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CJASN ePress. Published on November 9, 2016 as doi: 10.2215/CJN.

In-Depth Review

Diagnosis, Treatment, and Prevention of Hemodialysis

Manish Saha and Michael Allon

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 : cccccc, 2016. doi: 10.2215/CJN.05260516 35294. Email:

Introduction but has been the subject of some recent comprehen-

There are currently approximately 400,000 patients sive papers (36).
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 Dialysis Disequilibrium Syndrome
62 million dialysis sessions annually. Given the high Dialysis disequilibrium syndrome (DDS) is a rare
comorbidity in patients on HD and the complexity of syndrome occurring in patients with severe azotemia
the dialysis treatment, it is remarkable how rarely a undergoing their initial HD session. It is characterized
life-threatening complication occurs during dialysis. by nausea, vomiting, headache, encephalopathy, and
For example, a cardiac arrest occurs only seven times seizures (7,8). DDS is attributed to the faster decline
per 100,000 HD sessions (2). The low rate of major of urea concentration in the blood than in the brain
complications can be attributed to numerous safety during the dialysis session. This lag (reverse urea ef-
features in modern dialysis machines; meticulous fect) creates an osmotic gradient that promotes net
treatment and testing of the dialysate solution to pre- water shift from the blood into the brain, leading to
vent exposure to trace elements, toxins, and patho- cerebral edema and its associated manifestations
gens; adherence to detailed treatment protocols; and (9,10). Rosen et al. (11) studied 10 patients with AKI
extensive training of dialysis staff to handle medical (baseline BUN concentrations of 210460 mg/dl) un-
emergencies. Most HD emergencies can be attributed dergoing their initial HD session. They obtained con-
to human error. A smaller number are due to rare current plasma and cerebrospinal uid (CSF) samples
idiosyncratic reactions. Ongoing dialysis staff train- before dialysis, immediately after dialysis, and 24
ing is essential to both prevent human error as well hours after dialysis. The CSF-to-plasma BUN ratio
as ensure prompt and effective interventions when was 0.91 predialysis, 1.99 immediately after dialysis,
complications happen. and back to baseline 24 hours later.
This review highlights major emergencies that may In animal models of uremia, the alteration in brain
occur during HD treatments (Table 1), measures to urea and other electrolytes concentrations does not
minimize them, and specic interventions to prevent completely account for the increase in brain osmolal-
catastrophic consequences on the rare occasions when ity during rapid HD (12). Arieff et al. (12) suggested
such complications arise. We have provided case re- that generation of new solutes (idiogenic osmoles)
ports to illustrate these emergencies in Supplemental in brain tissue accounted for brain edema during
Appendix. Complications related to more frequent rapid HD. In contrast, Silver et al. (13) reported that
HD are not addressed in this review. Intradialytic retained urea in brain was sufcient to cause a change
hypotension, a relatively common complication dur- in brain water content in rapidly dialyzing animals.
ing dialysis, is also beyond the scope of this review Moreover, the content of brain organic osmolytes Vol , 2016 Copyright 2016 by the American Society of Nephrology 1

2 Clinical Journal of the American Society of Nephrology

Table 1. Major dialysis emergencies

Estimated Frequency, per

Type of Emergency Refs.
Million HD Sessions

Dialysis disequilibrium
Air embolism 8.533 Tennankore et al. (31), Wong et al. (32)
Vascular access hemorrhage
Venous needle dislodgement 1491 Tennankore et al. (31), Wong et al. (32), VA study (65),
Pennsylvania patient safety study (64)
Allergic reaction 21170 Villarroel and Ciarkowski (71), Daugirdas et al. (72),
Simon et al. (129)
Cardiac arrest 70 Karnik et al. (2)
Errors in following the HD

HD, hemodialysis.

(myoinosotol, glutamine, and taurine, etc.) did not increase removal rate. In a dog model of uremia, Arieff et al. (12)
in rapidly dialyzing animals (9,13,14). Idiogenic osmoles compared rapid and slow HD that achieved a similar re-
may be generated in brain during acute azotemia as an duction in BUN. Rapid HD (100 minutes with a blood ow
adaptive response to increased plasma BUN to prevent of 12 ml/kg per minute and a dialysate ow rate of 500
brain cell shrinkage (15) but are probably not generated ml/min) produced an elevated CSF pressure and seizures.
during rapid HD (9). Finally, in a CKD animal model, In contrast, slower HD (200 minutes at 5 ml/kg per minute
there was a decrease in brain urea transporters and an blood ow rate and a dialysate ow rate of 500 ml/min)
increase in aquaporins (AQPs; AQP4 and AQP9), provid- elevated the CSF pressure without causing seizures (12).
ing a potential molecular mechanism for the reverse urea Thus, a short HD session (2 hours) with a low blood ow
effect (16). (200 ml/min) and a urea reduction ratio goal of 0.4 is rec-
The spectrum of DDS ranges from headache and rest- ommended as the initial prescription for patients at risk for
lessness in mild forms to nausea, vomiting, and hyperten- DDS (7,17). Continuous RRT (CRRT) may be considered in
sion in patients with moderate cases to seizures and coma patients at high risk for DDS, including those with intra-
in patients with severe cases (7,17,18). There is no set BUN cranial mass or brain injury (20). Kidney Disease Improv-
value above which patients predictably develop DDS. ing Global Outcomes recommends CRRT over intermittent
Both a high BUN level (.175 mg/dl) and its rapid decline dialysis for AKI in patients with brain injury/edema or
are risk factors for DDS (7,18,19). Additional risk factors elevated intracranial pressure (21).
include preexisting neurologic conditions, the rst session Port et al. (22) reported that a higher dialysate sodium
of HD, hyponatremia, and liver disease (7,18,20). It is un- concentration (144154 mmol/L) prevented DDS symp-
known whether the risk of DDS is similar in patients with toms. Each 1-mmol/L increase in serum sodium offset
advanced CKD and those with AKI. Computed tomogra- the osmotic effect of 12 mg/dl BUN. Thus, sodium mod-
phy or magnetic resonance may show cerebral edema in eling may be useful in preventing DDS during the initial
patients with DDS. HD sessions in patients at risk (22). Adding glucose or
Several strategies may prevent DDS in patients with very glycerol to the dialysate may also prevent DDS (23).
high serum BUN undergoing their rst HD session (Table 2) Rodrigo et al. (24) studied patients on HD at risk for DDS
(7,12,17). The most important measure is to slow the urea by adding glucose to the dialysate or administering intrave-
nous mannitol. Increasing the dialysate glucose concen-
tration to 450 mg/dl contributed 23 mosM/kg H2O,
whereas intravenous mannitol (1 g/kg) added 8.510
Table 2. Potential strategies to prevent dialysis disequilibrium mosM/kg H2O (24).
syndrome in high-risk patients

(1) Limit the rst HD session to 22.5 h Air Embolism

(2) Limit the blood ow to 200250 ml/min Venous air embolism (VAE) during HD is thought to be
(3) Sodium modeling or a high-sodium dialysate rare, but because signs and symptoms of air embolism may
(4) Consider intravenous mannitol (1 g/kg) mimic other more common complications, careful vigilance
(5) Consider CRRT in patients at high risk for DDS and high suspicion are required for the diagnosis. Air
(traumatic brain injury, intracerebral hemorrhage,
bubbles trapped in the systemic (pulmonary or cerebral)
intracranial mass)
microcirculation may cause local ischemia, circulatory
arrest, activation of complement and coagulation sys-
HD, hemodialysis; CRRT, continuous RRT; DDS, dialysis dis-
equilibrium syndrome. tem, localized inammation, and vascular endothelial cell
damage (2527).
Clin J Am Soc Nephrol : cccccc, , 2016 Hemodialysis Emergencies, Saha et al. 3

Owing to safeguards in the modern HD machine, symp- follow-up of 190 patients on home HD (approximately
tomatic air embolism is exceedingly rare during HD. Air 117,000 HD sessions) for an incidence of less than one
may enter the extracorporeal HD circuit either as a re- episode per 100,000 HD sessions. This case resulted from
sult of residual air trapped in the tubing or dialyzer due not clamping the arterial line during disconnection, thereby
to incomplete priming or because of a broken or loose luer allowing air to enter the tubing (32).
connection prepump (where the arterial pressure is Most microbubbles ,50 mm in diameter and many mi-
negative) (25,2830) (Figure 1). Air entering the extracor- crobubbles between 50 and 200 mm pass through the ve-
poreal circuit presents to the venous air trap placed distal nous bubble catcher without triggering an alarm (33). The
to the dialyzer, immediately decreasing the blood level in rate of microbubble formation is dependent on the blood
the chamber. The change in uid level in this chamber is ow rate and negative arterial pressure. The total volume
recognized by a sensor that triggers an alarm and stops the of microbubbles during an HD session is a few milliliters, a
blood pump. As a consequence of these technologic safe- volume insufcient to cause acute symptoms (34). The ve-
guards, air embolism in the modern era results from hu- nous air trap and air detector prevent infusion of larger
man error. In a retrospective cohort study of 202 patients amounts of air. If the air detector triggered an alarm for
on home HD, only six patients had suspected air embolism every microbubble, HD would be regularly interrupted
that occurred during 183,603 dialysis sessions for an over- (28). Therefore, a safe limit of air infusion (0.1 ml/kg
all incidence less than one episode per 30,000 dialysis ses- body wt for bolus infusion and 0.03 ml/kg per minute
sions. These episodes were related to inadequate priming for continuous infusion) has been suggested (25,28).
or lack of clamping of the catheter or tubing (31). Another Measures to minimize the risk of air embolism include
study reported a single case of air embolism during avoidance of extremely high dialysis blood ow, 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.
4 Clinical Journal of the American Society of Nephrology

the arterial luer lock tightened, adequately priming the dialysate contaminants, or hyperthermia may each enhance
dialyzer and tubing system before initiation of an HD hemolysis (Table 3) (4952). Because blood ow is higher
session, and maintenance of a high blood level in the at the center of a laminar ow than at the edges (wall) of
venous air catcher (29,35). the extracorporeal circuit, the RBC membrane is exposed
Massive VAE manifests with chest pain, dyspnea, and to a differential force on two different sides, thereby
syncope. Cerebral air embolism may cause blurry vision, causing a shear stress (51). The low degree of hemolysis
altered mental status, seizures, or ischemic stroke. Patients that typically occurs during HD is insufcient to produce a
may develop hypotension and tachycardia due to right measurable drop in hematocrit. More signicant hemolysis
ventricular overload with involvement of the pulmonary may occur in cases of dialysate contamination with trace
capillary bed (26,27,36). The degree of end organ damage metals (copper or zinc), disinfectant added to city water
depends on the rate of air entry, volume of air, the pa- (chloramine), or nitrate (49,53). The normal starting dialy-
tients position, and underlying cardiac status. In dogs, sis blood ow with a new arteriovenous (AV) stula is 250
rapid injection of 7.5 ml/kg air is lethal. In humans, a vol- ml/min with a 17-gauge needle. In comparison, a dialysis
ume of 100300 ml air is considered fatal (37,38). A high blood ow of 500 ml/min can be delivered using a
clinical suspicion is required to diagnose VAE. Precordial 14-gauge needle without inducing hemolysis (54). The
Doppler can detect 0.05 ml/kg air, whereas transesopha- positive and negative pressures (approximately 1500 and
geal echocardiogram can detect 0.02 ml/kg air (39). Com- 2500 mmHg, respectively) sustained by RBCs in the ex-
puted tomography may detect air in suspected cases of tracorporeal circuit usually do not cause any hemolysis
cerebral embolism. (51). However, attempting a high dialysis blood ow
After VAE is suspected, the patient should be provided with a small gauge needle may induce hemolysis.
with 100% oxygen (27). Aspiration of air may be attempted Overheated dialysate may cause thermal injury and
if the catheter is still in place (26). Early studies suggested hemolysis. A 1948 study by Ham et al. (55) showed changes
that the left lateral recumbent (LLR) position could pre- in RBC morphology, osmotic fragility, and hemolysis at
vent right ventricular failure by preventing outow tract temperatures .47C. In 1975, Berkes et al. (56) reported
obstruction during air embolism by moving the air more on a patient with delayed hemolysis 48 hours after expo-
superiorly in the right ventricle (4042). Geissler et al. (43) sure to overheated dialysate of 50C. Because modern
and Mehlhorn et al. (44) studied the effect of injecting HD machines trigger an alarm at dialysate temperature
2.5 ml/kg air at a rate of 5 ml/s in dogs and concluded .39.5C, hyperthermic hemolysis is rare (55,57). If the
that the LLR position did not provide hemodynamic HD machine triggers an alarm for overheated dialysate,
advantage over the supine position. Although traditional an appropriate stepwise protocol should be followed: re-
teaching has been to maintain an LLR with head down sponding to the alarm, immediate cessation of dialysis,
position for suspected VAE, the supine position has been and informing concerned authorities and supervisor to
recommended more recently (26). The supine position also nd the source of heated water (57). Jepson and Alonso
provides additional advantage of appropriate delivery of (57) reported an issue with a valve system that led to
oxygen and hemodynamic support, a critical part of the heated dialysate of 39.8C; no harm was caused to the pa-
treatment (26). An LLR position has been recommended by tient due to the attentiveness of the nurse who followed an
Muth and Shank (26) if aspiration of air is to be attempted appropriate protocol (57).
through an existing central venous catheter (CVC) for Hemolysis due to osmotic changes and dialysate impu-
VAE (26,43). rities is also rare. Several investigators have reported
Air embolism may also occur during placement of an mechanical injury to RBCs caused by kinked dialysis
HD CVC, accidental disconnection during its use, or at its tubing (52,58). Sudden bends, turns, and the entry point
removal. Vesely (45) reported 15 cases of air embolism into the dialyzer are additional vulnerable areas for kink-
occurring during placement of 11,583 tunneled and non- ing. A simultaneous decrease of .25 mmHg in both the
tunneled CVCs (0.13%). All 15 cases occurred during in- arterial (prepump) and venous (postpump) pressures
sertion of tunneled CVCs; most patients had mild to suggests a severe postpump kinked tubing that may result
moderate symptoms, except one who died. Rinsing the in hemolysis; this drop in pressure results from decrease
catheter, placing the patient in a supine position, and blood ow due to severe obstruction. Therefore, it essen-
inserting the needle during expiration may prevent air tial to use the length of tubing recommended by the man-
embolism during CVC placement (46). A break in the cath- ufacturer, monitor the arterial and venous dialysis
eter or accidental disconnection may also lead to fatal air pressures, and avoid sudden bends in the tubing (59). A
embolism (47). During CVC removal, the patient should be multistate outbreak of hemolysis during HD led to the
supine, with catheter removal performed during exhala- nding of faulty blood tubing causing hemolysis. Narrow-
tion or a Valsalva maneuver to increase intrathoracic pres- ing of the blood tubing before its entry to the dialyzer led
sure (46). An air-occlusive dressing should be in place for to exposure of RBCs to increased pressure and consequent
24 hours to prevent delayed air entry through the subcu- hemolysis (60).
taneous track (48). Patients with severe intradialytic hemolysis complain of
nausea, shortness of breath, abdominal/back pain, and
chills and initially develop acute hypertension (61). Con-
Hemolysis rmatory laboratory data include low serum haptoglobin,
Red blood cells (RBCs) undergo shear stress when they elevated lactate dehydrogenase, reduction in hematocrit,
circulate through the HD circuit, and are, therefore, at risk and pink serum. When hemolysis is suspected, the HD
for fragmentation. Additionally, blood osmotic changes, session should be stopped immediately. Blood should
Clin J Am Soc Nephrol : cccccc, , 2016 Hemodialysis Emergencies, Saha et al. 5

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-
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
Singleneedle highow 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 ow of 300500 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.
6 Clinical Journal of the American Society of Nephrology

and one in 20,000 HD sessions (32). Data from Pennsylva- detailed 12-step protocol, including taping techniques,
nia public safety reported 32 patients with VND during assessment of risks for VND, and its prevention, is available
2.26 million HD session, for a frequency of about one in at
70,000 HD sessions (64). journal/vndArticle.pdf (65).
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 Allergic Reaction during HD
being looped loosely, or access site not being visible) and An allergic or allergic-like reaction during HD must be
patient factors (a confused patient pulling the needle out closely investigated, because re-exposure to the allergen
of the access) (65). An acute decrease in dialysis venous may result in worse signs and symptoms and a poor
pressure should theoretically ensue rapidly after dislodge- outcome. A 19821983 survey documented 3.3 allergic re-
ment of the venous needle from the access and trigger a actions per 1000 patient-years of dialysis with a hollow
pressure alarm to alert the dialysis nurse. However, the ber dialyzer (71). Daugirdas et al. (72) reported 21 severe
venous alarm monitor on HD machines is affected by allergic reactions to dialyzers in 260,000 dialysis sessions
not only the intra-access pressure but also, the dialysis for a frequency of approximately one episode in 12,000 HD
blood ow, blood viscosity, ow resistance of the extra- sessions. These allergic reactions included four respiratory
corporeal tubing, and the height difference between the arrests and one death. A patient may get an allergic reac-
access and venous drip chamber (66). In addition, the intra- tion to the dialyzer itself or more commonly, the sterilizer
access pressure is higher for grafts than stulas (by 27/15 (kills all micro-organisms, including bacterial spores),
mmHg) (67). Ideally, to ensure early detection of blood loss, disinfectant (kills micro-organisms on the surface but not
the venous pressure alarm would be set 10 mmHg below the bacterial spores), heparin, or other medications infused
baseline dialysis venous pressure. However, the venous pres- during dialysis (antibiotics, blood, or iron) (73,74).
sure varies by 3040 mmHg during a typical dialysis session Allergic reactions are classied as type A and type B
due to patient position (reclining versus sitting) and move- (75,76). Type A allergic reactions occur within 520 min-
ment of the access extremity (66,68). To prevent triggering utes of HD initiation and present with pruritus, urticaria,
multiple false pressure alarms during each dialysis session, bronchospasm, laryngeal edema, or anaphylactic shock.
the pressure monitor is usually set below that threshold. Type B reactions occur later in the dialysis session and
As a consequence, the dialysis staff may have a false sense are associated with less intense symptoms, such as chest
of security when, in fact, a substantial blood leak may occur and back pain. Type A reactions are mediated through IgE,
before the venous pressure drops by 40 mmHg and triggers whereas type B reactions are complement mediated (77).
the pressure alarm. Earlier dialyzers were composed of cellulose (a cotton
Various sensors can detect blood leaks during VND. derivative). Owing to their organic component, they
Some were initially developed to detect moisture related to activated the alternate complement cascade and were
enuresis but later, used off label for detection of VND by considered bioincompatible (77,78). Subsequent modica-
some dialysis units (65,66). Redsense, a device developed tions that added acetate side chains to the cellulose (cellu-
for detection of blood leakage, has been Food and Drug lose acetate, diacetate, and triacetate) reduced complement
Administration cleared for in-center and home HD. It con- activation, making the dialyzers more biocompatible. At
sists of an alarm unit connected by an optical ber to a present, most United States dialysis centers use synthetic
sensor patch; the sensor patch has an absorbent patch in dialyzers, which are considered highly biocompatible, be-
the center. The patch is placed over the venous needle, cause they only minimally activate complement (78). Syn-
with the absorbent area placed directly over the needle thetic dialyzers are composed of polymethylmethacrylate,
entry point. In the event of VND or signicant blood leak- polyether sulfone, polysulfone, or polyacrylonitrile (PAN)
age, the blood comes in contact with the optical sensor that (78). Dialyzers are sterilized with chemicals (ethylene ox-
is embedded within the patch and generates a continuous ide), steam (heat), or radiation (g or b). Ethylene oxide has
alarm (69). Ahlmn et al. (70) reported that Redsense cor- fallen out of favor due to its propensity to attach to the
rectly alarmed in 92.5% of cases of blood leakage; when potting compound of the dialyzer and cause type A aller-
the patch was modied and placed closer to the venous gic reactions (7982).
puncture site, the device functioned in 97.2% of all tests Various mechanisms (Figure 3) have been proposed for
(70). Although blood sensors add substantially to the cost allergic and allergic-like reactions during HD depending
of HD (Redsense costs about $550), they can be considered on the allergen (77,8288). Ethylene oxide mediates ana-
for additional safety in high-risk patients and patients on phylaxis through IgE-mediated hypersensitivity, whereas
home HD. However, sensors should never replace an ap- dialyzer components typically activate complement or
propriate stepwise protocol to prevent VND. This includes bradykinin. Tielemans et al. (89) reported ve cases of anaphy-
proper taping of access needle, adequate tightening of lactoid reactions to acrylonitrile 69 (AN69) dialyzers occurring
luer lock at all connections, and ensuring that all blood- within minutes of HD initiation in patients on an angiotensin
lines are loosely looped to prevent accidental dislodge- converting enzyme inhibitor (ACEi). This reaction is
ment. The access site should always be examined mediated by bradykinin rather than IgE, histamine, or
whenever the venous pressure monitor suggests a drop complement (89). The negatively charged moiety of
in pressure, even if the blood leakage detector does not AN69 during contact phase with blood may activate Ha-
generate an alarm. The two most important measures are geman factor (factor 12), leading to bradykinin formation.
maintaining the access site visible at all times and keep- ACEi also inhibits kininase, an enzyme that inactivates
ing high-risk patients close to the nurses station (65). A bradykinin, thereby further increasing plasma bradykinin
Clin J Am Soc Nephrol : cccccc, , 2016 Hemodialysis Emergencies, Saha et al. 7

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 heparininduced 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
activationrelated 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, angiotensinconverting enzyme inhibitor; AN69, acrylonitrile; HSA, human
serum albumin; IV, intravenous; PAN, polyacrylonitrile.

levels and producing hypotension and angioedema in the of anaphylaxis to heparin was caused by oversulfated chon-
absence of urticaria (90,91). PAN membranes pretreated droitin sulfate contaminants introduced during the
with positively charged polyethyleneimine, are associated manufacturing process (83).
with markedly reduced bradykinin activation (92). Patients Several measures can minimize the risk or severity of an
on ACEi can be safely dialyzed with AN69 dialyzers that allergic reaction during a dialysis session (Table 4). First,
are surface treated with polyethyleneimine (93). the dialyzer should be primed with sufcient saline to
Disinfectants, such as hypochlorite (bleach) and formal- wash out the sterilant. Second, switching from ethylene oxide
dehyde, which are frequently used to reprocess dialyzers, sterilization to g-radiation or steam sterilization is helpful
may also cause an allergic reaction if they are not ade- (81,86). Third, if a suspected allergic reaction occurs, it is critical
quately rinsed out before the dialysis session (76). to not return the blood into the extracorporeal circuit so as
Heparin may result in heparin-induced thrombocytope- to avoid aggravating the hypersensitivity reaction (86).
nia (HIT) (94). Five percent of patients with HIT develop When a suspected allergic reaction occurs, one should
allergic-like reactions characterized by nausea, cough, also rule out other complications that can mimic this con-
fever, and chills (83). Additional clinical features include dition, such as air embolism, hemolysis, or a pyrogenic
hypertension initially, transient global amnesia, and pro- reaction. Severe hypersensitivity reactions are treated
fuse diarrhea. HITassociated allergiclike reaction is me- with antihistamines, corticosteroids, and epinephrine
diated by IgG rather than IgE. In 20072008, an epidemic (77,86).
8 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 In case of more widespread loss of water, stepwise pro-
Intravenous iron, which is more efcacious than oral iron tocol should be followed, including saving water, alerting
in raising hemoglobin in the HD population, is adminis- higher authorities, and communication with the city water
tered to approximately 70% of patients on HD each month body. Patients needing acute dialysis may be switched to
(95). Adverse drug events to intravenous iron were esti- alternative RRT, like CRRT, or transferred to a different
mated at 94 per million intravenous doses in 19982000 medical facility (107).
and decreased to 38 per million by 20012003 after a Patients on in-center HD are exposed to close to 200 L
switch to safer formulations (96,97). The rate of fatal ad- water during an average dialysis session. With the dialysis
verse drug events was highest for higher molecular weight membrane being the only barrier between the dialysate and
dextran (11.3 per million), intermediate for lower molecu- blood, it is critical that municipal water undergo rigorous
lar weight dextran (3.3 per million), and lowest for sodium purication before its use during dialysis. Each dialysis
ferric gluconate (0.9 per million) and iron sucrose (0.6 per unit has its own water system for purication of municipal
million). Wysowski et al. (98) reported that the mortality water, protocol for sampling and monitoring, and man-
rate between 2002 and 2006 was exceedingly low (0.060.32 agement to adhere to the guidelines for water quality set by
deaths per million doses of iron purchased). the American National Standards Institute/Association for
Minor adverse reactions can occur with any intravenous the Advancement of Medical Instrumentation (104).
iron preparation, but severe lifethreatening reactions are Pyrogenic reaction during a dialysis session may be due
rare. Minor symptoms, such as pruritus, ushing, mild to multiple causes, including infection from various sources;
chest discomfort, arthralgia, myalgia, and nausea, usually water/dialysate bacterial contamination should be consid-
abate with cessation of the infusion; it can be restarted at a ered if there is cluster of similar events. Chloramine/
lower rate after symptoms resolve (73,87). If patients de- chlorine is added to city water for decontamination; this level
velop urticaria, then infusion should be stopped, and the of protection is abolished downstream of carbon tanks in
patient should be observed. Restarting the infusion after dialysis water systems, and thus, the reverse osmosis sys-
treatment with steroids may be considered after symptoms tem, storage tank, and pipes are subjected to contamination
resolve (99). A more severe reaction may present with se- (105,108,109). Dialysis units follow strict protocols to deliver
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 inammatory 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 rst trimester of pregnancy and should be used with
caution during the second and third trimesters (87).

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 (104106). 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 notication 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 : cccccc, , 2016 Hemodialysis Emergencies, Saha et al. 9

puried water for dialysis, including running water sys- An outbreak of uoride toxicity leading to severe
tem, maintenance, disinfection process, and periodic pruritus, headache, and cardiac arrest has been reported
checks and evaluating with water cultures and endotoxin (118). It was found that an exhausted resin of deionizer
assays. Nonadherence to the protocol may result in water was releasing uoride into the water. Fluoride (an anion)
contamination. binds to calcium and magnesium and lowers their serum
Chloramine and chlorine are removed by primary and level. Additionally, it may cause hyperkalemia by its ac-
secondary carbon tanks of the dialysis water system. Chlo- tion on the sodium-potassium ATPase pump and indi-
ramine may cause hemolysis and methemoglobinemia in rectly cause efux of potassium from cells (119).
patients on dialysis due to exhaustion of carbon tanks or To prevent such complications, appropriate protocol
excess load of chloramine in city water exceeding the should always be followed. A periodic communication with
capacity of carbon tanks (49,108111). Thus, total chlorine, the city water body and hospital maintenance may prevent
which is the sum of free chlorine and bound chlorine (chlo- additional complications. A cluster of adverse symptoms or
ramine), is measured from both carbon tanks every 4 events should prompt a thorough investigation.
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 Vascular Access Hemorrhage
chocolate brown color blood in the tubing and saturation Hemorrhage from an AV access is an uncommon but
gap (113). In such cases, the oxygen saturation calculated potentially fatal complication if it is not recognized
from arterial blood gas (PaO2$70 mmHg) is higher than promptly and acted on with an appropriate intervention.
that measured by pulse oximetry (SaO2#90%) (114,115). Most fatal vascular access hemorrhages occur outside of the
The diagnosis is conrmed by direct methemoglobin dialysis facility, but occasionally, they rupture at the
measurement. dialysis unit (120). Patients and their families should be
Hydrogen peroxide is commonly used for disinfection of educated about the recognition and emergent manage-
water storage tanks in hospitals. It is usually removed by ment of a bleeding AV access. Pseudoaneurysm (PSA)
carbon lters but not by reverse osmosis. There have been is a false aneurysm, because it does not have all of the
reports of hemolysis and methemoglobinemia from expo- layers of a vein, but it is rather composed of hematoma
sure of patients blood to hydrogen peroxide. This may and brous tissue. It results from trauma and repeated
happen if the potable water system does not have a carbon cannulation during HD. Aneurysms usually form at the
lter or if the carbon tanks gets exhausted when larger outow vein/graft of an AV access and result from in-
quantities of chlorine/chloramine and hydrogen peroxide creasing dilation due to high blood ow and vascular
have to be processed (113,116,117). damage (121,122). Physical examination of an aneurysm

Figure 5. | A basic scheme for root cause analysis (RCA) after an adverse event related to hemodialysis (HD).
10 Clinical Journal of the American Society of Nephrology

is the most important tool to determine the need for an be informed of the complication. An RCA should be
intervention (Figure 4). Any rapidly enlarging PSA, evi- exhaustive and condential. After a cause is found,
dence of outow stenosis (arm elevation testfailure to appropriate measures should be implemented to prevent
collapse, high-pitch bruit), thinning or ulceration of skin a similar occurrence. These measures may include a change
over the PSA, pulsatility, or evidence of infection should in policy or protocol, provider education, communication
prompt urgent intervention (121,123). Proper cannulation among different staff members and hospital personnel,
techniques may prevent PSA formation. Rope ladder tech- multidisciplinary approach, and periodic mock drills and
nique prevents aneurysm formation, whereas repeated skills testing.
cannulation of the same area may promote aneurysm
formation (123). Acknowledgments
If the aneurysm is stable without evidence of imminent This work was supported, in part, by National Institutes of Health
rupture (ulceration, thinning or shiny skin, or infection), grant T32DK007545 (to M.S.).
then referral should be made for a stulogram to evaluate
for potential underlying outow stenosis. Angioplasty to Disclosures
decrease the intra-access pressure may prevent aneurysm None.
formation or slow its growth.
In the event of bleeding from vascular access site, direct
continuous pressure with a nger for 1520 minutes is
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