In-Depth Review

Diagnosis, Treatment, and Prevention of Hemodialysis

Emergencies
Manish Saha and Michael Allon

Abstract
Given the high comorbidity in patients on hemodialysis and the complexity of the dialysis treatment, it is re-
markable how rarely a life-threatening complication occurs during dialysis. The low rate of dialysis emergencies
Division of
can be attributed to numerous safety features in modern dialysis machines; meticulous treatment and testing of the Nephrology,
dialysate solution to prevent exposure to trace elements, toxins, and pathogens; adherence to detailed treatment University of Alabama
protocols; and extensive training of dialysis staff to handle medical emergencies. Most hemodialysis emergencies at Birmingham,
can be attributed to human error. A smaller number are due to rare idiosyncratic reactions. In this review, we Birmingham, Alabama
highlight major emergencies that may occur during hemodialysis treatments, describe their pathogenesis, offer
measures to minimize them, and provide specific interventions to prevent catastrophic consequences on the rare Correspondence:
Dr. Michael Allon,
occasions when such emergencies arise. These emergencies include dialysis disequilibrium syndrome, venous air Division of
embolism, hemolysis, venous needle dislodgement, vascular access hemorrhage, major allergic reactions to the Nephrology, PB,
dialyzer or treatment medications, and disruption or contamination of the dialysis water system. Finally, we de- Room 226, 1530 Third
scribe root cause analysis after a dialysis emergency has occurred to prevent a future recurrence. Avenue South,
Birmingham, AL
Clin J Am Soc Nephrol 12: 357–369, 2017. doi: 10.2215/CJN.05260516 35294. Email:
mdallon@uab.edu

Introduction but has been the subject of some recent comprehen-

There are currently approximately 400,000 patients
with ESRD on maintenance hemodialysis (HD) in the
United States (1). Each one receives dialysis at least
thrice weekly (156 times per year) for a total of over
62 million dialysis sessions annually. Given the high
comorbidity in patients on HD and the complexity of
the dialysis treatment, it is remarkable how rarely a
life-threatening complication occurs during dialysis.
For example, a cardiac arrest occurs only seven times
per 100,000 HD sessions (2). The low rate of major
complications can be attributed to numerous safety
features in modern dialysis machines; meticulous
treatment and testing of the dialysate solution to pre-
vent exposure to trace elements, toxins, and patho-
gens; adherence to detailed treatment protocols; and
extensive training of dialysis staff to handle medical
emergencies. Most HD emergencies can be attributed
to human error. A smaller number are due to rare
idiosyncratic reactions. Ongoing dialysis staff train-
ing is essential to both prevent human error as well
as ensure prompt and effective interventions when
complications happen.
This review highlights major emergencies that may
occur during HD treatments (Table 1), measures to
minimize them, and specific interventions to prevent
catastrophic consequences on the rare occasions when
such complications arise. We have provided case re-
ports to illustrate these emergencies in Supplemental
Appendix. Complications related to more frequent
HD are not addressed in this review. Intradialytic
hypotension, a relatively common complication dur-
ing dialysis, is also beyond the scope of this review
sive papers (3–6).
Dialysis Disequilibrium Syndrome
Dialysis disequilibrium syndrome (DDS) is a rare
syndrome occurring in patients with severe azotemia
undergoing their initial HD session. It is characterized
by nausea, vomiting, headache, encephalopathy, and
seizures (7,8). DDS is attributed to the faster decline
of urea concentration in the blood than in the brain
during the dialysis session. This lag (reverse urea ef-
fect) creates an osmotic gradient that promotes net
water shift from the blood into the brain, leading to
cerebral edema and its associated manifestations
(9,10). Rosen et al. (11) studied 10 patients with AKI
(baseline BUN concentrations of 210–460 mg/dl) un-
dergoing their initial HD session. They obtained con-
current plasma and cerebrospinal fluid (CSF) samples
before dialysis, immediately after dialysis, and 24
hours after dialysis. The CSF-to-plasma BUN ratio
was 0.91 predialysis, 1.99 immediately after dialysis,
and back to baseline 24 hours later.
In animal models of uremia, the alteration in brain
urea and other electrolytes concentrations does not
completely account for the increase in brain osmolal-
ity during rapid HD (12). Arieff et al. (12) suggested
that generation of new solutes (“idiogenic osmoles”)
in brain tissue accounted for brain edema during
rapid HD. In contrast, Silver et al. (13) reported that
retained urea in brain was sufficient to cause a change
in brain water content in rapidly dialyzing animals.
Moreover, the content of brain organic osmolytes

www.cjasn.org Vol 12 February, 2017 Copyright © 2017 by the American Society of Nephrology 357
358 Clinical Journal of the American Society of Nephrology
Table 1. Major dialysis emergencies
Estimated Frequency, per
Type of Emergency
Million HD Sessions
Dialysis disequilibrium
Air embolism 8.5–33
Hemolysis
Vascular access hemorrhage
Venous needle dislodgement 14–91
Allergic reaction 21–170
Cardiac arrest 70
Errors in following the HD
prescription
HD, hemodialysis.
(myoinosotol, glutamine, and taurine, etc.) did not increase
in rapidly dialyzing animals (9,13,14). Idiogenic osmoles
may be generated in brain during acute azotemia as an
adaptive response to increased plasma BUN to prevent
brain cell shrinkage (15) but are probably not generated
during rapid HD (9). Finally, in a CKD animal model,
there was a decrease in brain urea transporters and an
increase in aquaporins (AQPs; AQP4 and AQP9), provid-
ing a potential molecular mechanism for the reverse urea
effect (16).
The spectrum of DDS ranges from headache and rest-
lessness in mild forms to nausea, vomiting, and hyperten-
sion in patients with moderate cases to seizures and coma
in patients with severe cases (7,17,18). There is no set BUN
value above which patients predictably develop DDS.
Both a high BUN level (.175 mg/dl) and its rapid decline
are risk factors for DDS (7,18,19). Additional risk factors
include preexisting neurologic conditions, the first session
of HD, hyponatremia, and liver disease (7,18,20). It is un-
known whether the risk of DDS is similar in patients with
advanced CKD and those with AKI. Computed tomogra-
phy or magnetic resonance may show cerebral edema in
patients with DDS.
Several strategies may prevent DDS in patients with very
high serum BUN undergoing their first HD session (Table 2)
(7,12,17). The most important measure is to slow the urea
Table 2. Potential strategies to prevent dialysis disequilibrium
syndrome in high-risk patients
(1) Limit the first HD session to 2–2.5 h
(2) Limit the blood flow to 200–250 ml/min
(3) Sodium modeling or a high-sodium dialysate
(4) Consider intravenous mannitol (1 g/kg)
(5) Consider CRRT in patients at high risk for DDS
(traumatic brain injury, intracerebral hemorrhage,
intracranial mass)
HD, hemodialysis; CRRT, continuous RRT; DDS, dialysis dis-
equilibrium syndrome.
Refs.
Tennankore et al. (31), Wong et al. (32)
Tennankore et al. (31), Wong et al. (32), VA study (65),
Pennsylvania patient safety study (64)
Villarroel and Ciarkowski (71), Daugirdas et al. (72),
Simon et al. (129)
Karnik et al. (2)
removal rate. In a dog model of uremia, Arieff et al. (12)
compared rapid and slow HD that achieved a similar re-
duction in BUN. Rapid HD (100 minutes with a blood flow
of 12 ml/kg per minute and a dialysate flow rate of 500
ml/min) produced an elevated CSF pressure and seizures.
In contrast, slower HD (200 minutes at 5 ml/kg per minute
blood flow rate and a dialysate flow rate of 500 ml/min)
elevated the CSF pressure without causing seizures (12).
Thus, a short HD session (2 hours) with a low blood flow
(200 ml/min) and a urea reduction ratio goal of 0.4 is rec-
ommended as the initial prescription for patients at risk for
DDS (7,17). Continuous RRT (CRRT) may be considered in
patients at high risk for DDS, including those with intra-
cranial mass or brain injury (20). Kidney Disease Improv-
ing Global Outcomes recommends CRRT over intermittent
dialysis for AKI in patients with brain injury/edema or
elevated intracranial pressure (21).
Port et al. (22) reported that a higher dialysate sodium
concentration (144–154 mmol/L) prevented DDS symp-
toms. Each 1-mmol/L increase in serum sodium offset
the osmotic effect of 12 mg/dl BUN. Thus, sodium mod-
eling may be useful in preventing DDS during the initial
HD sessions in patients at risk (22). Adding glucose or
glycerol to the dialysate may also prevent DDS (23).
Rodrigo et al. (24) studied patients on HD at risk for DDS
by adding glucose to the dialysate or administering intrave-
nous mannitol. Increasing the dialysate glucose concen-
tration to 450 mg/dl contributed 2–3 mosM/kg H2O,
whereas intravenous mannitol (1 g/kg) added 8.5–10
mosM/kg H2O (24).
Air Embolism
Venous air embolism (VAE) during HD is thought to be
rare, but because signs and symptoms of air embolism may
mimic other more common complications, careful vigilance
and high suspicion are required for the diagnosis. Air
bubbles trapped in the systemic (pulmonary or cerebral)
microcirculation may cause local ischemia, circulatory
arrest, activation of complement and coagulation sys-
tem, localized inflammation, and vascular endothelial cell
damage (25–27).
Clin J Am Soc Nephrol 12: 357–369, February, 2017 Hemodialysis Emergencies, Saha et al. 359

Owing to safeguards in the modern HD machine, symp-
tomatic air embolism is exceedingly rare during HD. Air
may enter the extracorporeal HD circuit either as a re-
sult of residual air trapped in the tubing or dialyzer due
to incomplete priming or because of a broken or loose luer
connection prepump (where the arterial pressure is
negative) (25,28–30) (Figure 1). Air entering the extracor-
poreal circuit presents to the venous air trap placed distal
to the dialyzer, immediately decreasing the blood level in
the chamber. The change in fluid level in this chamber is
recognized by a sensor that triggers an alarm and stops the
blood pump. As a consequence of these technologic safe-
guards, air embolism in the modern era results from hu-
man error. In a retrospective cohort study of 202 patients
on home HD, only six patients had suspected air embolism
that occurred during 183,603 dialysis sessions for an over-
all incidence less than one episode per 30,000 dialysis ses-
sions. These episodes were related to inadequate priming
or lack of clamping of the catheter or tubing (31). Another
study reported a single case of air embolism during
follow-up of 190 patients on home HD (approximately
117,000 HD sessions) for an incidence of less than one
episode per 100,000 HD sessions. This case resulted from
not clamping the arterial line during disconnection, thereby
allowing air to enter the tubing (32).
Most microbubbles ,50 mm in diameter and many mi-
crobubbles between 50 and 200 mm pass through the ve-
nous bubble catcher without triggering an alarm (33). The
rate of microbubble formation is dependent on the blood
flow rate and negative arterial pressure. The total volume
of microbubbles during an HD session is a few milliliters, a
volume insufficient to cause acute symptoms (34). The ve-
nous air trap and air detector prevent infusion of larger
amounts of air. If the air detector triggered an alarm for
every microbubble, HD would be regularly interrupted
(28). Therefore, a safe limit of air infusion (0.1 ml/kg
body wt for bolus infusion and 0.03 ml/kg per minute
for continuous infusion) has been suggested (25,28).
Measures to minimize the risk of air embolism include
avoidance of extremely high dialysis blood flow, keeping

Figure 1. | Venous air embolism may arise from 4 possible areas of air entry into the dialysis circuit. Schematic diagram of a hemodialysis
circuit depicting four possible areas of air entry. (1) A broken or loose luer connection between the arterial needle and the tubing can result in air
entry, because this segment has negative intraluminal pressure. (2) A hole in the arterial tubing can suck air into the arterial line. (3) Air entry can
occur during administration of anticoagulation or saline. (4) Inadequate priming can result in air entry from the dialyzer or dialysis tubing. A
crack in the venous bloodline will not cause air entry due to the positive intraluminal pressure. Air entering the circuit presents to the venous air
trap and forms foam/bubble at the top of blood level. As soon as the blood level in the venous air trap chamber falls below the air detector level,
it immediately triggers an alarm and stops blood flow. As a consequence, venous air embolism occurs due to human error.
360 Clinical Journal of the American Society of Nephrology
the arterial luer lock tightened, adequately priming the
dialyzer and tubing system before initiation of an HD
session, and maintenance of a high blood level in the
venous air catcher (29,35).
Massive VAE manifests with chest pain, dyspnea, and
syncope. Cerebral air embolism may cause blurry vision,
altered mental status, seizures, or ischemic stroke. Patients
may develop hypotension and tachycardia due to right
ventricular overload with involvement of the pulmonary
capillary bed (26,27,36). The degree of end organ damage
depends on the rate of air entry, volume of air, the pa-
tient’s position, and underlying cardiac status. In dogs,
rapid injection of 7.5 ml/kg air is lethal. In humans, a vol-
ume of 100–300 ml air is considered fatal (37,38). A high
clinical suspicion is required to diagnose VAE. Precordial
Doppler can detect 0.05 ml/kg air, whereas transesopha-
geal echocardiogram can detect 0.02 ml/kg air (39). Com-
puted tomography may detect air in suspected cases of
cerebral embolism.
After VAE is suspected, the patient should be provided
with 100% oxygen (27). Aspiration of air may be attempted
if the catheter is still in place (26). Early studies suggested
that the left lateral recumbent (LLR) position could pre-
vent right ventricular failure by preventing outflow tract
obstruction during air embolism by moving the air more
superiorly in the right ventricle (40–42). Geissler et al. (43)
and Mehlhorn et al. (44) studied the effect of injecting
2.5 ml/kg air at a rate of 5 ml/s in dogs and concluded
that the LLR position did not provide hemodynamic
advantage over the supine position. Although traditional
teaching has been to maintain an LLR with head down
position for suspected VAE, the supine position has been
recommended more recently (26). The supine position also
provides additional advantage of appropriate delivery of
oxygen and hemodynamic support, a critical part of the
treatment (26). An LLR position has been recommended by
Muth and Shank (26) if aspiration of air is to be attempted
through an existing central venous catheter (CVC) for
VAE (26,43).
Air embolism may also occur during placement of an
HD CVC, accidental disconnection during its use, or at its
removal. Vesely (45) reported 15 cases of air embolism
occurring during placement of 11,583 tunneled and non-
tunneled CVCs (0.13%). All 15 cases occurred during in-
sertion of tunneled CVCs; most patients had mild to
moderate symptoms, except one who died. Rinsing the
catheter, placing the patient in a supine position, and
inserting the needle during expiration may prevent air
embolism during CVC placement (46). A break in the cath-
eter or accidental disconnection may also lead to fatal air
embolism (47). During CVC removal, the patient should be
supine, with catheter removal performed during exhala-
tion or a Valsalva maneuver to increase intrathoracic pres-
sure (46). An air-occlusive dressing should be in place for
24 hours to prevent delayed air entry through the subcu-
taneous track (48).
Hemolysis
Red blood cells (RBCs) undergo shear stress when they
circulate through the HD circuit, and are, therefore, at risk
for fragmentation. Additionally, blood osmotic changes,
dialysate contaminants, or hyperthermia may each enhance
hemolysis (Table 3) (49–52). Because blood flow is higher
at the center of a laminar flow than at the edges (wall) of
the extracorporeal circuit, the RBC membrane is exposed
to a differential force on two different sides, thereby
causing a shear stress (51). The low degree of hemolysis
that typically occurs during HD is insufficient to produce a
measurable drop in hematocrit. More significant hemolysis
may occur in cases of dialysate contamination with trace
metals (copper or zinc), disinfectant added to city water
(chloramine), or nitrate (49,53). The normal starting dialy-
sis blood flow with a new arteriovenous (AV) fistula is 250
ml/min with a 17-gauge needle. In comparison, a dialysis
blood flow of 500 ml/min can be delivered using a
14-gauge needle without inducing hemolysis (54). The
positive and negative pressures (approximately 1500 and
2500 mmHg, respectively) sustained by RBCs in the ex-
tracorporeal circuit usually do not cause any hemolysis
(51). However, attempting a high dialysis blood flow
with a small gauge needle may induce hemolysis.
Overheated dialysate may cause thermal injury and
hemolysis. A 1948 study by Ham et al. (55) showed changes
in RBC morphology, osmotic fragility, and hemolysis at
temperatures .47°C. In 1975, Berkes et al. (56) reported
on a patient with delayed hemolysis 48 hours after expo-
sure to overheated dialysate of 50°C. Because modern
HD machines trigger an alarm at dialysate temperature
.39.5°C, hyperthermic hemolysis is rare (55,57). If the
HD machine triggers an alarm for overheated dialysate,
an appropriate stepwise protocol should be followed: re-
sponding to the alarm, immediate cessation of dialysis,
and informing concerned authorities and supervisor to
find the source of heated water (57). Jepson and Alonso
(57) reported an issue with a valve system that led to
heated dialysate of 39.8°C; no harm was caused to the pa-
tient due to the attentiveness of the nurse who followed an
appropriate protocol (57).
Hemolysis due to osmotic changes and dialysate impu-
rities is also rare. Several investigators have reported
mechanical injury to RBCs caused by kinked dialysis
tubing (52,58). Sudden bends, turns, and the entry point
into the dialyzer are additional vulnerable areas for kink-
ing. A simultaneous decrease of .25 mmHg in both the
arterial (prepump) and venous (postpump) pressures
suggests a severe postpump kinked tubing that may result
in hemolysis; this drop in pressure results from decrease
blood flow due to severe obstruction. Therefore, it essen-
tial to use the length of tubing recommended by the man-
ufacturer, monitor the arterial and venous dialysis
pressures, and avoid sudden bends in the tubing (59). A
multistate outbreak of hemolysis during HD led to the
finding of faulty blood tubing causing hemolysis. Narrow-
ing of the blood tubing before its entry to the dialyzer led
to exposure of RBCs to increased pressure and consequent
hemolysis (60).
Patients with severe intradialytic hemolysis complain of
nausea, shortness of breath, abdominal/back pain, and
chills and initially develop acute hypertension (61). Con-
firmatory laboratory data include low serum haptoglobin,
elevated lactate dehydrogenase, reduction in hematocrit,
and pink serum. When hemolysis is suspected, the HD
session should be stopped immediately. Blood should
Clin J Am Soc Nephrol 12: 357–369, February, 2017 Hemodialysis Emergencies, Saha et al. 361

erythrocytes. If several patients develop hemolysis in a sin-

Table 3. Causes of hemolysis during hemodialysis gle dialysis unit, contamination of the dialysate, faulty
tubing, and altered dialysate osmolality should be suspec-
Dialysate related ted. A systematic assessment of the potential causes is
Contamination with copper, zinc, nitrate, nitrite, and imperative to avoid recurrent hemolysis during a sub-
chloramine
sequent HD session (Figure 2). A root cause analysis
Hypo-osmolar dialysate
Hyperthermia (RCA) should be performed in each case, and every as-
Extracorporeal circuit related pect of the HD session should be well examined; blood
Blood pump malocclusion tubing and the needle system should be saved for future
Single–needle high–flow dialysis investigation.
Partial occlusion of HD catheter
Kinked tubing, faulty blood tubing
Patient related Venous Needle Dislodgement
Sickle cell anemia Venous needle dislodgement (VND) is a rare but life-
Hereditary spherocytosis threatening complication of HD. With a typical dialysis
Autoimmune hemolysis blood flow of 300–500 ml/min, hemorrhagic shock ensues
within minutes (after loss of 30%–40% of total blood vol-
HD, hemodialysis. ume) (62). The Veterans Administration National Center
for Patient Safety reported 40 major hemorrhages due to
VND or disconnection at the dialysis catheter site during
not be returned from the extracorporeal circulation to the 2.5 million dialysis sessions or approximately one episode
bloodstream due to the risk of precipitating severe hyper- per 60,000 HD sessions (63). Two large Canadian series of
kalemia by infusing potassium released from hemolyzed patients on home HD reported VND in one in 11,000 (31)

Figure 2. | Schematic diagram illustrating an approach to evaluation of a suspected case of hemolysis during hemodialysis (HD) and its root
cause analysis to prevent future episodes. LDH, lactate dehydrogenase.
362 Clinical Journal of the American Society of Nephrology
and one in 20,000 HD sessions (32). Data from Pennsylva-
nia public safety reported 32 patients with VND during
2.26 million HD session, for a frequency of about one in
70,000 HD sessions (64).
The major factors leading to needle dislodgement are
related to access care (improper taping of access tubing to
the skin, loose luer lock tubing connection, bloodlines not
being looped loosely, or access site not being visible) and
patient factors (a confused patient pulling the needle out
of the access) (65). An acute decrease in dialysis venous
pressure should theoretically ensue rapidly after dislodge-
ment of the venous needle from the access and trigger a
pressure alarm to alert the dialysis nurse. However, the
venous alarm monitor on HD machines is affected by
not only the intra-access pressure but also, the dialysis
blood flow, blood viscosity, flow resistance of the extra-
corporeal tubing, and the height difference between the
access and venous drip chamber (66). In addition, the intra-
access pressure is higher for grafts than fistulas (by 27/15
mmHg) (67). Ideally, to ensure early detection of blood loss,
the venous pressure alarm would be set 10 mmHg below the
baseline dialysis venous pressure. However, the venous pres-
sure varies by 30–40 mmHg during a typical dialysis session
due to patient position (reclining versus sitting) and move-
ment of the access extremity (66,68). To prevent triggering
multiple false pressure alarms during each dialysis session,
the pressure monitor is usually set below that threshold.
As a consequence, the dialysis staff may have a false sense
of security when, in fact, a substantial blood leak may occur
before the venous pressure drops by 40 mmHg and triggers
the pressure alarm.
Various sensors can detect blood leaks during VND.
Some were initially developed to detect moisture related to
enuresis but later, used off label for detection of VND by
some dialysis units (65,66). Redsense, a device developed
for detection of blood leakage, has been Food and Drug
Administration cleared for in-center and home HD. It con-
sists of an alarm unit connected by an optical fiber to a
sensor patch; the sensor patch has an absorbent patch in
the center. The patch is placed over the venous needle,
with the absorbent area placed directly over the needle
entry point. In the event of VND or significant blood leak-
age, the blood comes in contact with the optical sensor that
is embedded within the patch and generates a continuous
alarm (69). Ahlmén et al. (70) reported that Redsense cor-
rectly alarmed in 92.5% of cases of blood leakage; when
the patch was modified and placed closer to the venous
puncture site, the device functioned in 97.2% of all tests
(70). Although blood sensors add substantially to the cost
of HD (Redsense costs about $550), they can be considered
for additional safety in high-risk patients and patients on
home HD. However, sensors should never replace an ap-
propriate stepwise protocol to prevent VND. This includes
proper taping of access needle, adequate tightening of
luer lock at all connections, and ensuring that all blood-
lines are loosely looped to prevent accidental dislodge-
ment. The access site should always be examined
whenever the venous pressure monitor suggests a drop
in pressure, even if the blood leakage detector does not
generate an alarm. The two most important measures are
maintaining the access site visible at all times and keep-
ing high-risk patients close to the nurse’s station (65). A
detailed 12-step protocol, including taping techniques,
assessment of risks for VND, and its prevention, is available
at https://www.annanurse.org/download/reference/
journal/vndArticle.pdf (65).
Allergic Reaction during HD
An allergic or allergic-like reaction during HD must be
closely investigated, because re-exposure to the allergen
may result in worse signs and symptoms and a poor
outcome. A 1982–1983 survey documented 3.3 allergic re-
actions per 1000 patient-years of dialysis with a hollow
fiber dialyzer (71). Daugirdas et al. (72) reported 21 severe
allergic reactions to dialyzers in 260,000 dialysis sessions
for a frequency of approximately one episode in 12,000 HD
sessions. These allergic reactions included four respiratory
arrests and one death. A patient may get an allergic reac-
tion to the dialyzer itself or more commonly, the sterilizer
(kills all micro-organisms, including bacterial spores),
disinfectant (kills micro-organisms on the surface but not
bacterial spores), heparin, or other medications infused
during dialysis (antibiotics, blood, or iron) (73,74).
Allergic reactions are classified as type A and type B
(75,76). Type A allergic reactions occur within 5–20 min-
utes of HD initiation and present with pruritus, urticaria,
bronchospasm, laryngeal edema, or anaphylactic shock.
Type B reactions occur later in the dialysis session and
are associated with less intense symptoms, such as chest
and back pain. Type A reactions are mediated through IgE,
whereas type B reactions are complement mediated (77).
Earlier dialyzers were composed of cellulose (a cotton
derivative). Owing to their organic component, they
activated the alternate complement cascade and were
considered bioincompatible (77,78). Subsequent modifica-
tions that added acetate side chains to the cellulose (cellu-
lose acetate, diacetate, and triacetate) reduced complement
activation, making the dialyzers more biocompatible. At
present, most United States dialysis centers use synthetic
dialyzers, which are considered highly biocompatible, be-
cause they only minimally activate complement (78). Syn-
thetic dialyzers are composed of polymethylmethacrylate,
polyether sulfone, polysulfone, or polyacrylonitrile (PAN)
(78). Dialyzers are sterilized with chemicals (ethylene ox-
ide), steam (heat), or radiation (g or b). Ethylene oxide has
fallen out of favor due to its propensity to attach to the
potting compound of the dialyzer and cause type A aller-
gic reactions (79–82).
Various mechanisms (Figure 3) have been proposed for
allergic and allergic-like reactions during HD depending
on the allergen (77,82–88). Ethylene oxide mediates ana-
phylaxis through IgE-mediated hypersensitivity, whereas
dialyzer components typically activate complement or
bradykinin. Tielemans et al. (89) reported five cases of anaphy-
lactoid reactions to acrylonitrile 69 (AN69) dialyzers occurring
within minutes of HD initiation in patients on an angiotensin–
converting enzyme inhibitor (ACEi). This reaction is
mediated by bradykinin rather than IgE, histamine, or
complement (89). The negatively charged moiety of
AN69 during contact phase with blood may activate Ha-
geman factor (factor 12), leading to bradykinin formation.
ACEi also inhibits kininase, an enzyme that inactivates
bradykinin, thereby further increasing plasma bradykinin
Clin J Am Soc Nephrol 12: 357–369, February, 2017 Hemodialysis Emergencies, Saha et al. 363

Figure 3. | Flow chart of possible causes of allergic or allergic-like reactions during hemodialysis. Similar symptoms could also be caused by
other etiologies, like endotoxin back filtration causing pyrogenic reaction, hemolysis, and rarely, air embolism. Heparin can cause anaphylaxis
or anaphylactoid associated with positive heparin–induced thrombocytopenia (HIT) antibodies. Blood products, antibiotics, and other
medications used with dialysis may also cause allergic reaction. Intravenous iron may cause a reaction due to IgE-mediated or complement
activation–related pseudoallergy (CARPA); at-risk patients have history of atopy, faster infusion, and possible iron dextran exposure than iron
sucrose. Ethylene oxide may bind to HSA and act as a hapten to induce an allergic reaction. Although an allergic reaction to synthetic bio-
compatible dialyzers is rare, it has been reported. A dialyzer with different housing compound or modified cellulose dialyzer may be con-
sidered if other causes are ruled out. Occasionally, measuring tryptase and IgE levels may be helpful; additional immunoassays and prick testing
may be undertaken after consultation with an allergist. ACEi, angiotensin–converting enzyme inhibitor; AN69, acrylonitrile; HSA, human
serum albumin; IV, intravenous; PAN, polyacrylonitrile.

levels and producing hypotension and angioedema in the
absence of urticaria (90,91). PAN membranes pretreated
with positively charged polyethyleneimine, are associated
with markedly reduced bradykinin activation (92). Patients
on ACEi can be safely dialyzed with AN69 dialyzers that
are surface treated with polyethyleneimine (93).
Disinfectants, such as hypochlorite (bleach) and formal-
dehyde, which are frequently used to reprocess dialyzers,
may also cause an allergic reaction if they are not ade-
quately rinsed out before the dialysis session (76).
Heparin may result in heparin-induced thrombocytope-
nia (HIT) (94). Five percent of patients with HIT develop
allergic-like reactions characterized by nausea, cough,
fever, and chills (83). Additional clinical features include
hypertension initially, transient global amnesia, and pro-
fuse diarrhea. HIT–associated allergic–like reaction is me-
diated by IgG rather than IgE. In 2007–2008, an epidemic
of anaphylaxis to heparin was caused by oversulfated chon-
droitin sulfate contaminants introduced during the
manufacturing process (83).
Several measures can minimize the risk or severity of an
allergic reaction during a dialysis session (Table 4). First,
the dialyzer should be primed with sufficient saline to
wash out the sterilant. Second, switching from ethylene oxide
sterilization to g-radiation or steam sterilization is helpful
(81,86). Third, if a suspected allergic reaction occurs, it is critical
to not return the blood into the extracorporeal circuit so as
to avoid aggravating the hypersensitivity reaction (86).
When a suspected allergic reaction occurs, one should
also rule out other complications that can mimic this con-
dition, such as air embolism, hemolysis, or a pyrogenic
reaction. Severe hypersensitivity reactions are treated
with antihistamines, corticosteroids, and epinephrine
(77,86).
364 Clinical Journal of the American Society of Nephrology

Table 4. Measures to minimize an allergic reaction to a dialyzer

(1) Prime the dialyzer well

(2) Switch from ethylene oxide sterilization to g- or steam-sterilized dialyzer
(3) In the event of a hypersensitivity reaction, do not return the blood, because this may aggravate the allergic reaction
(4) Treat with antihistamines, corticosteroids, and epinephrine for a hypersensitivity reaction
(5) Rule out other conditions that may simulate an allergic reaction (air embolism, hemolysis, pyrogenic reaction)

Adverse Reactions with Intravenous Iron
Intravenous iron, which is more efficacious than oral iron
in raising hemoglobin in the HD population, is adminis-
tered to approximately 70% of patients on HD each month
(95). Adverse drug events to intravenous iron were esti-
mated at 94 per million intravenous doses in 1998–2000
and decreased to 38 per million by 2001–2003 after a
switch to safer formulations (96,97). The rate of fatal ad-
verse drug events was highest for higher molecular weight
dextran (11.3 per million), intermediate for lower molecu-
lar weight dextran (3.3 per million), and lowest for sodium
ferric gluconate (0.9 per million) and iron sucrose (0.6 per
million). Wysowski et al. (98) reported that the mortality
rate between 2002 and 2006 was exceedingly low (0.06–0.32
deaths per million doses of iron purchased).
Minor adverse reactions can occur with any intravenous
iron preparation, but severe life–threatening reactions are
rare. Minor symptoms, such as pruritus, flushing, mild
chest discomfort, arthralgia, myalgia, and nausea, usually
abate with cessation of the infusion; it can be restarted at a
lower rate after symptoms resolve (73,87). If patients de-
velop urticaria, then infusion should be stopped, and the
patient should be observed. Restarting the infusion after
treatment with steroids may be considered after symptoms
resolve (99). A more severe reaction may present with se-
vere chest pain, persistent hypotension, and cough, and it
may warrant stopping the infusion and treating with ste-
roids and epinephrine. Premedication with steroids should
be considered in patients at high risk of developing a re-
action: history of inflammatory arthritis, multiple drug al-
lergies, or severe asthma (100,101). Diphenhydramine
should be avoided as a premedication, because it may
cause symptoms similar to minor reactions and be falsely
interpreted as an adverse effect (102,103). A life-threatening
reaction (stridor, wheezing, periorbital edema, or symptom-
atic hypotension) to intravenous iron infusion precludes fu-
ture iron infusion (99). Intravenous iron is contraindicated in
the first trimester of pregnancy and should be used with
caution during the second and third trimesters (87).
In case of more widespread loss of water, stepwise pro-
tocol should be followed, including saving water, alerting
higher authorities, and communication with the city water
body. Patients needing acute dialysis may be switched to
alternative RRT, like CRRT, or transferred to a different
medical facility (107).
Patients on in-center HD are exposed to close to 200 L
water during an average dialysis session. With the dialysis
membrane being the only barrier between the dialysate and
blood, it is critical that municipal water undergo rigorous
purification before its use during dialysis. Each dialysis
unit has its own water system for purification of municipal
water, protocol for sampling and monitoring, and man-
agement to adhere to the guidelines for water quality set by
the American National Standards Institute/Association for
the Advancement of Medical Instrumentation (104).
Pyrogenic reaction during a dialysis session may be due
to multiple causes, including infection from various sources;
water/dialysate bacterial contamination should be consid-
ered if there is cluster of similar events. Chloramine/
chlorine is added to city water for decontamination; this level
of protection is abolished downstream of carbon tanks in
dialysis water systems, and thus, the reverse osmosis sys-
tem, storage tank, and pipes are subjected to contamination
(105,108,109). Dialysis units follow strict protocols to deliver

Emergencies Related to Dialysis Water System

This is a very brief review of the HD emergencies that can
arise due to water system issues. Several excellent review
articles provide greater detail (104–106). Acute loss of wa-
ter in a dialysis unit is an emergency. It may be localized
due to breakage in water pipes in the dialysis unit only or
represent a hospital-wide problem. If it is localized to
dialysis units, immediate notification to concerned author-
ities, nursing supervisor, and medical director should
be made. If water from other areas of the hospital can be Figure 4. | An arteriovenous graft with evidence of thin shiny surface
used, then a portable reverse osmosis system can be used. (arrow) and superficial ulceration (arrow head) over a pseudoaneurysm.
Clin J Am Soc Nephrol 12: 357–369, February, 2017
purified water for dialysis, including running water sys-
tem, maintenance, disinfection process, and periodic
checks and evaluating with water cultures and endotoxin
assays. Nonadherence to the protocol may result in water
contamination.
Chloramine and chlorine are removed by primary and
secondary carbon tanks of the dialysis water system. Chlo-
ramine may cause hemolysis and methemoglobinemia in
patients on dialysis due to exhaustion of carbon tanks or
excess load of chloramine in city water exceeding the
capacity of carbon tanks (49,108–111). Thus, total chlorine,
which is the sum of free chlorine and bound chlorine (chlo-
ramine), is measured from both carbon tanks every 4
hours. The total chlorine level should be ,0.1 parts per
million (1 part per million 51 mg/L) (104,112).
Methemoglobinemia usually manifests as cyanosis with
chocolate brown color blood in the tubing and saturation
gap (113). In such cases, the oxygen saturation calculated
from arterial blood gas (PaO2$70 mmHg) is higher than
that measured by pulse oximetry (SaO2#90%) (114,115).
The diagnosis is confirmed by direct methemoglobin
measurement.
Hydrogen peroxide is commonly used for disinfection of
water storage tanks in hospitals. It is usually removed by
carbon filters but not by reverse osmosis. There have been
reports of hemolysis and methemoglobinemia from expo-
sure of patients’ blood to hydrogen peroxide. This may
happen if the potable water system does not have a carbon
filter or if the carbon tanks gets exhausted when larger
quantities of chlorine/chloramine and hydrogen peroxide
have to be processed (113,116,117).
Figure 5. | A basic scheme for root cause analysis (RCA) after an adverse event related to hemodialysis (HD).
Hemodialysis Emergencies, Saha et al. 365
An outbreak of fluoride toxicity leading to severe
pruritus, headache, and cardiac arrest has been reported
(118). It was found that an exhausted resin of deionizer
was releasing fluoride into the water. Fluoride (an anion)
binds to calcium and magnesium and lowers their serum
level. Additionally, it may cause hyperkalemia by its ac-
tion on the sodium-potassium ATPase pump and indi-
rectly cause efflux of potassium from cells (119).
To prevent such complications, appropriate protocol
should always be followed. A periodic communication with
the city water body and hospital maintenance may prevent
additional complications. A cluster of adverse symptoms or
events should prompt a thorough investigation.
Vascular Access Hemorrhage
Hemorrhage from an AV access is an uncommon but
potentially fatal complication if it is not recognized
promptly and acted on with an appropriate intervention.
Most fatal vascular access hemorrhages occur outside of the
dialysis facility, but occasionally, they rupture at the
dialysis unit (120). Patients and their families should be
educated about the recognition and emergent manage-
ment of a bleeding AV access. Pseudoaneurysm (PSA)
is a false aneurysm, because it does not have all of the
layers of a vein, but it is rather composed of hematoma
and fibrous tissue. It results from trauma and repeated
cannulation during HD. Aneurysms usually form at the
outflow vein/graft of an AV access and result from in-
creasing dilation due to high blood flow and vascular
damage (121,122). Physical examination of an aneurysm
366 Clinical Journal of the American Society of Nephrology
is the most important tool to determine the need for an
intervention (Figure 4). Any rapidly enlarging PSA, evi-
dence of outflow stenosis (arm elevation test—failure to
collapse, high-pitch bruit), thinning or ulceration of skin
over the PSA, pulsatility, or evidence of infection should
prompt urgent intervention (121,123). Proper cannulation
techniques may prevent PSA formation. Rope ladder tech-
nique prevents aneurysm formation, whereas repeated
cannulation of the same area may promote aneurysm
formation (123).
If the aneurysm is stable without evidence of imminent
rupture (ulceration, thinning or shiny skin, or infection),
then referral should be made for a fistulogram to evaluate
for potential underlying outflow stenosis. Angioplasty to
decrease the intra-access pressure may prevent aneurysm
formation or slow its growth.
In the event of bleeding from vascular access site, direct
continuous pressure with a finger for 15–20 minutes is
the most effective method of controlling the bleeding. In
the event of rupture of a PSA or aneurysm away from
dialysis unit or hospital, direct pressure with a finger at
the site of bleeding is the best method of controlling
bleeding. Patients should be advised to continue holding
direct pressure until emergency medical help arrives and
avoid applying a tourniquet, towel, or BP cuff to the
extremity (124).
RCA
Any adverse event, whether it has occurred, has the
potential to occur, or was averted by appropriate in-
tervention, requires a thorough investigation to identify
its root cause (125). All dialysis units must have proto-
cols for reporting such events and taking appropriate
measures toward RCA. The culture of safety in the
health care field comes from education, following proto-
cols, and a balance between staffing and work burden
(126,127). There is often one main root cause leading to
an adverse event and multiple other related factors; all of
these factors should be evaluated. There are various
guidelines regarding performing an RCA, including
one by the Centers for Medicare and Medicaid Services
(128).
During an adverse event, patient safety and management
of the adverse event are paramount. The nursing staff and
other care providers should work as a team to achieve that
goal rather than blaming each other or attempting to find a
cause. After the patient has been stabilized, additional
stepwise measures should be undertaken toward an RCA.
This may start with an incident report completed by
nursing staff. The nurses are encouraged to elaborate the
sequence of events, including those related to the patient,
surrounding environment, and the dialysis machine. The
dialysis log, including patient and machine vital measure-
ments, should be completed. The HD machine, dialyzer,
and tubing should be sequestered pending completion of
the investigation. In an isolated event, like hemolysis
during HD, a stepwise protocol toward that event may
be considered (Figure 2). In other cases, a broader view
may be more appropriate (Figure 5).
The appropriate authorities, including the dialysis su-
pervisor, legal system, and hospital authorities, should
be informed of the complication. An RCA should be
exhaustive and confidential. After a cause is found,
appropriate measures should be implemented to prevent
a similar occurrence. These measures may include a change
in policy or protocol, provider education, communication
among different staff members and hospital personnel,
multidisciplinary approach, and periodic mock drills and
skills testing.
Acknowledgments
This work was supported, in part, by National Institutes of Health
grant T32DK007545 (to M.S.).
Disclosures
None.
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