Hemoglobin Modification

1. A 47-year-old man is brought to the emergency department after being evacuated from an
apartment fire. He reports headache, weakness, and vertigo. Physical examination is significant for
confusion. Although carboxyhemoglobin levels are within normal limits, arterial blood gas analysis
shows a pH of 7.2. The patient is treated with high-flow oxygen, sodium nitrite, amyl nitrite, and
sodium thiosulfate. He is then admitted to the hospital for observation.
Which of the following laboratory findings would be most consistent with this patient’s
presentation?

A.Decreased arterial oxygen saturation

B.Decreased venous oxygen saturation
C.Increased arterial-venous oxygen gradient
D.Increased lactic acidosis
E.Metabolic alkalosis
F.Non-anion-gap acidosis

2. A 47-year-old man presents with a 4-day history of weakness, dizziness, and shortness of breath
after starting treatment with dapsone for dermatitis herpetiformis. His lips and fingernails have a
bluish tint. Blood gas analysis shows his arterial partial oxygen pressure is 100 mm Hg and arterial
partial carbon dioxide pressure is 40 mm Hg.
Which of the following is the most appropriate treatment?
A.Hyperbaric oxygen
B.Methylene blue
C.N-Acetylcysteine
D.Protamine
E.Thiosulfate

3. A 36-year-old, disheveled patient is brought to the emergency department (ED) after being found
unresponsive in his home. He was awakened by emergency medical technicians; in the ED he
reports headache, dizziness, and nausea. He is unable to provide any more details. The patient’s
sister arrives and reveals that he has seemed a bit confused at times, and because of his chronic
financial difficulties he has not been able to replace his poorly functioning gas-heating system. His
vital signs are: temperature 98.6°F (37°C), blood pressure 118/76 mm Hg, pulse 90/min,
respirations 18/min, and SPO2 99% on room air. Physical examination demonstrates labored
breathing.
Which of the following is an adverse effect of the substance used to treat this patient’s
symptoms?
A.Absorptive atelectasis
B.Hypotension
C.Lacrimation
D.Metabolic alkalosis
E.Nephrotoxicity
F.Serotonin syndrome
4. An elderly woman living in a low-income housing project is brought into the
emergency department on a bitterly cold January night after being found unconscious
in her apartment. They found her sitting at the kitchen table in the kitchen with an
open gas stove.

Which of the following conditions would present with a similar shift in the oxygen-
hemoglobin dissociation curve seen in this woman?
A.Decreased pH
B.Increased PCO2
C.Increased pH
D.Increased physical activity
E.Increased temperature

5. During a physiology lecture, the factors affecting hemoglobin affinity to oxygen are
discussed. The professor discusses that one rare cause of congenital polycythemia is a
genetic defect leading to an increased affinity of hemoglobin for oxygen, because of
the inability to produce a particular chemical that normally works to decrease the
affinity of hemoglobin for oxygen. The effect seen in this type of congenital
polycythemia is presented diagrammatically as a shift in the oxygen-hemoglobin
dissociation curve in one direction.

Which of the following conditions is most likely to cause a shift in the oxygen-
hemoglobin dissociation curve in the same direction?
A.Decreased pH
B.Increased 2,3-bisphosphoglycerate levels
C.Increased adult hemoglobin
D.Increased carboxyhemoglobin levels
E.Increased temperature

6. A 63-year-old man with a history of hypertension is brought to the emergency department

reporting a headache, nausea, and vomiting. His blood pressure is found to be 200/130
mm Hg, and he is admitted for treatment of a hypertensive emergency. The intern starts
an intravenous infusion of nitroprusside. Twelve hours later, the patient reports that his
headache has returned. Although his blood pressure has decreased, he becomes
confused and complains of abdominal pain. On examination, his lips appear very red. A
medication is provided to treat this patient’s symptoms.

Which of the following is the most likely mechanism responsible for this patient’s acute
presentation?

A.Impaired release of oxygen from hemoglobin chain

B.Inhibition of Na+-K+ ATPase
C.Inhibition of acetylcholinesterase
D.Inhibition of d-aminolevulinic acid dehydratase
E.Inhibition of mitochondrial cytochrome C oxidase
 Answers

Hemoglobin Modifications

1. A 47-year-old man is brought to the emergency department after being evacuated from an
apartment fire. He reports headache, weakness, and vertigo. Physical examination is significant for
confusion. Although carboxyhemoglobin levels are within normal limits, arterial blood gas analysis
shows a pH of 7.2. The patient is treated with high-flow oxygen, sodium nitrite, amyl nitrite, and
sodium thiosulfate. He is then admitted to the hospital for observation.
Which of the following laboratory findings would be most consistent with this patient’s
presentation?

A.Decreased arterial oxygen saturation

B.Decreased venous oxygen saturation
C.Increased arterial-venous oxygen gradient
D.Increased lactic acidosis
E.Metabolic alkalosis
F.Non-anion-gap acidosis

Correct answer: D [ 39% ]

This patient is most likely experiencing cyanide poisoning as evidenced by his confusion and
headache following exposure to a house fire and successful treatment with nitrates and sodium
thiosulfate. Cyanide poisoning impairs aerobic metabolism, causing lactic acidosis.

Cyanide binds and inhibits cytochrome c oxidase (complex IV), the final enzyme in the electron
transport chain, which impairs oxidative metabolism in the mitochondria. Without oxidative
metabolism, anaerobic metabolism takes place, leading to a metabolic lactic acidosis.

Apartment fires are common causes of cyanide poisoning because furniture and other household
items are often lined with synthetic materials that release cyanide and other toxic chemicals when
burned. The antidote of cyanide toxicity utilizes sodium nitrite or amyl nitrite to produce
methemoglobinemia.This acts as a sponge for cyanide, removing it from cytochrome c. Sodium
thiosulfate, the second part of the antidote, enhances the activity of rhodanese, an endogenous
enzyme that uses toxic cyanide to form the renally excreted thiocyanate.

Other causes of high-anion-gap metabolic acidosis can be remembered using the mnemonic
MUDPILES: Methanol, Uremia, Diabetic ketoacidosis, Paraldehyde, Isoniazid, Lactic acidosis,
Ethylene glycol, Salicylates.

Cyanide poisoning causes an anion-gap acidosis due to increased serum lactate.

Cyanide causes elevated venous oxygen saturation, because it inhibits the body’s ability to utilize
oxygen.

[ A ] [ 33% ]
Carbon monoxide toxicity disrupts oxygen-carrying capacity of hemoglobin and decreases arterial
oxygen saturation by producing carboxyhemoglobin. Carbon monoxide toxicity can occur from
smoke inhalation or car exhausts (parking garages) and presents with dyspnea, fatigue, confusion,
headache, and cherry-red lips. This patient shares some of these features but has normal
carboxyhemoglobin levels, ruling out carbon monoxide poisoning.

[ B ] [ 5% ]
Decreased venous oxygen saturation can be seen in various conditions, either caused by increased
peripheral oxygen utilization or decreased cardiac output. A common example of this would be in
severe sepsis, as metabolism is substantially increased. However, the type of poisoning seen in
this patient would cause an increased venous oxygen saturation.

[ C ] [ 7% ]
An increased arterial-venous oxygen gradient would be seen in conditions that have increased
oxygen utilization in the periphery. These can be physiologic (eg, exercise) or pathologic (eg,
severe sepsis). With the reduced level of oxygen utilization in tissues as a result of the toxic agent,
the arterial-venous oxygen gradient would decrease, not increase.

[ E ] [ 4% ]
The five main causes of metabolic alkalosis are:
• loss of hydrogen ions (usually by vomiting or renal loss);
• bicarbonate retention (usually by the kidneys);
• shift of hydrogen ions to the intracellular space (seen in hypokalemia);
• alkalotic agents such as bicarbonate or antacids;
• and contraction alkalosis (water lost as a diuretic while bicarbonate is retained).
This patient's clinical presentation of a recent exposure to a apartment fire does not suggest any
of these aforementioned conditions and therefore a metabolic alkalosis is unlikely to be the
correct answer.

[ F ] [ 12% ]
A non-anion-gap (or normal-anion-gap) acidosis is typically seen in conditions where there is an
increase in chloride or an increased excretion of bicarbonate. Remember the causes of non-anion-
gap acidosis with the mnemonic HARDASS: Hyperalimentation, Addison disease, Renal tubular
acidosis, Diarrhea (most common), Acetazolamide (and other carbonic anhydrase antagonists,
Spironolactone, Saline infusion. This patient’s clinical presentation of a recent exposure to an
apartment fire does not suggest any of the ‘HARDASS’ clinical scenarios and therefore a non-anion
gap acidosis is unlikely to be the correct answer.

Bottom Line:
In cyanide poisoning, oxygen is unable to serve as the final electron acceptor in the electron
transport chain. Thus, oxidative phosphorylation is shut down, which forces the cells to rely on
anaerobic metabolism for generation of adenosine triphosphate.
2. A 47-year-old man presents with a 4-day history of weakness, dizziness, and shortness of breath
after starting treatment with dapsone for dermatitis herpetiformis. His lips and fingernails have a
bluish tint. Blood gas analysis shows his arterial partial oxygen pressure is 100 mm Hg and arterial
partial carbon dioxide pressure is 40 mm Hg.
Which of the following is the most appropriate treatment?
A.Hyperbaric oxygen
B.Methylene blue
C.N-Acetylcysteine
D.Protamine
E.Thiosulfate

Correct answer: B [ 51% ]

This patient presents with weakness, dizziness, and dyspnea, while appearing to be cyanotic, all of
which are signs and symptoms of poor tissue perfusion. The dapsone he was given for dermatitis
herpetiformis is an oxidizing agent, and oxidizing agents can cause methemoglobinemia. Given his
signs, symptoms, and recent dapsone use, it’s likely that this patient developed
methemoglobinemia.
Methemoglobinemia is characterized by a high blood level of methemoglobin, in which the
oxygen-carrying iron is present in the oxidized (ferric Fe3+) state instead of the reduced (ferrous
Fe2+) state. Methemoglobin cannot bind to oxygen. Moreover, any remaining ferrous hemes in the
hemoglobin tetramer exhibit increased oxygen affinity (ie, the oxygen-hemoglobin dissociation
curve is shifted to the left). Thus, signs and symptoms of methemoglobinemia reflect decreased
blood oxygen content and an even greater decrease in oxygen delivery to tissues (ie, cellular
hypoxia).
Additional symptoms include headache, nausea, confusion, seizures, and coma. Because oxygen
diffusion at the alveolar-arterial level is not impaired, the arterial partial pressure of oxygen is
normal. Blood may have a characteristic muddy color, secondary to the oxidization state of iron.
Methemoglobinemia may occur as an adverse effect of oxidizing agents such as sulfonamides,
dapsone, and local anesthetics (eg, benzocaine), from hereditary hemoglobin abnormalities, or
secondary to a hereditary deficiency of the reduced form of nicotinamide adenine dinucleotide.
Methylene blue has been shown to increase the conversion of Fe3+ back to Fe2+. An alternative
treatment for methemoglobinemia is ascorbic acid (vitamin C).
The other treatments listed are antidotes to toxic substances to which this patient has not been
exposed and which manifest with a different constellation of signs and symptoms.
• Hyperbaric oxygen therapy (HBO) is used to treat carbon monoxide (CO) poisoning. CO
exerts its effects by binding reversibly to hemoglobin with an affinity more than 200 times
that of oxygen and forming carboxyhemoglobin. HBO works by increasing the dissociation of
carboxyhemoglobin, dramatically and quickly lowering CO levels and increasing the plasma
concentration of oxygen.
• N-Acetylcysteine (NAC) is used to treat acetaminophen toxicity and is thought to work by
restoring hepatic glutathione. By the fourth day (when this patient presented for medical
attention), patients with acetaminophen toxicity have ongoing fulminant hepatitis,
hallucinations, and other signs and symptoms incompatible with those seen in this scenario.
• Protamine is an antidote to heparin overdose. It carries a positive charge and works by
binding to negatively charged heparin. Heparin overdose is characterized by excessive
bleeding, which is absent in this patient. Lab findings would include elevated PTT.
• Thiosulfate is used to treat hydrogen cyanide toxicity and works by acting as a sulfur donor
to promote the conversion of cyanide to thiocyanate, which is then safely expelled in the
 urine. Presentation of cyanide toxicity depends upon the route, length, and level of
exposure as well as the type of cyanide. However, cyanosis is not typically seen in patients
with cyanide toxicity.

[ A ] [ 16% ]
Hyperbaric oxygen therapy (HBO) is used to treat carbon monoxide (CO) poisoning. CO binds
reversibly to hemoglobin with an affinity more than 200 times that of oxygen to form
carboxyhemoglobin. Its presence impairs the ability of hemoglobin’s three other binding sites to
unload oxygen into peripheral tissues, which can lead to fatal hypoxia.
In HBO, patients are exposed to 100% oxygen in a pressurized room to enable the lungs to take in
more oxygen than in normal air pressure. This increases the dissociation of carboxyhemoglobin,
dramatically and quickly lowers CO levels, and increases plasma concentration of oxygen.
CO poisoning typically manifests with headache and altered mental status, and patients will often
describe a history of time spent in an enclosed space with a CO source, such as a fire or gas
heater. Family members or others living with the patient will typically have similar symptoms. Still,
because the symptoms are nonspecific, it can be a challenge to diagnose CO poisoning if the
patient has no known exposure to it. A careful neurologic exam is critical to assess for changes in
mental status, and the level of carboxyhemoglobin should be checked using co-oximetry of an
arterial blood gas sample. Note that CO does not affect PaO2.
This patient’s symptoms of bluish lips and fingernails are not characteristic of carbon monoxide
poisoning, nor is his history suggestive of CO exposure. If there were suspicion of CO poisoning, a
test of carboxyhemoglobin level and a neurologic assessment would be essential to making the
diagnosis.

[ C ] [ 11% ]
N-Acetylcysteine (NAC), a glutathione precursor, is used to treat acetaminophen toxicity and is
thought to work by restoring hepatic glutathione. In the first 24 hours after an acute overdose,
patients with acetaminophen toxicity present with nausea, vomiting, pallor, diaphoresis, and
malaise. By the fourth day (when this patient presented for medical attention), patients with
acetaminophen toxicity have ongoing fulminant hepatitis, are typically jaundiced, and may display
confusion and hallucinations caused by hepatic encephalopathy. Lab abnormalities would include
elevations in AST, ALT, and INR as liver structure and synthetic function deteriorates. These
patients would not typically display cyanosis or symptoms of anemia and poor tissue perfusion, as
seen in the patient in this case.

[ D ] [ 5% ]
Protamine is used to reverse the effects of heparin. It is a positively charged molecule that works
by binding to negatively charged heparin. Heparin overdose can lead to excessive anticoagulation
and bleeding, such as nosebleeds, bleeding from IV sites, or spontaneous hemorrhages, which
aren’t exhibited by the patient in this case. Lab abnormalities would include an elevated PTT.

[ E ] [ 17% ]
Thiosulfate is used together with sodium nitrite to treat hydrogen cyanide toxicity. Thiosulfate
acts as a sulfur donor to promote the conversion of cyanide to thiocyanate. Thiocyanate, which is
less toxic than cyanide, is then safely expelled in the urine. Cyanide binds irreversibly to, and
inhibits the function of, the enzyme cytochrome C oxidase (also called complex IV), thus impairing
the electron transport chain and aerobic respiration.
 The presentation of cyanide toxicity depends upon the route, length, and level of exposure and
the type of cyanide. It may begin within seconds of exposure or occur even hours later. People
who survive the exposure often develop long-term neurologic problems. Early symptoms may
include headache, vertigo, seizures, vomiting, tachycardia, and tachypnea; later effects may
include bradycardia, hypotension, bradypnea, and pulmonary edema, progressing to multiorgan
system failure and eventual cardiac collapse. It is unlikely that a person who had been exposed to
cyanide 4 days earlier and not received treatment would appear as relatively well as this patient.
Furthermore, cyanide toxicity results in the inability of the tissues to utilize oxygen bound to
hemoglobin, though tissue perfusion remains intact, which is why these patients don’t typically
present with cyanosis.

Bottom Line:
Methemoglobinemia may occur as an adverse effect of oxidizing agents such as dapsone. Patients
with methemoglobinemia carry a large amount of oxidized iron (ferric Fe3+) instead of reduced
iron (ferrous Fe2+). Fe3+ does not bind oxygen effectively. Methylene blue increases the conversion
of Fe3+ back to Fe2+, increasing hemoglobin oxygen content and overall oxygen delivery to body
tissues.

3. A 36-year-old, disheveled patient is brought to the emergency department (ED) after being found
unresponsive in his home. He was awakened by emergency medical technicians; in the ED he
reports headache, dizziness, and nausea. He is unable to provide any more details. The patient’s
sister arrives and reveals that he has seemed a bit confused at times, and because of his chronic
financial difficulties he has not been able to replace his poorly functioning gas-heating system. His
vital signs are: temperature 98.6°F (37°C), blood pressure 118/76 mm Hg, pulse 90/min,
respirations 18/min, and SPO2 99% on room air. Physical examination demonstrates labored
breathing.
Which of the following is an adverse effect of the substance used to treat this patient’s
symptoms?
A.Absorptive atelectasis
B.Hypotension
C.Lacrimation
D.Metabolic alkalosis
E.Nephrotoxicity
F.Serotonin syndrome

Correct answer: A [ 30% ]

This patient presenting with headache, dizziness, and nausea is suffering from the classic
symptoms of carbon monoxide (CO) poisoning. Diagnosis is based primarily on symptoms and
history. His poorly functioning gas-heating system is the likely source of the CO poisoning. Smoke
from burning wood is another common cause. A high suspicion of CO poisoning should prompt
measurement of the patient’s carboxyhemoglobin levels, which would be elevated. Treatment is
100% hyperbaric oxygen or 100% oxygen with a high-flow mask.
Adverse effects of oxygen therapy include the formation of free radicals, causing parenchymal
lung injury, as well as absorptive atelectasis. Absorptive atelectasis occurs when high FiO2 causes
a large volume of nitrogen in the lungs to be replaced with oxygen, reducing the volume of the
alveoli, and resulting in alveolar collapse.
Dimercaprol is the antidote to heavy-metal poisoning and can cause nephrotoxicity as a side
effect. Hypotension is a side effect of thiosulfate, the antidote for cyanide poisoning. Methylene
blue is the antidote to methemoglobinemia, which can cause serotonin syndrome. NaHCO3 is the
antidote for tricyclic-antidepressant overdose, which can cause metabolic alkalosis as an adverse
event. Lacrimation is associated with physostigmine, the antidote for anticholinergic poisoning.

[ B ] [ 15% ]
Cyanide toxicity presents with general weakness, progressive hypoxia, neurologic manifestations,
apnea, respiratory arrest, and eye and mucous membrane irritation (depending on the route of
exposure to the cyanide). In addition, almost half of patients with cyanide toxicity report noticing
an odor of bitter almonds. Cyanide poisoning occurs secondary to smoke from fires, certain toxic
ingestions, and sodium nitroprusside.
Thiosulfate is an antidote for cyanide toxicity and acts by donating a sulfur moiety to form
thiocyanate, which is much less toxic than cyanide and can be renally excreted. Adverse effects of
thiosulfate include hypotension, headache, and disorientation. As this patient is not presenting
with weakness, hypoxia, difficulty breathing, or eye/mucous membrane irritation, treatment for
cyanide poisoning is unlikely.

[ C ] [ 4% ]
Overdose of anticholinergic agents presents with flushing, dry skin, mydriasis, fever, tachycardia,
urinary retention, and myoclonic jerking. A popular mnemonic for the manifestations of
anticholinergic toxicity is: mad as a hatter, blind as a bat, hot as a hare, dry as a bone, red as a
beet.
Physostigmine salicylate, an acetylcholinesterase inhibitor, is an antidote for toxicity caused by
antimuscarinic and anticholinergic agents, such as atropine. Common adverse effects of
physostigmine and other organophosphates can be remembered by the mnemonic DUMBBELSS:
Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Excitation of skeletal muscle and CNS,
Lacrimation, Sweating, and Salivation. As this patient is not presenting with flushing, dry skin,
mydriasis, tachycardia, or urinary retention, anticholinergic poisoning is unlikely. Thus
physostigmine would not be indicated, nor would the patient be expected to experience
associated adverse effects.

[ D ] [ 28% ]
Symptoms of tricyclic-antidepressant toxicity manifest within 2 hours of ingestion and include
cardiovascular symptoms (palpitations, hypotension, chest pain), central nervous system
symptoms (convulsions, drowsiness, decreased mental status), and peripheral autonomic issues
including dry mouth, urinary retention, and blurred vision.
NaHCO3 is an antidote for toxicity caused by tricyclic antidepressants. Metabolic alkalosis is an
adverse effect that may result from too high a dose of NaHCO3. As this patient is not experiencing
any cardiovascular or autonomic issues, it is unlikely that he has overdosed on a tricyclic
antidepressant or that he would be treated with NaHCO3.

[ E ] [ 18% ]
Overdose with any of the heavy metals can lead to headaches, kidney dysfunction, and abdominal
symptoms. Lead poisoning is often seen in people who live in houses built before 1976 (owing to
 lead-based paint), or in children who inadvertently swallow or lick lead objects. Symptoms of lead
poisoning in children include abdominal cramps, aggressive behavior, anemia, and loss of
developmental skills. Symptoms of arsenic and mercury overdose also include abdominal cramps
and muscle cramps, but can additionally include hair loss, convulsions, and a persistent metallic
taste in the mouth.
Dimercaprol, a metal chelator, is an antidote for toxicity caused by arsenic, gold, mercury, or lead.
Nephrotoxicity may occur as a result of dimercaprol-metal complex breakdown, which occurs in
acidic urine. Therefore to prevent nephrotoxicity associated with dimercaprol, urine should be
alkalized. As this patient is not presenting with aggressive behavior, abdominal/muscle cramps,
hair loss, or convulsions, which are symptoms of heavy metal overdose, it would be unlikely for
him to be taking dimercaprol.

[ F ] [ 5% ]
Acquired methemoglobinemia presents with cyanosis, chocolate-colored blood, lightheadedness,
tachycardia, fatigue, dyspnea, and lethargy. High enough doses of the agents that cause
methemoglobinemia can lead to respiratory depression and worsening altered mental status.
Methemoglobinemia can be induced by certain drugs including sulfonamide and dapsone
antibiotics, local anesthetics, aniline dyes, and metoclopramide.
Methylene blue, the antidote to methemoglobinemia, is an oxidizing agent that speeds up the
conversion of methemoglobin to hemoglobin. Serotonin syndrome is a black box warning for
methylene blue when taken in combination with serotonin reuptake inhibitors. As the patient is
not displaying cyanosis or chocolate-colored blood, it is unlikely he is suffering from
methemoglobinemia or the serotonin syndrome associated with methylene blue treatment.

Bottom Line:
Patients with CO poisoning present with headache, dizziness, confusion, and nausea. Heating-
system problems are strongly suggestive of this condition. CO poisoning is treated with 100%
hyperbaric oxygen or high-flow oxygen; absorptive atelectasis is a possible adverse event
associated with this treatment.

4. An elderly woman living in a low-income housing project is brought into the

emergency department on a bitterly cold January night after being found unconscious
in her apartment. They found her sitting at the kitchen table in the kitchen with an
open gas stove.

Which of the following conditions would present with a similar shift in the oxygen-
hemoglobin dissociation curve seen in this woman?
A.Decreased pH
B.Increased PCO2
C.Increased pH
D.Increased physical activity
E.Increased temperature
Correct answer: C [ 77% ]
This elderly woman presents with carbon monoxide poisoning from the gas stove,
characterized by severe headache and eventual loss of consciousness, which are
symptoms of decreased oxygen delivery to the brain and body. Carbon monoxide has
a much higher affinity for hemoglobin than oxygen, and consequently reduces the
number of binding sites available for oxygen. Carbon monoxide causes a left shift, as
shown in the hemoglobin dissociation curve, similar to that seen with an increased
pH.

Image courtesy of Chris Nickson, MD, Anesthesia UK

[ A ] [ 14% ]
With increased metabolism, there is an increase in carbon dioxide production,
resulting in a lowering of pH. To meet the oxygen demands, hemoglobin decreases its
affinity for oxygen (ie, a right shift in the oxygen-hemoglobin dissociation curve).

[ B ] [ 6% ]
Increased partial pressure of carbon dioxide causes a decreased affinity for oxygen
(ie, a right shift in the oxygen-hemoglobin dissociation curve).

[ D ] [ 2% ]
With increased physical activity, more carbon dioxide is produced and more oxygen is
required to meet the demand, causing a right shift in the oxygen-hemoglobin
dissociation curve.
 [ E ] [ 1% ]
Increased body temperature, such as that that occurs with exercise, would require
increased oxygen delivery to the working tissues. In this situation, hemoglobin has a
decreased affinity for oxygen (ie, a right shift in the oxygen-hemoglobin dissociation
curve).

Bottom Line:
Carbon monoxide, decreased 2,3-diphosphoglycerate, decreased temperature,
decreased partial carbon dioxide pressure, and increased pH all shift the oxygen-
hemoglobin dissociation curve to the left.

5. During a physiology lecture, the factors affecting hemoglobin affinity to oxygen are
discussed. The professor discusses that one rare cause of congenital polycythemia is a
genetic defect leading to an increased affinity of hemoglobin for oxygen, because of
the inability to produce a particular chemical that normally works to decrease the
affinity of hemoglobin for oxygen. The effect seen in this type of congenital
polycythemia is presented diagrammatically as a shift in the oxygen-hemoglobin
dissociation curve in one direction.

Which of the following conditions is most likely to cause a shift in the oxygen-
hemoglobin dissociation curve in the same direction?
A.Decreased pH
B.Increased 2,3-bisphosphoglycerate levels
C.Increased adult hemoglobin
D.Increased carboxyhemoglobin levels
E.Increased temperature

Correct answer: D [ 58% ]

A left shift in the oxygen-hemoglobin dissociation curve indicates an increase in
oxygen affinity, which would be consistent with the predicted effect in the subtype of
congenital polycythemia described in the vignette. This increased affinity also means
oxygen dissociation from hemoglobin in tissues is decreased. A left shift can be seen
with increased amounts of fetal hemoglobin, decreased amounts of 2,3-
diphosphoglycerate (2,3-DPG), decreased temperature, increased pH, and decreased
carbon dioxide. A good way to remember these last three factors is to recall that
changes seen with exercise (increase in temperature, decrease in pH, increase in
carbon dioxide) all decrease oxygen affinity, so that the opposite increases oxygen
affinity. Exposure to carbon monoxide leads to an allosteric change in the hemoglobin
molecule, increasing carboxyhemoglobin levels and reducing the offloading of oxygen
in the periphery. Carbon monoxide displaces the oxygen-hemoglobin dissociation
curve to the left, so the poisoned blood less readily gives up the little O2 it has.
• Lowering pH decreases the affinity of hemoglobin for oxygen, resulting in a
right shift of the oxygen-hemoglobin dissociation curve.
• Elevated 2,3-diphosphoglycerate levels causes decreased affinity of
hemoglobin for oxygen, resulting in a right shift of the oxygen-hemoglobin
dissociation curve.
• Increased adult hemoglobin compared to fetal hemoglobin would cause
decreased affinity of hemoglobin for oxygen, resulting in a right shift.
• Increased temperature would also result in a right shift of the oxygen-
hemoglobin dissociation curve.

[ A ] [ 11% ]
A decrease in pH is associated with a right shift of the hemoglobin curve. This makes
sense intuitively because tissue not getting enough oxygen produces more acid in the
form of lactic acid. Thus, one would want oxygen to be released more easily in the
presence of a decreased pH. This is not the same effect seen in the subtype of
congenital polycythemia described in the vignette.

[ B ] [ 16% ]
An increase in 2,3-DPG causes a right shift by decreasing the hemoglobin affinity for
oxygen. Higher levels of this can be found in people living at high altitudes. This is not
the same effect seen in the subtype of congenital polycythemia described in the
vignette.

[ C ] [ 11% ]
Fetal hemoglobin binds oxygen with greater affinity than adult hemoglobin, in order
to facilitate diffusion of oxygen across the placenta. Therefore, increasing levels of
adult hemoglobin relative to fetal hemoglobin would cause a right, not a left, shift.
This is not the same effect seen in the subtype of congenital polycythemia described in
the vignette.

[ E ] [ 4% ]
An increase in temperature is associated with a right shift of the oxygen-hemoglobin
dissociation curve. This is not the same effect seen in the subtype of congenital
polycythemia described in the vignette.

Bottom Line:
Exposure to carbon monoxide converts hemoglobin to carboxyhemoglobin, causing a
left shift in the oxygen-hemoglobin dissociation curve.
6. A 63-year-old man with a history of hypertension is brought to the emergency department
reporting a headache, nausea, and vomiting. His blood pressure is found to be 200/130
mm Hg, and he is admitted for treatment of a hypertensive emergency. The intern starts
an intravenous infusion of nitroprusside. Twelve hours later, the patient reports that his
headache has returned. Although his blood pressure has decreased, he becomes
confused and complains of abdominal pain. On examination, his lips appear very red. A
medication is provided to treat this patient’s symptoms.

Which of the following is the most likely mechanism responsible for this patient’s acute
presentation?

A.Impaired release of oxygen from hemoglobin chain

B.Inhibition of Na+-K+ ATPase
C.Inhibition of acetylcholinesterase
D.Inhibition of d-aminolevulinic acid dehydratase
E.Inhibition of mitochondrial cytochrome C oxidase

Correct answer: E [ 47% ]

A 63-year-old man is admitted to the hospital with symptoms of hypertensive emergency
(blood pressure of 200/130 mm Hg with headache, nausea, and vomiting). Nitroprusside
treatment is initiated to lower his blood pressure; however, his headache returns
accompanied by confusion and abdominal pain. In the body, nitroprusside is converted
into nitric oxide and cyanide ions. When inappropriate doses or prolonged infusions are
administered, nitroprusside exposure can lead to cyanide toxicity. Cyanide toxicity is
characterized by nonspecific signs and symptoms such as headaches, confusion,
seizures, vomiting, arrhythmias, cherry-red–colored lips and mucous membranes, and
later the development of cyanosis.

Cyanide has a high affinity for binding the ferric ion (Fe3+) in mitochondrial cytochrome C.
Binding of cyanide to cytochrome C causes inhibition of mitochondrial cytochrome C
oxidase, the last step in the electron transport chain. This halts oxidative phosphorylation
and forces the body to switch to anaerobic metabolism for ATP production, leading to a
lactic acidosis and a shortage of ATP. A small amount of cyanide also binds to the ferrous
ion (Fe2+) in hemoglobin, forming a compound that cannot deliver oxygen to the tissues.

Patients with cyanide poisoning should receive sodium thiosulfate or hydroxocobalamin.

Sodium thiosulfate acts as a sulfur donor to detoxify cyanide to thiocyanate, which can be
eliminated. Hydroxocobalamin binds cyanide and forms the nontoxic cyanocobalamin,
which is renally excreted.

• Lead inhibits d-aminolevulinic acid dehydratase. Lead poisoning can result in

abdominal pain, constipation, headaches, irritability, anemia, and neurologic
deficits.
 • Organophosphates inhibit acetylcholinesterase and can present with symptoms of
excess salivation, watery eyes, diarrhea, altered mental status, hyperhidrosis, and
miosis.
• Carbon monoxide poisoning impairs the release of oxygen from hemoglobin.
Although it can also cause red lips and headache, the temporal association of this
patient’s symptoms with the nitroprusside infusion makes this a less likely diagnosis.
• Digitalis inhibits Na+-K+ ATPase and can result in headaches, nausea, vomiting,
and cardiac arrhythmias (not seen in this patient).

[ A ] [ 29% ]
Carbon monoxide poisoning can impair the release of oxygen from hemoglobin. Carbon
monoxide competes with oxygen for binding to the heme group and increases the affinity
of hemoglobin for oxygen, thus preventing it from releasing oxygen. Symptoms can
include headache, nausea, vomiting, and altered mental status. On physical examination,
a patient with carbon monoxide poisoning can present with red lips. However, because
this patient developed symptoms shortly after medication administration in a hospital
setting and because other patients did not develop symptoms, carbon monoxide poisoning
is an unlikely diagnosis.

[ B ] [ 10% ]
Digitalis, an inotrope, acts by inhibition of Na+-K+ ATPase. Digitalis poisoning usually
results in cardiac arrythmias, which can manifest with palpitations and chest pain. Other
symptoms include headache, nausea, vomiting, and confusion. An ECG may reveal
premature ventricular beats as the earliest sign of toxicity. Although this patient is
experiencing confusion and a headache, digitalis toxicity does not explain his red lips.

[ C ] [ 7% ]
Organophosphate toxicity, which can sometimes occur with exposure to insecticides,
occurs via the inhibition of acetylcholinesterase. Symptoms can include excess salivation,
watery eyes, diarrhea, altered mental status, hyperhidrosis, and miosis. With the
exception of confusion, these symptoms are not seen in this patient, nor does he have any
history suggestive of organophosphate poisoning.

[ D ] [ 8% ]
Lead binds to sulfhydryl groups in the body and inhibits d-aminolevulinic acid dehydratase
and ferrochelatase. These enzymes are required for heme biosynthesis. Lead also exerts
its toxic effects by competing with calcium ions, inhibiting membrane enzymes, and
inhibiting the production of active vitamin D. Although lead poisoning can cause
headaches and abdominal pain, it also leads to anemia and neurologic deficits, such as
low IQ and hyperactivity, which are not seen in this patient. Lead poisoning also does not
explain the patient’s red lips.

Bottom Line:
Inappropriate use of nitroprusside can lead to cyanide toxicity. Cyanide acts primarily via
inhibition of mitochondrial cytochrome C oxidase in the electron transport chain.