Anesthesia Case of the Month

Hope F. Douglas Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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Amy P. Dowling Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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Andréanne Cléroux Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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Ciara A. Barr Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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History

A 4-year-old 4.6-kg (10.1-lb) spayed female Pomeranian was referred for airway examination, endotracheal wash, tracheoscopy, and CT because of progressive exercise intolerance and respiratory distress with stridor. Dynamic collapse of the trachea and mainstem bronchi had been diagnosed previously, and dynamic pharyngeal collapse was suspected. Food but not water had been withheld from the dog overnight.

On preanesthetic physical examination, the dog had a body condition score of 7/9, and a cough could be elicited on tracheal palpation. The remaining findings from physical examination were unremarkable, and results of venous blood gas analysisa were within reference limits.

The dog was premedicated with butorphanol (0.3 mg/kg [0.14 mg/lb], IV) and preoxygenated with 100% oxygen delivered through a face mask attached to an anesthesia machine by way of a pediatric single-limb rebreathing circuit. Lead II ECG was monitored throughout the induction process. Anesthesia was induced with IV administration of midazolam (0.3 mg/kg), lidocaine (1 mg/kg [0.45 mg/lb]), and propofol (1 mg/kg).

For the airway examination, endotracheal wash, and tracheoscopy, general anesthesia was maintained with IV constant rate infusions of propofol (0.2 to 0.3 mg/kg/min [0.09 to 0.14 mg/lb/min]) and butorphanol (0.1 to 0.3 mg/kg/h [0.045 to 0.14 mg/lb/h]). After visual examination of the dog's airway, the dog was intubated with a 5.5-mm-internal-diameter orotracheal tube, and the endotracheal wash was performed. Tracheoscopy was then completed with a 3.8-mm-outer-diameter video bronchoscopeb passed through the orotracheal tube and with the dog breathing spontaneously.

For CT, the propofol infusion was discontinued, and general anesthesia was maintained with isoflurane in oxygen (0.5 to 2 L/min) delivered via mechanical ventilation (tidal volume, 13 mL/kg [5.9 mL/lb]; positive inspiratory pressure, 10 cm H2O; and end-tidal isoflurane concentration, 0.57% to 0.88%). Lactated Ringer solution (3 mL/kg/h [1.36 mL/lb/h], IV) was administered throughout the procedure, and patient monitoring included indirect blood pressure, lead II ECG, oxygen saturation of hemoglobin as measured with pulse oximetry (Spo2), respiratory rate, capnography waveform analysis, end-tidal carbon dioxide partial pressure, end-tidal isoflurane concentration, and rectal temperature.

Throughout anesthesia, all patient vital signs and other monitored variables remained within reference limits, except for the Spo2, which was 89% (reference range, 95% to 100%) following induction and 93% at its highest recorded value. There were no apparent problems with oxygen delivery from the anesthesia machine and breathing circuit, the orotracheal tube was correctly placed, and the capnography waveforms appeared clinically normal. Because of the dog's persistently low Spo2, a blood gas analysis,c including co-oximetry, was performed on an arterial blood sample (Table 1). The dog's fraction of inspired oxygen was 95% when the arterial blood sample was obtained for analysis.

Table 1

Results of blood gas analysis, including co-oximetry, performed on an arterial blood sample obtained from a 4-year-old 4.6-kg (10.1-lb) spayed female Pomeranian with dynamic tracheal and mainstem bronchial collapse and suspected dynamic pharyngeal collapse undergoing general anesthesia for diagnostic imaging because of progressive exercise intolerance and respiratory distress with stridor.

Parameter Result (reference range)
pH 7.225 (7.35 to 7.45)
Paco2 (mm Hg) 51.3 (35 to 45)
Pao2 (mm Hg) 489.5 (90 to 663)
Bicarbonate (mmol/L) 20.8 (18 to 25)
Base excess (mmol/L) −7.1 (−4 to 4)
Hct (%) 38 (30 to 45)
tHb (g/dL) 12.8 (13 to 20)
Sao2 (%) 99.9 (95 to 100)
FHbo2 (%) 78.5 (95 to 99)
FHbco (%) 0.3 (0 to 1)
FMetHb (%) 21.1 (0 to 1)
FHHb (%) 0.1 (0 to 5)

FHbco = Fraction of carboxyhemoglobin. FHbo2 = Fraction of oxyhemoglobin. FHHb = Fraction of deoxyhemoglobin. FMetHb = Fraction of methemoglobin. Paco2 = Arterial partial pressure of carbon dioxide. Pao2 = Arterial partial pressure of oxygen. Sao2 = Arterial oxygen saturation of hemoglobin. tHb = Total hemoglobin.

The dog's fraction of inspired oxygen was 95% when the arterial blood sample was obtained for analysis.

Question

What was the most likely explanation for the dog's persistently low Spo2?

Answer

Methemoglobinemia, a type of dyshemoglobinemia, was the most likely reason for the dog's persistently low Spo2 throughout anesthesia, despite having had an arterial oxygen saturation of hemoglobin (Sao2) of 99.9% (reference range, 95% to 100%) and an arterial partial pressure of oxygen of 489.5 mm Hg (reference range, 90 to 663 mm Hg). On the basis of co-oximetry results from arterial blood gas analysis, the dog's fraction of methemoglobinemia (FMetHb) was 21.1% (reference range, 0 to 1%) of the total hemoglobin. Because the dog's vital signs and other hematologic parameters were otherwise stable, no intervention was performed to treat the dog's methemoglobinemia, and the CT was completed. Afterward, flumazenil (0.02 mg/kg [0.01 mg/lb], IV) was administered, and the dog recovered from anesthesia without complication. The following day, results of a PCR assay on the tracheal wash sample indicated the presence of Mycoplasma sp, and treatment with doxycycline (5 mg/kg [2.27 mg/lb], PO, q 12 h) was initiated. Because methemoglobinemia may have contributed to the dog's signs of respiratory distress, nutritional supplementation with riboflavin was recommended, with the administration of ascorbic acid or methylene blue also considered depending on the dog's response to initial treatment.

Discussion

Methemoglobin is a type of dyshemoglobin that forms when the iron in ≥ 1 heme subunit of affected hemoglobin molecules is oxidized from the ferrous (Fe+2; can bind oxygen) to the ferric (Fe+3; cannot bind oxygen) state, resulting in a leftward shift of the oxygen dissociation curve of hemoglobin and less oxygen delivery to tissues. Relative to pulse oximetry, methemoglobin absorbs red light at a 660-nm wavelength, similar to deoxyhemoglobin, a fact that also explains why methemoglobin gives blood a dark appearance; however, methemoglobin absorbs more near-infrared light at a 940-nm wavelength than does deoxyhemoglobin or oxyhemoglobin.1 This absorbance of red and infrared light by methemoglobin will increase perceived measurements of both deoxyhemoglobin and oxyhemoglobin by a pulse oximeter, causing the ratio of relative absorbances detected by the device to approach 1 and the Spo2 measurements to approach and plateau at 85%.1 Thus, in patients with methemoglobinemia, the Spo2 measurement overestimates the Sao2 in those with true hypoxemia and underestimates the Sao2 in those with true normoxemia. Co-oximetry is required to determine the FMetHb.1,2,3

Because of oxidation reactions, 2% to 3% of hemoglobin undergoes transformation to methemoglobin daily in dogs.4,5 Normally, the FMetHb is maintained at ≤ 1% of the total hemoglobin by the reduction of methemoglobin back to hemoglobin.4 This reaction is primarily catalyzed by methemoglobin reductase, a 2-enzyme system that consists of cytochrome b5 and cytochrome b5 reductase and that relies on the reduced form of nicotinamide adenine dinucleotide.4,5,6,7 The FMetHb increases when there is increased oxidation caused by exposure to various exogenous substances (eg, toxic exposure to acetaminophen or topical benzocaine) or there is reduced or deficient endogenous reduction enzyme activity.4 When the FMetHb is between 10% and 20%, skin and mucous membrane discoloration and cyanosis may occur; FMetHb > 20% is typically associated with exercise intolerance, anxiety, tachycardia, and dyspnea; FMetHb between 50% and 70% is associated with coma, seizures, and arrhythmias; and FMetHb > 70% is considered lethal. Concurrent anemia or cardiopulmonary disease generally results in more substantial clinical signs.2,3,4,8

Methemoglobinemia may result from acquired (eg, toxic exposure) or congenital underlying causes. Although rare, congenital methemoglobinemia in dogs and cats is most commonly caused by a genetic mutation affecting methemoglobin reductase, similar to the case in people.9 Cytochrome b5 reductase has a soluble form present in RBCs and a membrane-bound, somatic form.10 Mutations involving cytochrome b5 have been reported in a dog,7 and mutations involving cytochrome b5 reductase have been documented in cats5,8 and dogs.10,11,12 Furthermore, mutations in cytochrome b5 reductase appear to be most common in dogs and cats and have been documented in the Pomeranian breed,10,11,13 which was the breed of the dog in the present report. Specifically, a mutation in the CYB5R3 gene has been documented in results of genetic analysis of Pomeranians.10,11 Dogs and cats with (vs without) mutations affecting cytochrome b5 reductase have lower cytochrome b5 reductase activity and higher FMetHb (from 13% to 41%10,12 and 40% to 52%,4,8 respectively). Clinical signs associated with congenital methemoglobinemia continue to be explored, and although cyanosis is frequently the most common clinical sign, lethargy and exercise intolerance can also be observed.10,14 Although affected animals may show no clinical signs aside from cyanosis, their clinical signs can worsen with comorbidities or stressors. For instance, acute decompensation may be triggered by exposure to oxidative toxins or certain drugs, an inflammatory process that increases oxidant levels, or concurrent anemia. Deterioration of clinical signs has also been observed in an affected dog with an upper respiratory tract infection.12

Methemoglobinemia can be diagnosed with a variety of assessments during physical or preanesthetic examinations or intraoperatively.5,6,7,8,11,12,15,16 For instance, a straightforward blood spot test can be performed without advanced equipment and involves placing a test drop of venous blood on white paper alongside a drop of a control sample of blood; the control blood will turn red, whereas a test sample will remain dark when the FMetHb is > 10%.9,14 Co-oximetry is required to measure the FMetHb and was used to confirm the diagnosis of methemoglobinemia in the dog of the present report. Additional diagnostic techniques include the use of newer pulse co-oximetry technology or spectrophotometric assays.9,15 In vitro analysis of methemoglobin reductase activity can confirm enzyme activity dysfunction, and genomic analysis can be performed to verify a genetic mutation as an underlying cause.5,7,8,10,11,12

Treatment of methemoglobinemia will depend on its etiology and the severity of clinical signs. Intravenous administration of methylene blue is a mainstay of treatment for methemoglobinemia.2,8 Yet because treatment with methylene blue can also contribute to oxidative RBC damage and can exacerbate Heinz body anemia, particularly in cats, close hematologic monitoring is imperative following treatment.8,9 Additional treatment for decompensated congenital methemoglobinemia includes administration of an antioxidant (eg, ascorbic acid or riboflavin as considered for the dog of the present report), transfusion, and hyperbaric oxygen treatment.2,9 In people, treatment is advised in any symptomatic patient. Treatment intervention is also recommended when the FMetHb is ≥ 30% or when the FMetHb is ≥ 10% and substantial comorbidities are present, because affected patients will be particularly sensitive to any reduction in oxygen transport and delivery.2,3 People with an FMetHb > 20% may be pretreated with IV administration of methylene blue before their anesthetic procedures because common anesthetic agents can overwhelm disabled redox systems in RBCs,12,17,18 and immediate availability of methylene blue for IV administration has been advocated for people with congenital methemoglobinemia undergoing anesthesia.19

In veterinary patients with congenital methemoglobinemia undergoing general anesthetic procedures, adequate preoxygenation is essential, and we recommend that these patients have arterial catheters placed for direct arterial blood pressure monitoring and frequent blood sampling for co-oximetry and oxygenation monitoring. Additionally, patient monitoring with ECG is important for the detection of myocardial ischemia. Packed RBCs or whole blood should also be available for transfusion if needed, and continued postanesthetic arterial blood gas and co-oximetry analyses should be performed until hemodynamic stability has been achieved.

Findings in the dog of the present report underscored that, although uncommon, methemoglobinemia should be included in the differential diagnosis list for veterinary patients with cyanosis, an Spo2 < 95%, or an Spo2 that does not improve with administration of supplemental oxygen. Acidosis, tachycardia, and differences in results for Spo2 versus Sao2 combined with results from co-oximetry can support a diagnosis of methemoglobinemia. For affected veterinary patients without exposure to a known toxin, congenital methemoglobinemia should be suspected, particularly in Pomeranians because of a documented responsible genetic mutation in the breed.10,11,13

Footnotes

a.

Stat Profile Prime Plus VET, Nova Biomedical, Waltham, Mass.

b.

EB 1170K, Pentax Medical, Montvale, NJ.

c.

RAPIDPoint 500, Siemens Medical Solutions USA Inc, Malvern, Pa.

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