obvious that the basis for furtherMH research, particularly genetics, is larger in Europe com-pared withNorth America. Pooled clinical data, in vitro mus-cle contracture testing, and genetic data of several MH inves-tigation units led to the publication of guidelines using bothcontracture testing and genetic screening according to theindividual patient.22 The reason for this approach is patientsafety, because it is crucial that a MH negative diagnosis is cor-rect. The application of trigger agents may be harmful in suchpersons and relatives in case of a false-negative diagnosis.

Knowledge GAP

Because there are numerous causes of increased end-tidalcarbon dioxide, and each can have a variable course, it isdifficult to use the capnograph as a diagnostic tool by itself.Thus, the current diagnostic specificity of capnography is notlikely to be improved. It is possible, however, that furtherresearch into each cause of increased end-tidal carbon diox-ide will reveal patterns of accompanying measures (such asheart rate, blood pressure, respiratory flow, and inspired/expired volumes) that, when combined with the capnograph,will improve diagnostic accuracy. Such a grading scale wouldbe similar to that used for the diagnosis of a MH episode.

One of the most important goals of research of MH is tominimizemorbidity andmortality. This could be achieved inseveral ways, including having a test for MH susceptibilitythat is inexpensive and could be applied to all patients un-dergoing general anesthesia. Although this might not seempracticable by the standards of today, the advances in phar-macogenetics make it likely that one day patients will betested for a wide variety of diseases and drug sensitivities, andthat this could be done cheaply.

In the short term, however, our understanding of all ge-netic mutations that are associated with and cause MH sus-ceptibility is incomplete. Once all (or nearly all) mutationsare known, a sensitive and specific genetic test can be used fordiagnosing MH. Nonetheless, spontaneous mutations willoccur and the list of genetic defects will lengthen over time.Thus, genetic testing will require continual updating. In ad-dition, advances are being made in developing a less invasivetest than muscle biopsy. One of these techniques uses in vivomicrodialysis of skeletal muscle.23 In brief, a small microdi-alysis probe is placed into the muscle, and halothane andcaffeine are passed through the probe. Lactic acid is measuredin the dialysate. Patients with MH susceptibility have in-creased lactic acid compared with normal patients. Whilestill experimental and under development, microdialysisholds some promise in replacing the more invasive musclebiopsy procedure. There is also an interest in testing bloodlymphocytes for a diagnosis of MH susceptibility.24

# Center for Medical Genetics, http://path.upmc.edu/divisions/mdx/diagnostics.html. Accessed July 9, 2009; Prevention Genetics,LLC, http://www.preventiongenetics.com/. Accessed July 9, 2009.

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We also do not have a thorough understanding of how thedefect in the ryanodine receptor leads to the clinical syn-drome, nor do we know all the specific details regarding themode of action of dantrolene. Although dantrolene has beenlifesaving, it is not a perfect drug. Drawbacks include phle-bitis, respiratory muscle weakness with difficulty weaningfrom a ventilator, difficulty with solvation, and others. Find-ing a replacement for dantrolene would be an advance. Fi-nally, we still do not completely understand the relationshipbetween MH and other diseases.25–27

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case scenario - increased end-tidal carbon dioxide

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